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EUDRACT number: 1 DRINK Clinical Trial Protocol Trial Title: Determining feasibility of Randomisation to high vs. ad libitum water Intake in Polycystic Kidney Disease: THE DRINK RANDOMISED FEASIBILTY TRIAL Protocol Number: CCTU0192 ISRCTN Number: This could be replaced with the clinicaltrials.gov number or removed if not relevant Protocol Version: 1.1 May 2016 Chief Investigator: Dr Thomas Hiemstra CI Address: Cambridge Clinical Trials Unit Box 401 Addenbrookes Hospital Hills Road Cambridge CB2 0QQ Telephone: 01223 336817 Trial Sponsor: Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge SAE Reporting: Dr Ragada El-Damanawi [email protected] Tel: 01223254666 Fax: 01223256763 DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 2 PROTOCOL SIGNATURES: I give my approval for the attached protocol entitled “Determining feasibility of Randomisation to high vs. ad libitum water Intake in Polycystic Kidney Disease: THE DRINK PILOT STUDY” dated April 2016. Chief Investigator Name: Thomas Hiemstra Signature: ________________________________________ Date: ____________________________ DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 3 TRIAL MANAGEMENT COMMITTEE & PROTOCOL CONTRIBUTORS Dr Thomas F Hiemstra Prof. Ian B. Wilkinson Prof. Fiona Karet Dr Richard Sanford Dr Ragada El-Damanawi Cambridge Clinical Trials Unit and School of Clinical Medicine, University of Cambridge Clinical Pharmacology Unit, University of Cambridge Cambridge Institute for Medical Research, University of Cambridge Academic Department of Medical Genetics, University of Cambridge Cambridge Clinical Trials Unit, University of Cambridge Dr Michael Lee University of Cambridge Dr Sabine Kläger Cambridge Clinical Trials Unit Dr Simon Bond Cambridge Clinical Trials Unit Tess Harris CEO Polycystic Kidney Disease Charity Nicola Fernandez Research Dietician DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 4 Trial Statistician: Dr Simon Bond Cambridge Clinical Trials Unit (Box 111) Addenbrookes Hospital, Hills Road Cambridge, CB2 0QQ Telephone: 01223 596475 Fax: 01223 596471 e-mail: [email protected] Trial Coordination: Ragada El-Damanawi Cambridge Trials Unit (Box 401) Addenbrookes Hospital, Hills Road Cambridge, CB2 0QQ Tel: 01223 254666 Fax: 01223 256763 Email: [email protected] Sponsor: Cambridge University Hospitals NHS Foundation Trust and University of Cambridge Research & Development Department (Box 277) Addenbrookes Hospital, Hills Road Cambridge, CB2 0QQ Telephone: 01223 245151 e-mail: r&[email protected] Amendment History Version No. History V Final Protocol DRINK trial Date Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 5 Table of Contents PROTOCOL SIGNATURES: .........................................................................................................................2 GLOSSARY OF ABBREVIATIONS..............................................................................................................7 TRIAL FLOW CHART ...................................................................................................................................9 TRIAL SYNOPSIS........................................................................................................................................ 10 BACKGROUND............................................................................................................................................ 15 Burden of disease in ADPKD ............................................................................................................................ 15 Mechanism of renal cyst development and renal failure ................................................................................ 15 The role of vasopressin in renal cyst development ......................................................................................... 16 Current and potential treatment options ........................................................................................................ 17 Trials of water intake in ADPKD ....................................................................................................................... 19 Safety and Tolerability of prescribed water intake.......................................................................................... 20 Rationale for the DRINK trial............................................................................................................................ 21 TRIAL DESIGN ............................................................................................................................................ 22 Statement of design ......................................................................................................................................... 22 Number of Centers .......................................................................................................................................... 22 Number of Participants .................................................................................................................................... 22 Participants Trial duration ............................................................................................................................... 22 Trial objectives ................................................................................................................................................. 22 Trial Outcome Measures.................................................................................................................................. 22 Primary outcome measure .......................................................................................................................... 22 Secondary outcome measure ...................................................................................................................... 22 SELECTION AND WITHDRAWAL OF PARTICIPANTS .................................................................... 23 Inclusion Criteria .............................................................................................................................................. 23 Exclusion Criteria ............................................................................................................................................. 23 Treatment Assignment and Randomisation Number ...................................................................................... 23 Blinding ............................................................................................................................................................ 23 Subject withdrawal criteria .............................................................................................................................. 23 TRIAL TREATMENT ................................................................................................................................. 24 Trial Interventions ............................................................................................................................................ 24 Intervention Group .......................................................................................................................................... 24 Fluid Prescription ......................................................................................................................................... 24 Dietician input – role of solutes ................................................................................................................... 25 Measured Glomerular filtration rate ........................................................................................................... 25 Participant self-monitoring and self-reporting ............................................................................................ 25 Participant questionnaire ............................................................................................................................ 25 Control Group .................................................................................................................................................. 25 PROCEDURES AND ASSESSMENTS ...................................................................................................... 26 Pre-Screening ................................................................................................................................................... 26 Screening evaluation........................................................................................................................................ 26 Run-in for Patients Receiving Diuretic Treatment ........................................................................................... 26 Informed Consent ............................................................................................................................................ 26 Subject Registration and Randomisation......................................................................................................... 27 Trial assessments ............................................................................................................................................. 27 Methods and Materials.................................................................................................................................... 28 Schedule of Assessments ....................................................................................................................... 33 DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 6 Trial restrictions ............................................................................................................................................... 34 ASSESSMENT OF SAFETY ....................................................................................................................... 35 Safety Monitoring throughout DRINK.............................................................................................................. 35 Definitions ........................................................................................................................................................ 35 Adverse event (AE) ....................................................................................................................................... 35 Adverse reaction to an investigational medicinal product (AR) .................................................................. 35 Unexpected adverse reaction ...................................................................................................................... 35 Serious adverse event or serious adverse reaction (SAE / SAR) ................................................................... 36 Expected Adverse Events/Serious Adverse Events (AE/SAE) ........................................................................ 36 Evaluation of adverse events ........................................................................................................................... 36 Assessment of causality ............................................................................................................................... 36 Clinical assessment of severity .................................................................................................................... 37 Recording of adverse events............................................................................................................................ 37 Reporting serious adverse events .................................................................................................................... 38 POTENTIAL ADVERSE EFFECTS ........................................................................................................... 38 EVALUATION OF RESULTS..................................................................................................................... 40 Response criteria ............................................................................................................................................. 40 STORAGE AND ANALYSIS OF SAMPLES ............................................................................................. 40 STATISTICS ................................................................................................................................................. 40 Statistical methods .......................................................................................................................................... 40 Interim analyses ............................................................................................................................................... 41 Number of Participants to be enrolled ............................................................................................................ 41 Criteria for the premature termination of the trial ......................................................................................... 41 Procedure to account for missing or spurious data......................................................................................... 41 Definition of the end of the trial ...................................................................................................................... 41 DATA HANDLING AND RECORDING ................................................................................................... 42 Case Report Form ............................................................................................................................................ 42 Source Data ...................................................................................................................................................... 42 Data Protection & Patient Confidentiality ....................................................................................................... 42 TRIAL STEERING COMMITTEE ............................................................................................................. 43 ETHICAL AND REGULATORY CONSIDERATIONS ........................................................................... 43 Consent ............................................................................................................................................................ 43 Ethical committee review ................................................................................................................................ 43 Regulatory Compliance .................................................................................................................................... 43 Protocol Amendments ..................................................................................................................................... 43 Peer Review ..................................................................................................................................................... 44 Declaration of Helsinki and Good Clinical Practice .......................................................................................... 44 GCP Training ..................................................................................................................................................... 44 SPONSORSHIP, FINANCIAL AND INSURANCE .................................................................................. 44 MONITORING, AUDIT & INSPECTION ................................................................................................ 44 PROTOCOL COMPLIANCE AND BREACHES OF GCP ....................................................................... 45 PUBLICATIONS POLICY........................................................................................................................... 45 REFERENCES............................................................................................................................................... 46 APPENDICES ............................................................................................................................................... 48 DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 7 GLOSSARY OF ABBREVIATIONS ADPKD Autosomal Dominant Polycystic Kidney Disease ACEI Angiotensin Converting Enzyme Inhibitor ARB Angiotensin Receptor Blocker AE Adverse event AR Adverse reaction ADH Anti-diuretic hormone AQ2 Aquaporin 2 AVP Arginine vasopressin BP Blood pressure cAMP Cyclic adenosine monophosphate CFTR Cystic fibrosis transmembrane conductance regulator channel CI Chief Investigator CKD Chronic kidney disease CrCl Creatinine clearance CRF Case Report Form CRISP Consortium of Radiologic Imaging in Polycystic kidney disease eGFR Estimated glomerular filtration rate GFR Glomerular filtration rate HMA CoA 3-Hydroxy-3-methyl-glutaryl CoA HRQoL Health Related Quality of Life htTKV Height adjusted total kidney volume DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: IQR KDIGO 8 Inter-quartile range Kidney Disease Improving Global Outcomes MAP Mitogen activated protein MRI Magnetic resonance imaging MQS Medication Quantification Scale NICE National Institute of health and Clinical Excellence PI Principal Investigator PKA Protein Kinase A PKD Polycystic Kidney disease PC1 Polycystin 1 PC2 Polycystin 2 PRN Pro re nata PLRH Patient Led Research Hub QDS Quarter die sumendum SD Standard deviation SAE Serious adverse event SAR Serious adverse reaction RRT Renal replacement therapy SG Specific Gravity USS Ultrasound Scan V2 DRINK trial Vasopressin 2 Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 9 TRIAL FLOW CHART SCREENING AND INFORMED CONSENT WEEK -24 to 0 *Participants will be required to self-monitor urine SG twice weekly at home in between visits RANDOMISATION WEEK 0 CONTROL (AW) GROUP N=25 INTERVENTION (HW) GROUP N=25 WEEK 0 - STUDY VISIT WEEK 0 - STUDY VISIT WEEK 2 - STUDY VISIT WEEK 2 - STUDY VISIT WEEK 4 - STUDY VISIT WEEK 4 - STUDY VISIT WEEK 8 - STUDY VISIT WEEK 8 - STUDY VISIT Return to normal drinking habits WEEK 12 – END OF TRIAL VISIT DRINK trial WEEK 12 - END OF TRIAL VISIT Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 10 TRIAL SYNOPSIS Title of Study Determining feasibility of Randomisation to high vs. ad libitum water Intake in Polycystic Kidney Disease – the DRINK randomised feasibility trial Study Description Prospective, open labeled, randomised controlled feasibility trial to determine the safety, tolerability and sustainability of a personalised daily water prescription aimed at achieving dilute urine (urine osmolality < 270mosmo/kg). The study will establish the reliability of self-monitoring and reporting of urine specific gravity. Study Population ADPKD, ages ≥ 16 years and an estimated glomerular filtration rate (eGFR) ≥ 20ml/min/1.73m2 Intervention group Personalised daily water intake prescription to achieve urine osmolality < 270 mOsm/kg Control group Ad libitum water intake, defined as intake guided by thirst, insufficient to achieve a urine osmolality < 270 mOsm/kg Study hypothesis In participants with ADPKD and an eGFR ≥ 20ml/min/1.73m2 it is safe to prescribe high water intake to produce dilute urine. The high volumes of water intake required to achieve this are well tolerated and sustained by the participants without significant impact on quality of life. Adequate separation in urine osmolality can be achieved between the high versus ad libitum water intake groups. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: Study Objectives 11 Primary objective To determine the feasibility of a randomised trial of high versus ad libitum water intake in patients with PKD. Secondary objectives To determine the optimal randomisation strategy To evaluate participant adherence to high water intake and measure the impact on their quality of life. Primary Outcome Measures Study Design The number of patients eligible for, and randomised to the trial The proportion of patients in the high water intake group achieving a urine osmolality < 270 mOsm/kg This is a randomised controlled, open label feasibility trial evaluating water intake in ADPKD. All participants will undergo an initial screening visit. This is designed to gather information about the baseline characteristics, concomitant medical issues and a review of the medication history. Participants should meet all of the inclusion criteria and none of the exclusion criteria. Eligible participants will also be consented during the screening visit. At baseline (week 0), participants will undergo a physical examination for assessment of fluid status, blood tests (in particular renal function, serum osmolality and electrolytes), and well as measures of urine osmolality with a 24-hour collection and urine SG as a surrogate marker. Participants will be randomly assigned (1:1) to prescribed water intake (Group HW) or ad libitum water intake (Group AW). The AW group will be allowed to drink water as guided by thirst, patients who consume large quantities will be encouraged to reduce excessive water intake in a supervised manner aiming for a urine osmolality > 300mosom/kg. In the HW group, each participant has an individualised daily water prescription based on the free water clearance formula. They will be monitored throughout and if they are not achieving urine osmolality <270mosom/kg the water prescription will be adjusted further. Overall, participants will have five face-to-face visits, with an DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 12 additional end of trial visit. During each visit they will undergo interview, targeted physical examination (fluid assessment, vital signs and weight), routine biochemistry and urine SG evaluation. They will be required to provide 24-hour urine collections at the screening visit, week 2 and week 8. This will guide adjustments to water prescription in the intervention group, and provide some information about the degree of correlation of measured urine osmolality with urine SG. Participants will be taught how to measure their own urine SG by stick testing. They will receive an SMS text twice weekly prompting them to measure their urine SG and input the result online via a web portal. If they are unable to do so, they can provide the results via a phone call. Participants also will receive a dietary review at the screening visit and each subsequent visit. This will include an assessment of their current diet, and encourage reduced solute intake as necessary. Sample size 50 participants with ADPKD (n = 25 for each group) Calculation: Assuming 15% of controls will achieve urine osmolality less than target threshold, then 28 participants (n=14 for each group) are required to achieve 99% power to detect 85% target urine osmolality at intervention group. Therefore 50 participants to be recruited with a minimum recruitment target of 30 participants. Study Criteria Inclusion Criteria Participants aged 16 years or older and able to provide consent A diagnosis of ADPKD (fulfilling radiological diagnostic criteria ± genetic evidence) eGFR ≥ 20ml/min/1.73m2 Able to self-monitor urine SG Exclusion Criteria eGFR < 20ml/min/1.73m2 DRINK trial Fluid overload states e.g. heart failure, cirrhosis, or requirement for fluid restriction Confounding illnesses impacting on renal disease e.g. Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 13 diabetes, glomerulonephritis Study Duration Statistical Methods Treatment with diuretics for fluid overload (for patients treated with diuretics for hypertension, participation will be permitted after a run-in period of 2 weeks) Treatment with Tolvaptan in the last 4 weeks Pregnant 12 weeks For baseline characteristics, categorical variables will be reported as number of participants, and percentage of the total number within the group. Continuous variables will be expressed either as mean with standard deviation or median with interquartile range (25-75th), minimum and maximum values, as appropriate. We will report the proportion of participants in each group achieving their target urine osmolality after 8 weeks. A between-group comparison of urine osmolality at the end of 8 week treatment period will be compared between the intervention and control group to estimate the mean difference with 95% confidence intervals and p-values, using linear regression that adjusts for baseline observations. A longitudinal model for the repeated measurements of eGFR at week 0, 4 and 8 will also be fitted. A subset of 8 participants within the intervention group will be having a measured GFR using Cr51-EDTA at Week 0, 2 and 4. Similarly we will review the change in measured GFR slope to look for any acute effects. A statistical analysis plan will be written before any analyses are undertaken. Procedure for safety monitoring DRINK trial Participants will initially be screened by a clinician to ensure there are no contraindications to entering the trial. They will receive regular monitoring throughout, including bloods tests to monitor renal function, sodium and serum osmolality. Twice weekly self-monitoring of urine specific gravity will be performed by trial participants. Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 14 Participants will also undergo four face-to-face study visits during the 8 weeks of the trial. Serious Adverse Events of special interest (heart failure, clinical fluid overload, hyponatraemia) will be reported to the sponsor within 24h of investigators becoming aware of events occurring. Criteria for withdrawal DRINK trial Participants will be withdrawn from the trial for: Persistent hyponatraemia < 132mmol/L (2 consecutive samples) Fluid overload – pulmonary oedema, significant lower limb swelling Uncontrolled hypertension, on two consecutive visits, despite optimal antihypertensive treatment, as judged by the responsible clinician Decline in baseline eGFR by ≥10ml/min/1.73m2, or by ≥ 25%, on two consecutive visits Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 15 BACKGROUND Burden of disease in ADPKD Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited condition affecting 12.5 million people worldwide1, 70000 of which are living in the UK2. The majority of cases are caused by mutations in PKD1 and PKD2 genes. The disease is characterized by the formation of hundreds of cysts within the kidneys, which are present even in early childhood. Over time cysts grow in both number and size, replacing much of the functional renal tissue and ultimately causing end stage renal disease requiring renal replacement therapy (RRT) to stay alive. The UK renal registry data shows that between the years of 2000-2011, 7% of those starting renal replacement therapy had ADPKD. The median age for starting RRT in ADPKD is much earlier (55 years) compared with other renal diseases (66 years)2. The current cost of RRT for those with ADPKD is €1.5 billion/year in the European Union alone3. ADPKD impacts significantly on an affected individual’s quality of life. The cysts can grow considerably, with kidneys weighting up to 5kg each in some cases. This leads to severe chronic pain, the mechanism of which is not clearly understood. Patients are often escalated up the analgesic ladder with little relief causing anxiety and difficulties with employment4. Cysts also become infected and rupture with significant hemorrhage. Compression of surrounding organs can cause obstructive symptoms. Extra-renal manifestations include polycystic liver, pancreatic cysts, cardiac disorders and intracranial aneurysm’s which can be fatal5,6. The condition has a significant psychological impact with more than 60% of ADPKD sufferers being diagnosed with anxiety and depression1. The dominant genetic nature of the disease means that family members know they have a significant chance of passing on the condition to their children. Affected individuals are constantly faced with dilemmas such as whether to have children, pre-implantation screening, or early genetic testing of their children and what impact this knowledge will have. Mechanism of renal cyst development and renal failure The PKD1 and PKD2 genes encode the polycystin 1 (PC1) and polycystin 2 (PC2) proteins respectively. PC1 encodes a protein with a large extracellular domain, 11 transmembrane domains and a cytoplasmic tail. PC2 encodes a transient calcium permeable channel with 6 transmembrane domains7. Both are primarily localised within the primary cilium found on the surface of the renal epithelial cells. They are thought to play a crucial role in cellular differentiation, planar cell polarity and regulating the cell cycle. Deficiency of the polycystin proteins, usually along with another hit, leads to cyst formation5. The process of cyst formation is reliant on two key factors; firstly, there is proliferation of poorly differentiated epithelial cells. Secondly there is an increase in fluid within the cyst this comes from increased transepithelial secretion of chloride rich fluid, and unabsorbed glomerular filtrate. When the cyst reaches > 2mm in size, it often detaches from the main tubule forming an isolated cyst in the interstitium and continues to grow in size6. The majority of the cysts are derived from the principal cells of the collecting duct. The growing cysts compress surrounding structures including DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 16 the draining pelvicalyceal system, arteries, veins and glomerulus. This leads to the well-known consequences of hypertension (reduced renal perfusion activates renin-angiotensin system), cyst infection and hemorrhage, urinary tract obstruction and decline in glomerular filtration6,8. The presence of the obstructing cysts leads to cytokine release, this in turn causes interstitial fibrosis. Interestingly, measurement of glomerular filtration rate is not helpful early on in the condition as there is an adaptive hyper-filtration in the remaining normal nephrons to compensate. However, as the cysts continue to enlarge there is disruption of the renal parenchyma and the compensatory processes will become overwhelmed resulting in a decline in GFR as a late response usually by the fourth and fifth decade of life. In the Consortium of Radiologic Imaging in PKD cohort (CRISP) study, MRI measured height adjusted total kidney volume (htTKV), in participants with ADPKD and CrCl> 70ml/min showed that an htTKV > 600ml/m predicted the development of CKD3 within 8 years9. Additionally further studies showed that kidney length (measured by USS) and htTKV (measured using MRI) both predicted CKD 3 development equally10. Thus kidney length determined by USS could be used as a surrogate for htTKV, negating the need for multiple MRI scans. The role of vasopressin in renal cyst development Vasopressin (AVP), also known as Anti-Diuretic hormone (ADH), is a peptide hormone produced by the hypothalamus with a primary role in water homeostasis. It is released as pre-pro-vasopressin, this is then cleaved into neurophysin, vasopressin and copeptin11. Although vasopressin is rapidly cleared from the serum, copeptin has a longer half-life and can be used as a marker of ADH levels. Plasma osmolality is usually kept within a narrow range 285-290mosmo/kg. In order to do this the excretion of water from the body must change to accommodate water and solute intake. During water loading the body is able to excrete up to 25litres of dilute urine, whilst during water deprivation states the urine volume can be as low as 0.5 liters per day12. Under normal circumstances the osmo-receptors associated with the hypothalamus will be stimulated in response to a high serum osmolality. Consequently ADH is released from the posterior pituitary, where it is normally stored. It binds to the V2 receptors on the basolateral surface of the principal cells of the collecting duct. This stimulates intracellular adenyl cyclase leading to the formation of cyclical 3’5 monophosphate (cAMP). This in turn results in the insertion of aquaporin 2 (AQ2) channels in the apical membrane of the principal cells, enhancing water reabsorption and returning the osmolality to normal range. In states of low serum osmolality, ADH release is suppressed, enhancing renal excretion of water and again returning serum osmolality to normal levels11,13. In adults with ADPKD the process of osmoregulation is thought to be defective. Although adults with ADPKD have similar levels of vasopressin to controls at baseline, their vasopressin response to water deprivation is more blunted (central defect) thus they are unable to increase the amount of vasopressin in response to increasing serum osmolality in the same way as normal controls. In addition there appears to be an element of peripheral resistance to vasopressin (nephrogenic defect)11. Looking at characteristics of patients with ADPKD, those with a lower GFR (<60ml/min) and higher TKV had lower urine osmolality, higher serum osmolality, and higher serum copeptin levels14. The role of ADH in ADPKD is pathological. It stimulates cAMP signaling which plays a central role in the pathophysiology of ADPKD. High levels of cAMP stimulate downstream events, including stimulating the Protein Kinase A (PKA). This has two main effects firstly activation of DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 17 the CFTR channel that stimulates chloride rich fluid secretion and activates the MAP (Mitogen Activated Protein) kinase pathway ultimately causing increased cell proliferation and dedifferentiation (figure 1)15. Figure 1 AVP-cAMP-PKA pathway for cyst growth15 Thus one of the critical therapeutic targets to halt progression of cyst growth is vasopressin16. Current and potential treatment options Treatment of hypertension Hypertension is common in those with ADPKD and often the first presenting feature. It is associated with activation of the renin-angiotensin system, increased total kidney volume and progression of CKD. Therefore blood pressure control is vital. There are currently no specific BP targets for those with ADPKD, but the general KDIGO guidelines for CKD of ≤ 140/90 are followed. Measures for reducing BP include lifestyle measure and low sodium intake. Agents that block the renin-angiotensin-aldosterone system are first line for BP control in ADPKD1,6. The HALT PKD trial consisted of two studies. Study A was a double blinded, placebo controlled trial where 558 participants with ADPKD and eGFR> 60ml/min were randomly allocated either to standard BP targets (120/70-130/80mmHg) or lower BP (95/60-110/75mmHg) and either lisinopril plus telmisartan or lisinopril plus placebo. The primary outcome was annual percentage change in TKV. Lower more rigorous BP control group had a smaller percentage increase in TKV, a greater decline Left Ventricular mass index, and reduction in urine albumin excretion. There was no difference in eGFR between standard and lower BP control groups. The addition of telmisartan to lisinopril made no difference to TKV17. In Study B 486 participants with ADPKD and eGFR 2560ml/min were randomly allocated to receive lisinopril and temlisartan or lisinopril plus placebo aiming for a target BP 110/70-130/80 mmHg). Although the use of both agents together was safe, the was no difference in the primary endpoints of time to death, end stage renal disease and 50% DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 18 reduction in eGFR from baseline, between both groups18. Thus tight BP control with agents that block the renin-angiotensin system is Reno protective. However, the concomitant use of both an angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) confers no additional benefit. Suppression of vasopressin Over the last decade, there have been great advances in understanding the molecular mechanisms underpinning the pathophysiology of ADPKD, helping to identify therapeutic targets. The role of vasopressin-cAMP-PKA pathway in mediating cyst growth has led to great interest in trying to suppress vasopressin7,15. Recently, the National institute of health and clinical excellence (NICE) has approved the use of Tolvaptan, a highly selective vasopressin V2 receptor antagonist. The evidence for its use is underpinned by the TEMPO 3:4 trial. This was a large multi-center, double blinded, placebo controlled trial, where 1445 participants with ADPKD, and TKV ≥ 750mls and eGFR ≥ 60ml/min were randomly assigned to Tolvaptan or placebo. At the end of the three-year trial period the increase in TKV in the Tolvaptan group was 2.8% per annum compared with 5.5% in the control group. There were also lower rates of decline in renal function and kidney pain in the Tolvaptan group. However, of the 961 participants randomised to Tolvaptan, 23% discontinued the study (compared with 14% in the placebo group). This was commonly due to adverse events in the Tolvaptan group including thirst, polyuria, nocturia, pollakiuria, dry mouth, dizziness, polydipsia and diarrhea. These were mostly related to aquaresis. Serious adverse events included abnormal liver function tests, headache and chest pain19. Despite the fact that the recent approval of Tolvaptan has been greatly welcomed by the PKD community, there remain some reservations. Firstly, the associated adverse and serious adverse events may limit its tolerability and use. Also, NICE currently recommends its use for CKD 2 or 3 (at the start of treatment) and evidence of rapid progression. However rapid progression remains undefined and will be up to the discretion of the nephrologist with responsibility for that patients care. This may lead to inequalities with regards to some physicians holding back the drug whilst others proactively giving it. Blocking the V2 receptor, causes high levels of vasopressin, the longterm effects of this are unclear. Finally the yearly cost of Tolvaptan will be £15,750 per person, which will be a significant financial burden on healthcare trusts20. Another way to suppress vasopressin is to use our understanding of its role in water homeostasis. If participants with ADPKD were asked to drink enough water daily to achieve an dilute urine (urine osmolality < 270mosom/kg), this would physiologically suppress ADH secretion by the posterior pituitary gland, thus inhibiting the stimulus for the pathological cAMP-PKA pathway of cyst growth5,6,13,14. Although some nephrologists give patients the advice to drink plenty throughout the day anyway given our molecular understanding of the condition, there have been no large randomised controlled trial to assess whether this has any impact on disease progression and whether this advice would be safe. Clearly, there are significant benefits of asking people to drink water over taking drugs, and if the same effect can be achieved by taking water, particularly in the group of patients with very early slow progressing disease where Tolvaptan will currently not have a role, then this would be life-changing for people with ADPKD. The condition can be controlled at an earlier stage, rather than waiting for progression. We will go on to review some of the evidence for increased water intake in ADPKD. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 19 Other interventions such as somatostatin analogues and HMA CoA reductase inhibitors remain unproven and are therefore not currently recommended therapeutic options5. Trials of water intake in ADPKD Animal Studies Nagao et al took PKD rats and divided them into two group, the control group was given normal tap water, whilst the intervention group was given 5% glucose which stimulated thirst and increased their water intake by 3.5 fold compared to controls. Results showed the intervention group had a reduced urine osmolality, reduced expression of the vasopressin V2 receptors, and reduced urinary excretion of vasopressin. High water intake was also associated with reduced kidney/total body weight and improved renal function21. There have been a number of other studies in rat and mice models of PKD with similar results. This suggests that vasopressin inhibition is key to preventing cyst growth and progressive renal impairment. Human Studies Barash et al performed a small trial of 13 ADPKD participants and 10 healthy volunteers with an eGFR > 60ml/min/1.73m2. There was an acute water-loading phase where both groups were not allowed to eat and drink for 12 hours, following this they had to drink 200mls of water every 15 minutes for 2.5 hours. Interestingly, the control group was able to achieve a higher urine osmolality than the ADPKD group (901±54 versus 628±57 mOsm/L). The second phase included chronic water loading where participants were asked to drink 3L/day for 7 days. ADPKD participants increased their urine volume by 64% (1.9±0.3L to 3.1±0.3L, p<0.001) and reduced their urine osmolality by 46% (501±54mosm/L to 207±21mosom/L, p=0.04)22. Higashihara et al performed a trial with ADPKD participants with a CrCl≥50ml/min. Participants were randomised based on their own preference to High water intake (n=18) where they had to drink 2.5-3L/day, or free water intake (n=16) where no specific drinking instructions were given. The study period was 12 months. At the end of the study, the High group had larger urine volumes and lower plasma levels of copeptin. However, the TKV and eGFR slopes were worse (p=0.014 and p=0.034 respectively) in those with high water intake. This trial must be interpreted with caution for a number of reasons; 1) High water intake group had larger urine volumes in the prestudy period indicating that the High and Free water intake groups were not matched at baseline, 2) This was not a randomised trial, patient choice determined group allocation which introduces bias, 3) The sample size was small which meant that the study was not sufficiently powered to detect the primary outcomes of change in TKV and eGFR23. There is an ongoing study by Clark and his group in Canada looking at high water intake in CKD generally. 489 participants have been recruited to-date and randomized to either the hydration or control group. An interim analysis of preliminary data has shown that a significant separation in urine volume can be achieved between both groups (mean difference between both groups 1.0L/day at 6 months and 1.2L/day at 12 months, P<0.001), the difference was maintained over time indicating that those in the hydration group were able to maintain increased fluid intake and urine volumes over a long period of time with no serious adverse events24. The trial is due to conclude in July 2016. In addition to this, Perrone et al, presented a small randomized controlled study at the ASN in 2015. 34 participants with ADPKD were randomised to a low osmolar diet and adjusted water intake to achieve a urine osmolality of ≤ 280 mOsmo/L or no intervention for two weeks. The results were DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 20 encouraging, showing the mean plasma copeptin level and urine osmolality declined in the intervention group, with a non significant increase in the control group. The change from baseline to 2 weeks in copeptin levels and urine osmolality was statistically significant between intervention and control arms. In addition the dietary intervention meant that less water intake was required to achieve vasopressin suppression. (http://www.abstracts2view.com/asn_2015/view.php?nu=6233&terms=&type=abstract) Recently, Rangan and his group in Australia have started to recruit participants for the PREVENTADPKD trial. This study will similarly be looking at high water intake in ADPKD. The team plan to recruit 180 participants who will be randomized to either ad libitum water intake (Group A) or prescribed water intake to produce dilute urine at the threshold of vasopressin suppression (Group B). The primary endpoint will be the percentage change in the height adjusted TKV from baseline to the end of the study at 36 months. We have collaborated closely with the group in Australia during our protocol development. Further details of the trial can be found on the Australian New Zealand Clinical Trials Registry. (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=367285&isReview=true). Thus it is clear that although its makes scientific sense that vasopressin suppression through high water intake should slow the progression of ADPKD, there are currently no published large longterm randomised controlled trials that have assessed this and hence the need for the DRINK feasibility study. Safety and Tolerability of prescribed water intake Normal kidneys are remarkable in their ability to generate many (> 25) liters of urine if required. Solute intake is one of the major determinants of minimum obligatory urine volume. Therefore in order to produce large volumes of urine there needs to be reasonable intake of solute (sodium and protein). In those with salt depletion, through for example strict low salt diet, gastrointestinal disorders causing significant loss, or diuretic use (loop and thiazide diuretics cause sodium chloride wasting in the distal nephron), this can results in significant hyponatraemia. In the context of increased fluid intake, the kidneys will be unable to excrete excess fluid, causing fluid overload states. ADPKD patients may be at increased risk of this through salt restriction and diuretics as part of their hypertension management. High water intake can also cause diminished medullary hypertonicity, in fact urine concentrating ability can be reduced by as much as 30%13,14. Additionally severe polyuria, associated with diabetes insipidous, or very high water intake can cause obstructive uropathy by causing bladder distension, intramural thickening with resultant ureteric obstruction and hydronephrosis14. Therefore there is a risk of hyponatraemia, fluid overload, obstruction and loss of medullary hypertonicity13. However the risk of these are rare (<1/100000)14. In participants with ADPKD and CKD 4 or better, a daily fluid prescription of up to 4 liters is thought to be safe as the ability to produce dilute urine is generally preserved in those with CKD and an eGFR ≥ 10ml/min 13. One small study showed that in participants with an eGFR 10-15mls/min/1.73m2, an extra 2 litres/day was safe and well tolerated with no adverse effects on blood pressure, sodium levels or renal function25. The key here is patient selection to ensure that only those with the ability to generate and excrete free water load are included. As such patients for example on diuretics, or who are hyponatraemic or with heart failure and fluid overload states have been excluded. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 21 One of the other key questions is whether participants will tolerate high water intake and be able to comply, and what impact this has on their quality of life. As an example frequent stone formers are encouraged to drink throughout the day to ensure a urine volume > 2.5L/day as this has been shown to prevent stone recurrence. However, adherence to high fluid intake is generally poor13. There is some evidence that regular follow up helps to improve compliance26. We will employ several methods to improve compliance including dietician review, nurse follow up telephone appointments and self-monitoring. In addition this feasibility study should help us to identify any issues with tolerability, and determine ways in which can be overcome/improved for the definitive trial. Rationale for the DRINK trial DRINK is a feasibility study to establish whether it would be feasible and safe to examine the effects of increased water intake on ADPKD. Animal studies using rat models of PKD have supported the role of high water intake in preventing progression of cyst growth and renal impairment21. However thus far evidence in humans is lacking. To date there have been no large, well-designed rigorous trials to answer this question. Having elucidated the molecular mechanisms behind ADPKD, it makes sense from a basic science point of view that water may have a protective role through vasopressin suppression. The main benefits of using water are that it is physiological, present in abundance, cheap and widely available. Therefore if it were shown to be beneficial this would impact greatly on our care of ADPKD, at no real extra cost. More importantly most medications carry a side effect profile, which in early disease may not be beneficial given the risk benefit ratio. Thus, water intake could provide a safe therapeutic option in early slowly progressive disease, as well as late rapidly progressive disease. ADPKD patients are currently given varying advice regarding water intake depending on the beliefs of their responsible clinician, a trial to show whether this was associated with any harm or benefit would be helpful. In fact, the patient led research hub (PLRH) in Cambridge, were contacted by a number of patients with ADPKD suggesting research ideas to investigate the impact of high water intake on PKD progression. A recent study recruited participants with ADPKD and their care-givers to join focus groups, in order to identify key priority topics. Interestingly, non-pharmacological management (diet, fluid intake and physical activity) was identified as one of the key priority topics. The groups reason for this was the vagueness and conflicting advice in the current guidance on fluid intake and dietary management27. Therefore, this is clearly a question of great importance and concern to affected individuals. The aim of the DRINK trial is to inform the design of a large definitive randomised control trial of water intake in ADPKD. It will also provide information regarding recruitment, compliance, tolerability and the safety profile of water as a therapeutic interventions. The benefits if this trial are; 1) it is a randomised trial, 2) participants will be monitored regularly for the occurrence of any adverse events, 3) self-monitoring and reporting will be tested to see if it enhances compliance, and also to see if we can reduce the visit burden on participants thereby enhancing participation in future trials, 4) we are using water which is not a medicinal product, 5) patients with advanced stages of chronic kidney disease (CKD 3 and 4) are included in the trial, these are often excluded from trials and therefore beneficial therapies cannot confidently be extrapolated to this group, 6) we are attempting to answer an important therapeutic question which could impact on the lives of those with ADPKD and their families DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 22 TRIAL DESIGN Statement of design DRINK is a prospective, open label, randomised controlled feasibility study to assess the viability and safety of randomisation to prescribed versus ad libitum water intake on the progression of autosomal dominant polycystic kidney disease (ADPKD). Number of Centers This is a single center trial. Number of Participants We plan to enroll 50 participants. Participants Trial duration 12 weeks. Trial objectives Primary objective To determine the feasibility of a randomised trial of high versus ad libitum water intake in patients with PKD. Secondary objectives To determine the optimal randomisation strategy To evaluate participant adherence to high water intake and measure the impact on their quality of life. Trial Outcome Measures Primary outcome measure The number of patients eligible for, and randomised to the trial The proportion of patients in the high water intake group achieving a urine osmolality < 270 mOsm/kg Secondary outcome measure Between group separation in urine osmolality Proportion of participants that can self-monitor and report urine SG reliably Proportion of patients experiencing a serious adverse event Proportion of patients experiencing adverse event of special interest Within-group change in eGFR between baseline and week 2, and baseline and week 4 Between-group comparison of change in HRQoL Other outcome measures Impact of a dietician consultation on adherence to water intake Is it best to randomise patients on an individual basis or cluster randomisation of family kindred’s DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 23 SELECTION AND WITHDRAWAL OF PARTICIPANTS Inclusion Criteria To be eligible for the trial the participant must satisfy all the following criteria: Have given written informed consent to participate Aged 16 years or older Have a diagnosis of ADPKD (fulfilling radiological diagnostic criteria ± genetic evidence) eGFR ≥ 20ml/min/1.73m2 Able to self-monitor urine SG Exclusion Criteria The presence of any of the following will preclude participant inclusion: Inability to provide informed consent eGFR < 20ml/min/1.73m2 Fluid overload states e.g. heart failure, cirrhosis, or requirement for fluid restriction Confounding illness impacting on renal disease e.g. concomitant diabetes or glomerulonephritis Treatment with diuretics for fluid overload (those on diuretics for hypertension may participate in the trial after a run-in period of 2 weeks) Treatment with Tolvaptan in the last 4 weeks Pregnancy or breastfeeding Treatment Assignment and Randomisation Number Participants will be randomised 1:1 Blinding DRINK will be an open-label trial. Subject withdrawal criteria Participants may withdraw consent to participation in the trial at any point. They can either withdraw fully from both participation and further data collection, or participation alone. This should be documented on the CRF. Participants may be withdrawn at the discretion of the PI or CI if the trial is deemed to be against the participant’s best interest. Participants will be withdrawn for persistent hyponatraemia (defined as a serum sodium concentration ≤ 132mmol/L on two consecutive measurements). Participants will be withdrawn for clinical evidence of fluid overload in the opinion of the PI or delegated staff, or if any evidence of pulmonary oedema is noted. Uncontrolled hypertension, on two consecutive visits, despite optimal antihypertensive treatment, as judged by the responsible clinician Decline in baseline eGFR by ≥10ml/min/1.73m2, or by ≥ 25%, on two consecutive visits Clinical requirement for the introduction of diuretics DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 24 The reason for withdrawal will be clearly documented in the Case Report Form. Withdrawn participants will not be replaced, and should be reviewed again at the end of trial visit if possible. TRIAL TREATMENT Trial Interventions We are studying the impact of prescribed high water intake on ADPKD. Intervention Group Participants randomised to the intervention group will receive an individualised fluid prescription and will undergo a dietary assessment to discuss lifestyle measures and solute intake. Fluid Prescription The objective of the fluid prescription is to maintain a urine osmolality < 270mosm/kg, this equates to a urine SG ≤ 1.010. The free water clearance formula is used to do this for each subject (see below). Fluid intake = {Total solutes (mOsm)/270 } + insensible losses (mls) Insensible losses include skin and respiratory tract, and are arbitrarily estimated at 500mls. Although it is noted that participants who exercise regularly may have greater insensible losses, and therefore require an increased fluid intake to account for this. Total solute is equal to the urine osmolality (mOsm/Kg) x urine volume (mls), and is calculated from the average of two 24hour urine collections which participants will be asked to provide at the screening visit, week 2 and week 8 (end of active treatment period). For a hypothetical patient (where the objective is a urine osmolality of 270mosm/kg) that produced a daily urine volume of 1000mls at a urine osmolality of 600 mOsmo/kg, the calculation would be as follows: Total solutes = 600 (mOsm/kg) x 1000 (mls) = 600000 Fluid intake = (600000/270) + 500mls (insensible loss) = 2722mls/day Therefore, for this patient to maintain a urine osmolality of 270mosm/kg, s/he would require a daily fluid intake of 2.7 liters. The resultant fluid prescription would vary for individuals depending on their 24-hour collection results. Although we have stated we are looking at water intake, essentially we will include all fluid intake within this for example tea, coffee, squash and plain water. Alcohol does not count towards the fluid intake. A diet with moderate alcohol and caffeine intake will be encouraged to avoid the diuretic effects of these substances. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 25 Dietician input – role of solutes The volume of urine excreted is highly dependent on the amount of solute the body must clear to maintain a steady solute state. This can be referred to as the minimum obligatory volume of urine. The relationship between solute intake and urine volume is shown in the following equation13: Obligatory Urine Volume (Liters) = {Daily osmolar excretion (mOsm)} / {Maximal Urine Osmolality (mOsm/kg H2O)} For participants who have a high protein and/or salt intake, in order to produce dilute urine they will require significantly higher fluid intake, which may make it more difficult to achieve the target urine osmolality. All participants will therefore undergo a dietary assessment. Participants will be advised to maintain a moderate protein (0.75-1g/kg/day) and reduced salt (sodium intake < 2g/day or < 87mmol/day) diet28,29. Measured Glomerular filtration rate There will be a sub-study, in which eight participants from the intervention group will have measured glomerular filtration rate using Cr-51 EDTA as the isotope. This will be carried out at Weeks 0, 2 and 4 to monitor for any acute effects on glomerular filtration rate. Participant self-monitoring and self-reporting Participants will all be trained to measure urine specific gravity (SG), so that they can independently do this at home. They will receive an SMS text message twice weekly to remind them to do this. The results will be self-recorded by the patients online via a web portal. We may also use a smartphone application for this purpose. If they would prefer not to do so or feel unable, they can telephone the trial office and provide the results over the phone. Participant questionnaire At each of their visits, participants will have a dietary review. They will also be required to fill out questionnaires on HRQoL, tolerability and kidney pain. Control Group Participants of the control group will be asked to drink to thirst. This should result in a urine osmolality > 300 mOsm/kg, corresponding with a urine specific gravity > 1.010. Although the control group will not have a specific fluid prescription, if their results show that their urine SG ≤ 1.010 on two consecutive results, they will be reviewed by a member of the study team and asked to reduce excessive fluid intake. The control group will similarly perform urine SG self-monitoring and reporting, participate in the questionnaires and receive dietary assessments. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 26 PROCEDURES AND ASSESSMENTS Pre-Screening Eligible patients will be identified in the nephrology genetics clinic, by the PI or delegated member of the research team. They will be given a participant information sheet to take away and read. Potential participants may also be contacted through a trial invitation letter, which will allow patients to indicate their agreement to be contacted by returning a tear-off slip or by telephoning the trial office. Screening evaluation Screening will be performed by a trained member of the research team. Screening Assessments Trial specific assessments will only be conducted after participants have given written informed consent. The screening visit will include a medical history, physical examination, as well as urine and blood tests. The information and results of the screening visit will be reviewed by the PI or delegated medically trained researcher, to ensure the participant is eligible and safe to be included into the trial. Specifically, the screening visit will record the following: 24 hour urine collection – two will be required Urine SG Demographics Medication review Height, weight Vital observations Physical examination Blood test – biochemistry (FBC, LFTs, Urea, Creatinine, eGFR, electrolytes, serum osmolality) Dietary and fluid intake assessment Run-in for Patients Receiving Diuretic Treatment Patients treated with diuretics for hypertension, but not for fluid management, may be eligible for the trial following discontinuation of diuretic treatment for at least 14 days, if in the opinion of the principal investigator or delegated staff diuretic treatment can be safely withdrawn. Patients proceeding with the run-in period will be assessed for any evidence of extracellular fluid excess at the time of the baseline visit, which should occur after 14 days from diuretic discontinuation. Informed Consent At the start of the screening visit, a delegated member of the research team will obtain written informed consent. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 27 Subject Registration and Randomisation Once eligibility has been confirmed, participants will be randomised using a central computerised algorithm. Baseline assessments (Week 0) All participants will undergo the following; Urine SG Medication review Weight Vital observations Physical examination Blood test – biochemistry (FBC, LFTs, Urea, Creatinine, eGFR, electrolytes, serum osmolality, copeptin levels) Measured GFR – only for a subset within the intervention group Dietary and fluid intake assessment Trial assessments Assessments at time point Week 2 24 hour urine collection Urine SG – during visit and by participants twice weekly at home. Medication review Weight Vital observations Physical examination Blood test – biochemistry (Urea, Creatinine, eGFR, electrolytes, serum osmolality) Measured GFR – only for a subset within the intervention group Dietary and fluid intake assessment Week 4 Urine SG – during visit and by participants twice weekly at home. Medication review Weight Vital observations Blood test – biochemistry (Urea, Creatinine, eGFR, electrolytes, serum osmolality, copeptin levels) Measured GFR – only for a subset within the intervention group Dietary assessment Dietary and fluid intake assessment DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 28 Week 8 24 hour urine collection Urine SG – during visit and by participants twice weekly at home. Medication review Weight Vital observations Physical examination Blood test – biochemistry (Urea, Creatinine, eGFR, electrolytes, serum osmolality, copeptin levels) Dietary and fluid intake assessment Assessments at the end of trial visit (4 weeks after last visit) The active treatment period is 8 weeks. At this point participants will be asked to return back to their normal drinking habits. Once the treatment is completed, participants will be reviewed once more at 4 weeks after the end of the trial. The following outcomes will be measured: 24 hour urine collection Urine SG – during visit Medication review Weight Vital observations Physical examination Blood test – biochemistry (Urea, Creatinine, eGFR, electrolytes, serum osmolality, copeptin levels) Dietary and fluid intake assessment Methods and Materials Demographics The participant’s date of birth, gender and ethnic origin will be recorded at the screening visit. Medical History Participants medical and surgical history will be reviewed at the screening visit, with particular focus on timing of ADPKD diagnosis, family history, renal and extra-renal manifestations and previous interventions. Also lifestyle factors such as smoking status, alcohol intake and level of physical exercise. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 29 Medication review A medication review will be performed at the screening visit. Medications that commonly (> 1/100 patients) cause hyponatraemia include loop diuretics, thiazide diuretics, potassium sparing diuretics, aldosterone antagonists and non-steroidal anti-inflammatory drugs will need to be stopped with a washout period of 2 weeks before being entered into the trial. If this is not possible, participants will not be included in the trial. Medication reviews will be carried out at every subsequent visit, including the end of trial visit. Height Height will be measured to the nearest centimeter using a stadiometer at the screening visit, along with weight to calculate the body mass index. Weight Weight will be measured to the nearest 0.1kg using class III weighing scales. Participants will be weighed at the screening visit, and then on every subsequent visit including the end of trial visit to look for any concerning trends in weight gain which may indicate fluid overload. Vital signs Vital signs will be recorded on the screening visit and all subsequent visits. After 5 minutes of being seated participants will have their temperature, pulse and respiratory rate measured. If abnormal, they will be repeated again in 5 minutes. If they remain abnormal the results will be discussed with the investigator who will determine clinical significance and course of action. Blood pressure will also be measured after 10 minutes of the participants being seated, using a standard NHS digital monitor (Omron), the cuff should be placed so the center of the bladder is above the brachial artery, three measurements will be taken in the right arm, the mean of the last two measurements will be reported. Cuff size should be appropriate as per the British hypertension society guidelines30. Physical examination Physical examination will be carried out at the screening visit to review skin, fluid balance status, cardiovascular and respiratory and abdominal examination. It will also be performed at week 0, 2, 8 and at the end of trial visit. Any subsequent changes picked up after screening for example new peripheral oedema, maybe indications of adverse events that need to be recorded. 24-hour urine collection At the screening visit participants will be given two 24-hour urine collection bottles. They will be asked to throw away the first urine sample of the morning and collect everything passed over the next 24 hours including the next days first morning sample. Participants will be asked to hand these in locally. The mean urine volume and osmolality of both these collections will be used to provide an individualised fluid prescription for participants in the intervention group. At the subsequent visits they will be required to provide one 24 hour urine collection at weeks 2, 8 and the end of trial meeting to assess urine volume, osmolality, urine sodium. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 30 Spot urine sample Participants will be asked to provide a 100ml container of urine (ideally early morning sample) each visit, this will be required to dipstick the urine for urine SG as well as any evidence of proteinuria or glycosuria which may interfere with urine SG accuracy. Also, proteinuria can be an indication of disease severity. 50mls of this will also be sent to the laboratory to obtain a spot urine osmolality result. Urine Specific gravity (urine SG) Urine SG can be used as an estimate of urine osmolality and therefore be used as a guide to alter fluid intake aiming for urine osmolality < 270mosom/kg (target urine SG in the intervention group and > 300mosom/kg in the control group. Urine SG ranges from 1.000 (dilute) to 1.030 (concentrated). For every 0.001 rise in urine SG, this is roughly equivalent to 35mosom/kg in urine osmolality. For example if we are aim for urine osmolality of 270mosom/kg and a patient has a urine SG of 1.015, then we would calculate the urine osmolality as follows; (1.015-1.000)/0.001 x 35 = 525 mOsm/kg Thus, this patient must drink more to achieve his target urine osmolality. Participants will have their urine SG measured on spot urine samples at the screening visit and week 0. At Week 0, that they will be shown how to measure their own urine SG twice weekly (Monday and Thursday). Participants will be required to dipstick their urine between 4-8pm, using urine reagent strips (Siemens Multi-stix 10SG, pack of 100 strips – see figure). This will reflect their drinking practices throughout the day. They will then be required to record the result online, or telephone in the result. We may develop a smartphone application which allows participants to input their results directly in to the application. But this is dependent on securing funding. Participant instructions for urine SG measurement; 1) Remove the cap from the bottle 2) Take one strip and replace the cap 3) Place the reagent strip under a stream of urine 4) Wait for 60 seconds 5) Compare the colour on the strip with that on the bottle 6) Record the number the coincides with the colour 7) Discard the strip DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 31 Based on the results they record, participants will be given advice to either maintain or alter their fluid consumption (see table). Urine SG 1.005 1.010 1.015 1.020 1.025 1.030 Each cup = 250mls Predicted urine osmolality mOsm/kg 175 350 525 700 875 1050 Intervention Group Advice Control Group Advice Maintain Maintain intake by 2 cups intake by 3 cups intake by 4 cups intake by 5 cups intake by 3 cups intake by 2 cups Maintain Maintain Maintain Maintain Blood tests Around 50mls of blood will be sampled at the screening visit and the end of trial visit, samples will be sent for FBC, urea, Creatinine, eGFR, sodium, potassium, bone profile, liver function tests, and serum osmolality. In between this 30mls of blood will be taken at each visit and sent for urea, Creatinine, eGFR, sodium, potassium and serum osmolality. Samples will be taken for serum copeptin levels (a surrogate marker for vasopressin) will be measured at week 0, 4, 8 and 12. These will be stored and may be analysed at a later date. Measured GFR In a radioisotope GFR sub-study, 8 patients will be enrolled to receive, in addition to the study protocol, a 51 Cr EDTA GFR measurement at weeks 0, 2 and 4 to determine whether high water intake results in acute changes in GFR (Appendix 4). SMS Text messages At the baseline visit (week 0), participants will monitor urine SG twice weekly, on Monday and Thursday between the hours of 4-8pm. On the morning of Monday and Thursday between 9am12pm they will receive a text message reminding them to monitor urine SG today and record it. Dietary and fluid intake assessment Participants will receive a dietary assessment by a trained member of the research team at the screening visit. Participants in the HW group, who are not achieving their target urine osmolality (or urine SG) will be advised to maintain a moderate protein (0.75-1g/kg/day) and reduced salt (sodium < 2g/day or < 87mmol/day) diet. Further dietary assessments will occur at week 0 and week 4 and at the end of trial visit after returning to usual eating habits. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 32 Specific visit questions Kidney pain Analgesia: During the screening visit we will review participants current use of analgesia. This will be done using the Medication Quantification Scale (MQS III) 2003. This is a tool used to quantify medication regimens for chronic nonmalignant pain. It assesses drug class, dosage and detriment (risk). Based on the medication class e.g. opioid or anti-convulsants etc. the medication is given a detriment score, this is multiplied by the dosage level to give an MQS score. The participant will receive a total score based on all the difference classes of analgesia they are taking. This is explained further in appendix 2. An MQS score will be calculated for each of their subsequent visits to look for significant differences. Pain Questionnaire: Participants will be asked to fill out a pain questionnaire which looks in detail at the type of pain they are experiencing (appendix 3). They will be asked to fill this out at the screening and end of trial visit. Adverse events Participants will be asked open questions about general well-being to detect any adverse events. This will be followed by more specific questions about symptoms of fluid overload (breathlessness, orthopnea, ankle swelling), polyuria, nocturia, sleep deprivation and other symptoms related to aquaresis. Patient acceptability Participants will be asked the following question. 1) Could you drink this amount of water every day for the rest of your life? Yes No Health-related quality of life (HRQoL) questionnaire This will be measured using the EQ-5D-5L questionnaire. This questionnaire is a widely used standardised measure of health status. A copy is included in appendix 5. They will be asked to fill this out at the screening visit and again at week 8. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 33 Schedule of Assessments Determinations Screening W0 W2 W4 W8 End of trial X Informed consent X Randomisation X X X X 24h Urine collection (osmolality) X X X X X X Urine SG X Demographics X X X X X X Medication review X Medical History Review X Height X X X X X X Weight X X X X X X Vital sings X X X X X Physical examination X X X X X X Biochemistry X X X Measured GFR* X X X X Dietary assessment X X X X X X Adverse events / kidney pain X X X X Patient acceptability question X X HRQoL Questionnaire *Measured GFR will be determined using CR-51 EDTO GFR in a subgroup of 8 participants in the intervention group to assess acute effects on GFR. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 34 Trial restrictions Participants who are commenced on medications associated with a significant risk of hyponatraemia (NSAIDS, loop and thiazide diuretics, aldosterone antagonists) who must remain on them will be excluded from the trial. Participants should not be on Tolvaptan, or have received the drug in the last 4 weeks Participants who have a diagnosis of SIADH (syndrome of inappropriate anti diuretic hormone secretion) due to any cause will also be excluded. No specific contraception is required for male and female participants in the trial. However if female participants do become pregnant during the trial, they should inform a member of the research team so they can be withdrawn. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 35 ASSESSMENT OF SAFETY Safety Monitoring throughout DRINK Participants will be monitored for adverse events throughout the study period in the following ways; 1) Clinic visits - participants will be asked general open questions “how do you feel”, followed by more specific questions targeted at expected adverse events. They will also have physical examination to detect signs such as fluid overload, raised blood pressure etc. 2) Regular blood tests will allow us to monitor any abnormalities indicating adverse events such as hyponatraemia 3) Regular urine tests to detect those at risk of dehydration or fluid overload. 4) Regular medication reviews will allow the detection of adverse events, for example the addition of diuretics for oedema, anti-hypertensive for rising blood pressure by another clinician. 5) Participants will be asked about admissions to hospital, attendance to hospital appointments. Definitions Adverse event (AE) Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational medicinal product, whether or not considered related to the investigational medicinal product. All recording of adverse events must start from the point of Informed Consent regardless of whether a patient has yet received a medicinal product. Adverse reaction to an investigational medicinal product (AR) All untoward and unintended responses to an investigational medicinal product related to any dose administered. All adverse events judged by either the reporting investigator or the sponsor as having a reasonable causal relationship to a medicinal product qualify as adverse reactions. The expression reasonable causal relationship means to convey in general that there is evidence or argument to suggest a causal relationship. Unexpected adverse reaction An adverse reaction, the nature, or severity of which is not consistent with the applicable reference safety information (RSI). When the outcome of the adverse reaction is not consistent with the applicable RSI this adverse reaction should be considered as unexpected. The term “severe” is often used to describe the intensity (severity) of a specific event. This is not the same as “serious,” which is based on patient/event outcome or action criteria. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 36 Serious adverse event or serious adverse reaction (SAE / SAR) Any untoward medical occurrence that at any dose: results in death, is life-threatening requires hospitalisation or prolongation of existing inpatients´ hospitalisation, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect. is an important medical event - Some medical events may jeopardise the subject or may require an intervention to prevent one of the above characteristics/ consequences. Such events (hereinafter referred to as ‘important medical events’) should also be considered as ‘serious’. Life-threatening in the definition of a serious adverse event or serious adverse reaction refers to an event in which the subject was at risk of death at the time of event; it does not refer to an event which hypothetically might have caused death if it were more severe. Expected Adverse Events/Serious Adverse Events (AE/SAE) There are expected adverse events attributed to polycystic kidney disease and also ones that are expected as part of participating in the water intervention trial. Although they will be recorded in the trial AE log, they will not be reported. These are highlighted in the table below. Expected AE due to ADPKD Renal pain Back pain Urinary tract infection Haematuria Renal cyst haemorrhage Renal cyst infection Expected AE intervention Polydipsia Polyuria Nocturia Pollakiuria due to trial Evaluation of adverse events The Sponsor expects that adverse events be recorded from the point of Informed Consent regardless of whether a patient has yet received a medicinal product. The investigator should evaluate individual adverse events. This includes the evaluation of its seriousness, causality and any relationship between the investigational medicinal product(s) and/or concomitant therapy and the adverse event. Assessment of causality When assessing causality the following criteria will be used in line with GCP guidance: Definitely Probable DRINK trial A causal relationship is clinically/biologically certain. (AR) A causal relationship is clinically / biologically highly plausible and there is a plausible time sequence between onset of the AE and administration of the investigational medicinal product Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: Possible Unlikely Unrelated 37 and there is a reasonable response on withdrawal. (AR) A causal relationship is clinically / biologically plausible and there is a plausible time sequence between onset of the AE and administration of the investigational medicinal product. (AR) A causal relation is improbable and another documented cause of the AE is most plausible. (AE) A causal relationship can be definitely excluded and another documented cause of the AE is most plausible. (AE) Unlikely and Unrelated causalities are considered NOT to be trial drug related Definitely, Probable and Possible causalities are considered to be trial drug related A pre-existing condition must not be recorded as an AE or reported as an SAE unless the condition worsens during the trial and meets the criteria for reporting or recording in the appropriate section of the CRF. Clinical assessment of severity The severity can be assessed using the following criteria as per the GCP guidelines and will be determined by the Investigator: Mild Moderate Severe The subject is aware of the event or symptom, but the event or symptom is easily tolerated The subject experiences sufficient discomfort to interfere with or reduce his or her usual level of activity Significant impairment of functioning; the subject is unable to carry out usual activities and / or the subject’s life is at risk from the event. Recording of adverse events Adverse events and adverse reactions should be recorded in the medical notes and the appropriate section of the CRF and the AE/AR log. Serious Adverse Events and Serious Adverse Reactions should be reported to the sponsor as detailed in the next section. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 38 Reporting serious adverse events SAE Identified Report to CI within 24 hours CI will assess whether SAE needs immediate reporting YES SAE form to be completed and sent to sponsor within 24 hours NO Record in CRF and AE log Will require follow up Related to the trial intervention? YES = SAR Is it Expected ? NO = SAE, need record in CRF and follow up The Chief Investigator is responsible for ensuring the assessment of all SAEs for expectedness and relatedness is completed and the onward notification of all SAEs to the Sponsor immediately but not more than 24 hours of first notification. The sponsor has to keep detailed records of all SAEs reported to them by the trial team. The completed SAE form can be faxed or emailed. Details of where to report the SAE’s can be found on the DRINK SAE form and the front cover of the protocol. POTENTIAL ADVERSE EFFECTS Water is a safe physiological substance, widely available. It does not fulfill the MHRA criteria for a medicinal product, thus will not require MHRA approval. It is a dietary supplement intervention in the form of hydration. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 39 An individualised water prescription is safe. This is further ensured by careful participant selection during the screening stage of the trial and regular monitoring of active participants throughout. However, the main possible toxicities include fluid overload, hypertension and hyponatraemia. Fluid overload: There is a small risk that participants may become fluid overloaded presenting with symptoms such as shortness of breath, reduced exercise tolerance, orthopnea, and lower limb swelling. Physical examination may reveal raised jugular venous pressure, pulmonary congestion, peripheral oedema and increasing weight and blood pressure. If this occurs patients will be withdrawn from the trial. Fluid overload states will be treated as per the local protocol with appropriate fluid restriction and commencement of diuretics as required. They will require follow up until resolution. Hypertension: Participants will have blood pressure monitored at each clinic visit for the development of new hypertension or worsening of pre-existing hypertension. If in the opinion of the supervising clinician the blood pressure has increased significantly, participants will be reviewed to determine if their fluid intake needs reducing and to confirm adherence to existing antihypertensive medication. The next step is to assess the need to introduce or increase anti-hypertensive treatment. Hypertension should be preferentially treated with a calcium channel blocker or alpha blocker. The de novo introduction of an ACE inhibitor or angiotensin receptor blocker is permissible. However, this should be avoided during the first 4 weeks of the trial, given the potential for acute effects on eGFR. If participant’s blood pressure remains elevated despite these measures, as judged by the clinician, participants will be withdrawn from the study. Hyponatraemia: Normal serum sodium levels are between 135-145mmol/l. As described previously, prescribed water intake is dependent on the ability of the kidneys to excrete solute free water. If this is not the case, participants will retain more water than they are able to excrete from the body causing hyponatraemia. Participants whose blood tests show a sodium < 132mmol/L will be asked to reduce their fluid intake, if the repeat bloods show sodium remains < 132mmol/L, they will be withdrawn from the trial. Any participant who develops severe hyponatraemia (sodium < 125mmol/L), will be immediately withdrawn from the study and be treated as clinically appropriate. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 40 EVALUATION OF RESULTS Response criteria Recruitment potential The recruitment rate of the trial will be measured as number of participants successfully recruited per month. Urine Osmolality The target urine osmolality for the intervention group is < 270mosm/Kg. This should be achieved by week 2, and maintained throughout the 8-week active treatment period. Adequate separation needs to be achieved between the urine osmolality of the intervention and control group. The target is to be achieved by week 2, and again maintained throughout the duration of the active treatment phase. Safety Safety will be assessed by a comparison of the proportion of participants between trial arms experiencing any SAE from the point of randomisation until the end of trial visit. Quality of life Using health related quality of life questionnaires at various time points (screening visit and week 8), we will assess the impact of the water intervention on quality of life. Within the intervention group, questionnaire scores at the screening visit and at the end of the active trial period will be compared. We will also compare questionnaire scores between the intervention and control group at the end of the active treatment phase of the trial. STORAGE AND ANALYSIS OF SAMPLES All the blood and urine samples obtained from participants will be anonymised with no participant specific details, apart from their unique trial identifier number. Samples will be analysed at our central laboratory. Both urine and blood samples may be stored in a -80oc freezer at a secure central storage facility at the university of Cambridge. STATISTICS Statistical methods For baseline characteristics, categorical variables will be reported as number of participants, and percentage of the total number within the group. Continuous variables will be expressed either as mean with standard deviation or median with interquartile range (25-75th), minimum and maximum values, as appropriate. We will report the proportion of participants in each group achieving their target urine osmolality after 8 weeks. A between-group comparison of urine osmolality at the end of 8 week treatment period will be compared between the intervention and control group to estimate the mean difference with 95% confidence intervals and p-values, using linear regression that adjusts for baseline observations. This will answer the question of whether participants can achieve their target urine osmolality and whether adequate separation can be achieved between the HW and AW groups. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 41 A longitudinal model for the repeated measurements of eGFR at week 0 4 and 8 will be fitted. This will consist of generalised linear model with an unstructured correlated within-patient error, and main and interaction effects of visit and treatment as fixed effects. The interaction of (week 4 vs 0) :(HW vs AW) and (week 8 vs 4):(HW vs AW) will be estimated with 95% confidence intervals and p-values, which quantifies the how the change over time in eGFR varies between the treatment arms. A subset of 8 participants within the intervention group will be having a measured GFR using Cr51EDTA at Week 0, 2 and 4. Similarly we will review the change in measured GFR slope to look for any acute effects. A statistical analysis plan will be written before the final data base lock. Interim analyses No interim analyses are planned for the trial. The TSC will consider the recruitment rate after 3 months, and if suboptimal, the trial will be extended to other sites. Number of Participants to be enrolled Assessing the proportion achieving target osmolality: Assuming that 15% of controls will have a urine osmolality below the target threshold (although this seems unlikely), a sample of 28 patients (14 per group) will have 99% power at α = 0.05 to detect an increase to 85% at target in the intervention group. In view of the above considerations, the target sample size is therefore 50 patients, recruited over 6 months, with a minimum recruitment target of 30 patients. Criteria for the premature termination of the trial The trial may be terminated prematurely on the recommendation of the Trial Steering Committee if in their view, in the light of analyses of safety and any other information considered relevant, the randomised comparisons in the study have provided both (i) “proof beyond reasonable doubt”1 that for all, or some specific types of, patients prolonged use prescribed water intake is clearly indicated or clearly contraindicated; and (ii) evidence that might reasonably be expected to influence materially the patient management of many clinicians who are already aware of the results of other trials. Procedure to account for missing or spurious data We do not anticipate that there will be a significant rate of missing data. In the case of missing values, the method of simple imputation will be employed, using the last-observation-carriedforward method. Definition of the end of the trial The end of trial will be the date of the last patient’s end of trial visit at week 12. 1 Appropriate criteria of proof beyond reasonable doubt cannot be specified precisely, but in general a difference of at least three standard deviations in major morbidity or mortality in an interim analysis would be needed to justify halting, or modifying, the study prematurely. This criterion has the practical advantage that the exact number of interim analyses is of little importance. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 42 DATA HANDLING AND RECORDING Case Report Form All data will be transferred into an anonymised Case Report Form (CRF). All trial data in the CRF must be extracted from and be consistent with the relevant source documents. The CRFs must be completed, dated and signed by the investigator or designee in a timely manner. The timing, completeness, legibility and accuracy of the CRF pages is the responsibility of the investigator. The CRF will be accessible to trial coordinators, data managers, the investigators, Clinical Trial Monitors, Auditors and Inspectors as required. All CRF pages must be clear, legible and completed in black ink. Any errors should be crossed with a single stroke so that the original entry can still be seen. Corrections should be inserted and the change dated and initialed by the investigator or designee. If it is not clear why the change has been made, an explanation should be written next to the change. Typing correction fluid must not be used. We may create electronic CRF forms built within EPIC, the online patient record system used at Addenbrooke’s Hospital. Source Data To enable peer review, monitoring, audit and/or inspection the investigator must agree to keep records of all participating patients (sufficient information to link records e.g., CRFs, hospital records and samples), all original signed informed consent forms and copies of the CRF pages. Source data include the following Patient medical records Original signed consent form Questionnaires – HRQoL and Pain questionnaires Electronic health records for urine, blood and imaging results (EPIC and TX database) Smartphone application for water intake CRF – baseline characteristics, kidney pain and acceptability questions, Medical review including history, examination and medication review. Data Protection & Patient Confidentiality All investigators and trial site staff involved in this trial must comply with the requirements of the Data Protection Act 1998 and Trust Policy with regards to the collection, storage, processing and disclosure of personal information and will uphold the Act’s core principles. The principal investigator and members of the research team will hold patient identifiable data on all trial participants including name, date of birth, gender, NHS number or equivalent, home address and postcode, telephone number and email address where applicable. Patient identifiable data will be stored separately from anonymised trial data on a secure server hosted within University of Cambridge School of Clinical Medicine Secure Data Hosting Service2. 2 http://cscs.medschl.cam.ac.uk/about-us/policies/patient-identifiable-data-2/ DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 43 TRIAL STEERING COMMITTEE The Trials Steering Committee is responsible for overall supervision of the trial. It will meet at regular intervals to monitor the progress and conduct of the trial. Through the independent members and Chair, they will also provide expert advice on continuation, termination or amendments to the trial protocol. Details of their role are included in the separate TSC charter for the DRINK trial. ETHICAL AND REGULATORY CONSIDERATIONS Consent The Informed Consent form must be approved by the REC and must be in compliance with GCP, local regulatory requirements and legal requirements. The investigator must ensure that each trial participant, or his/her legally acceptable representative, is fully informed about the nature and objectives of the trial and possible risks associated with their participation. The investigator will obtain written informed consent from each patient or the patient’s legally acceptable representative before any trial-specific activity is performed. The informed consent form used for this trial and any change made during the course of this trial, must be prospectively approved by the REC. The investigator will retain the original of each patient’s signed informed consent form. Should a patient require a verbal translation of the trial documentation by a locally approved interpreter/translator, it is the responsibility of the individual investigator to use locally approved translators. Any new information that becomes available, which might affect the patient’s willingness to continue participating in the trial will be communicated to the participant over the telephone or verbally at their next visit. Ethical committee review Before the start of the trial or implementation of any amendment we will obtain approval of the trial protocol, protocol amendments, informed consent forms and other relevant documents e.g., advertisements and GP information letters if applicable from the REC. All correspondence with the REC will be retained in the Trial Master File/Investigator Site File. Annual reports will be submitted to the REC in accordance with national requirements. It is the Chief Investigator’s responsibility to produce the annual reports as required. Regulatory Compliance This is not an investigation of a medicinal product. Protocol Amendments Protocol amendments must be reviewed and agreement received from the Sponsor for all proposed amendments prior to submission to the REC. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 44 The only circumstance in which an amendment may be initiated prior to REC approval is where the change is necessary to eliminate apparent, immediate risks to the patients (Urgent Safety Measures). In this case, accrual of new patients will be halted until the REC approval has been obtained. In the event of an Urgent Safety Measure, principal investigators will be notified by telephone, information will be posted on the trial-specific website, and the participants will be notified directly using their expressed preferred mode of communication. Peer Review The DRINK trial proposal has been extensively peer reviewed by the British Renal Society and the Addenbrookes Charitable Trust. Declaration of Helsinki and Good Clinical Practice The trial will be performed in accordance with the spirit and the letter of the declaration of Helsinki, the conditions and principles of Good Clinical Practice, the protocol and applicable local regulatory requirements and laws. GCP Training All trial staff must hold evidence of appropriate GCP training or undergo GCP training prior to undertaking any responsibilities on this trial. This training should be updated every 2 years or in accordance with your Trust’s policy. SPONSORSHIP, FINANCIAL AND INSURANCE This trial is sponsored by Cambridge University Hospitals NHS Foundation Trust and University of Cambridge. The study will be jointly funded by the Addenbrooke’s Charitable Trust (ACT), Polycystic Kidney Disease (PKD) charity and the British Renal Society (BRS). Cambridge University Hospitals NHS Foundation Trust, as a member of the NHS Clinical Negligence Scheme for Trusts, will accept full financial liability for harm caused to participants in the clinical trial caused through the negligence of its employees and honorary contract holders. There are no specific arrangements for compensation should a participant be harmed through participation in the trial, but no-one has acted negligently. The University of Cambridge will arrange insurance for negligent harm caused as a result of protocol design and for non-negligent harm arising through participation in the clinical trial. MONITORING, AUDIT & INSPECTION Should a monitoring visit or audit be requested, the investigator must make the trial documentation and source data available to the Sponsor’s representative. All patient data must be handled and treated confidentially. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 45 PROTOCOL COMPLIANCE AND BREACHES OF GCP Prospective, planned deviations or waivers to the protocol are not allowed. Protocol deviations, non-compliances, or breaches are departures from the approved protocol. They can happen at any time, but are not planned. They must be adequately documented on the relevant forms and reported to the Chief Investigator and Sponsor immediately. Deviations from the protocol that are found to occur constantly again and again will not be accepted and will require immediate action and could potentially be classified as a serious breach. PUBLICATIONS POLICY Ownership of the data arising from this trial resides with the trial team. On completion of the trial the trial data will be analysed and tabulated and a Final Study Report prepared. All funding bodies (BRS, PKD charity, ACT) will be acknowledged in the final publication. A national oral presentation of the trial results will be presented at the first BRS meeting following the final report. Regular progress reports and an end of study report will be submitted to the ACT throughout the duration of the trial. All surviving participants in the trial will be notified of the trial results using their preferred method of communication. A synopsis of trial results will be provided on the trial-specific website. Data may also be shared through the Cambridge Data Repository. DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 46 REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. Chapman, A. B. et al. Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. 1–11 (2015). doi:10.1038/ki.2015.59 Shaw, C., Simms, R. J., Pitcher, D. & Sandford, R. Epidemiology of patients in England and Wales with autosomal dominant polycystic kidney disease and end-stage renal failure. Nephrology Dialysis Transplantation 29, 1910–1918 (2014). Translating science into policy to improve ADPKD care in Europe. 1–52 (2015). Hogan, M. C. & Norby, S. M. Evaluation and Management of Pain in Autosomal Dominant Polycystic Kidney Disease. Advances in Chronic Kidney Disease 17, e1–e16 (2010). Torres, V. E. & Harris, P. C. Autosomal dominant polycystic kidney disease: the last 3 years. 76, 149–168 (2009). Autosomal Dominant Polycystic Kidney Disease. 1–9 (2008). Chebib, F. T., Sussman, C. R., Wang, X., Harris, P. C. & Torres, V. E. Vasopressin and disruption of calcium signalling in polycystic kidney disease. Nat Rev Nephrol 11, 451–464 (2015). Grantham, J. J., Mulamalla, S. & Swenson-Fields, K. I. Why kidneys fail in autosomal dominant polycystic kidney disease. Nature Publishing Group 7, 556–566 (2011). Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort. 1–11 (2003). Bhutani, H. et al. A comparison of ultrasound and magnetic resonance imaging shows that kidney length predicts chronic kidney disease in autosomal dominant polycystic kidney disease. Kidney International 88, 146–151 (2015). Bolignano, D. et al. Copeptin (CTproAVP), a new tool for understanding the role of vasopressin in pathophysiology. Clinical Chemistry and Laboratory Medicine (CCLM) 52, 1–10 (2014). Clinical Physiology of. 1–28 (2005). Wang, C. J., Grantham, J. J. & Wetmore, J. B. The medicinal use of water in renal disease. Kidney International 84, 45–53 (2013). Torres, V. E., Bankir, L. & Grantham, J. J. A Case for Water in the Treatment of Polycystic Kidney Disease. Clinical Journal of the American Society of Nephrology 4, 1140–1150 (2009). Devuyst, O. & Torres, V. E. Osmoregulation, vasopressin, and cAMP signaling in autosomal dominant polycystic kidney disease. Current Opinion in Nephrology and Hypertension 22, 459–470 (2013). Torres, V. E. & Harris, P. C. Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease. Journal of the American Society of Nephrology 25, 18–32 (2013). Schrier, R. W. et al. Blood Pressure in Early Autosomal Dominant Polycystic Kidney Disease. N Engl J Med 371, 2255–2266 (2014). Torres, V. E. et al. Angiotensin Blockade in Late Autosomal Dominant Polycystic Kidney Disease. N Engl J Med 371, 2267–2276 (2014). Torres, V. E. et al. Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease. N Engl J Med 367, 2407–2418 (2012). Tolvaptan for treating autosomal dominant polycystic kidney disease. 1–47 (2016). Nagao, S. Increased Water Intake Decreases Progression of Polycystic Kidney Disease in the PCK Rat. Journal of the American Society of Nephrology 17, 2220–2227 (2006). DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 22. 23. 24. 25. 26. 27. 28. 29. 30. 47 Barash, I., Ponda, M. P., Goldfarb, D. S. & Skolnik, E. Y. A Pilot Clinical Study to Evaluate Changes in Urine Osmolality and Urine cAMP in Response to Acute and Chronic Water Loading in Autosomal Dominant Polycystic Kidney Disease. Clinical Journal of the American Society of Nephrology 5, 693–697 (2010). Higashihara, E. et al. Does increased water intake prevent disease progression in autosomal dominant polycystic kidney disease? Nephrology Dialysis Transplantation 29, 1710–1719 (2014). Clark, W. F., Sontrop, J. M., Moist, L. & Huang, S. H. Increasing Water Intake in Chronic Kidney Disease: Why? Safe? Possible? Ann Nutr Metab 66, 18–21 (2015). J, P., J, P., KP, S., H, H. & FC, L. Effect of water and bicarbonate loading in patients with chronic renal failure. Clin Nephrol 47, 92–98 (1997). Parks, J. H. & Coe, F. L. Evidence for durable kidney stone prevention over several decades. BJU International 103, 1238–1246 (2009). Tong, A. et al. Identifying and integrating consumer perspectives in clinical practice guidelines on autosomal-dominant polycystic kidney disease. Nephrology 21, 122–132 (2016). Translational research in nephrology: chronic kidney disease prevention and public health. 1– 9 (2015). doi:10.1093/ckj/sfv082 Sodium intake for adults and children. 1–56 (2014). syst33. Cuff_Sizes. 1–1 (2012). DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 48 APPENDICES Appendix 1 – Medication Quantification Score (MQS) III Medication Class Topical/transdermal agents Antidepressants – serotonin reuptake inhibitors Antidepressants other Anticonvulsants GABAergic Antihypertensives Antianxiety Muscle relaxants – non dependency Acetaminophen Cycloxygenase inhibitors Antidepressants- tricyclics Analgesic - miscellaneous Anticonvulsants – sodium channel blockers Sedative hypnotics Opioids – schedule II Nonsteroidal antiinflammatories Antipsychotics Opioids – schedule IV Opioids – schedule III Example Lidocaine, capsaicin Fluoxetine, Paroxetine Detriment Weight 1.1 1.7 Venlafaxine, mirtazapine Gabapentin, topiramate 1.9 1.9 Clonidine, nifedipine Buspirone Cyclobezaprine, baclofen 2.0 2.1 2.2 Tylenol Celecoxib Amitriptyline, nortriptyline Tramadol Phenytoin, carbamazepine 2.2 2.3 2.3 2.3 2.8 Zolpidem, chloral hydrate Morphine, fentanyl, oxycodone Aspirin, diclofenac 3.1 3.4 Haloperidol, olanzapine Butorphanol Buprenorphine, codeine (combined) 3.6 3.7 3.7 3.4 Muscle relaxant dependency Benzodiazepines Clonazepam, midazolam Steroids Prednisolone Barbiturates Phenobarbital Table 1. Medication class, examples and detriment weight 3.8 3.9 4.4 4.5 Score Description 1 Subtherapeutic dose, occasional use, prn 2 Lower 50% of the therapeutic dose range 3 Upper 50% of the therapeutic dose range 4 Supratherapeutic dose Table 2 Relative Dosage score For example participant X take the following: Name Morphine Tramadol DRINK trial Daily dose Detriment Dosage weight Level score 5mg prn 3.4 1 50mg qds 2.3 2 Total MQS score Version Number: 1.2 MQS 3.4 4.6 8.0 Version Date: 18 June 2016 EUDRACT number: 49 Appendix 2 - Pain Questionnaire BASELINE/ SCREENING +/- other visits too. Throughout our lives, most of us have had pain from time to time (such as minor headaches, sprains, and toothaches). Have you had pain other than these everyday kinds of pain? YES/NO If YES, Body Map: Please shade using horizontal lines in the areas where all your pain(s) are. Now shade using vertical lines where you feel that your kidney problems are causing pain. Put X on where pain it hurts (bothers) you the most. For area marked X, DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: DRINK trial 50 Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: DRINK trial 51 Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 52 BASELINE & FOLLOW-UP visits McGill Pain Questionnaire: This questionnaire provides you with a list of words that describe some of the different qualities of pain and related symptoms. Please put an X through the numbers that best describe the intensity of each of the pain and related symptoms you felt during the past TWO WEEKS. Use 0 if the word does not describe your pain or related symptoms DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 53 Appendix 3 EQ-5D™ Questionnaire Under each heading, please tick the ONE box that best describes your health TODAY MOBILITY I have no problems in walking about I have slight problems in walking about I have moderate problems in walking about I have severe problems in walking about I am unable to walk about SELF-CARE I have no problems washing or dressing myself I have slight problems washing or dressing myself I have moderate problems washing or dressing myself I have severe problems washing or dressing myself I am unable to wash or dress myself USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) I have no problems doing my usual activities I have slight problems doing my usual activities I have moderate problems doing my usual activities I have severe problems doing my usual activities I am unable to do my usual activities PAIN / DISCOMFORT I have no pain or discomfort I have slight pain or discomfort I have moderate pain or discomfort I have severe pain or discomfort I have extreme pain or discomfort ANXIETY / DEPRESSION I am not anxious or depressed I am slightly anxious or depressed I am moderately anxious or depressed I am severely anxious or depressed I am extremely anxious or depressed DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 54 The best health We would like to know how good or bad your health is TODAY. you can imagine This scale is numbered from 0 to 100. 100 100 means the best health you can imagine. 95 0 means the worst health you can imagine. 90 Mark an X on the scale to indicate how your health is TODAY. Now, please write the number you marked on the scale in the box 85 80 below. 75 70 65 YOUR HEALTH TODAY = 60 55 -THIS WAS THE LAST QUESTION OF THE QUESTIONNAIRE- 50 45 40 35 30 25 20 15 10 5 0 The worst health you can imagine DRINK trial Version Number: 1.2 Version Date: 18 June 2016 EUDRACT number: 55 Appendix 4- Radioisotope Sub-Study In the Radioisotope Sub-study a group of 8 participants will have a measured glomerular filtration rate at weeks 0, 2 and 4 to look for any acute GFR changes. All participants in the intervention group (HW) will be invited to take part in the sub-study, the first 8 to consent will be recruited. Female participants who are trying to conceive or currently pregnant will not be able to participate in the substudy. All woman of child bearing age, who are able to conceive will be asked to have a pregnancy test before proceeding with the sub-study. In order to determine the GFR, we will be measuring the plasma clearance of Cr-51 EDTA (radiopharmaceutical) following a single injection. The day before the test participants will be asked to avoid high protein meals and excessive caffeine (no caffeinated drinks after 10pm). On the day of the test itself a light breakfast only is advised. For the test, participants will have a cannula sited, preferably in the ante-cubital fossa. They will receive a single injection of Cr-51 EDTA which will be dosed according to their weight. Venous blood samples will then be drawn from the contralateral arm at baseline, 2, 3 and 4 hours. Using the slope-intercept method, the GFR will then be calculated from the area under the plasma clearance curve. DRINK trial Version Number: 1.2 Version Date: 18 June 2016
