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1) Title of study project : - Comparison of Efficacy of Bromocriptine mesylate and Pioglatazone in Type 2 Diabetes Patients: A Randomized Controlled clinical trial. 2) Location of study : SMT KASHIBAI NAVALE MEDICAL COLLEGE AND GENERAL HOSPITAL, NARHE, PUNE Department / Institution : DEPARTMENT OF MEDICINE AND PHARMACOLOGY 3) Name(s) & signature(s) of the Principal investigator(s) : DR. RADHA YEGNANARAYAN, DR. YOGENDRA KECHE Designation & Department PROFESSOR AND HEAD, LECTURER, DEPARTMENT OF PHARMACOLOGY, SKMNC & GH 4) Name(s) & signature(s) of the co-investigator(s) : Designation & Department: DR. Y. D. SINGH PROFESSOR DEPARMENT OF MEDICNE, SKNMC & GH DR. J. SASTRY HEAD, DEPARTMENT OF CLINICAL RESEARCH 5) Approval of the Head(s) of the Department(s) undertaking the study : Name(s) & Signature 1) DR RADHA YEGNANARAYAN PROFESSOR AND HEAD, DEPARTMENT OF PHARMACOLOGY, SKMNC & GH 2) DR BABAN SANAS PROFESSOR AND HEAD, DEPARTMENT OF MEDICNE, SKMNC & GH 3) DR D. P. GHADAGE PROFESSOR AND HEAD, CENTRAL CLINICAL LABORATORY, SKMNC & GH 6) Duration of study: 1 year 7) Deadlines for periodic progress review & data analysis : 3 months 8) Detailed Research Plan : This study will start after approval from Ethics Committee of Smt Kashibai Navale Medical College and General Hospital in department of Medicine and Department of Pharmacology. Patients of Type 2 Diabetes on Sulphonylureas/ Metformin not responding adequately and having Hb1Ac > 8% will be recruited from Medicine OPD with the help of physician. Patients will be given information about the drugs including adverse effect (See Annexure VII). A written informed consent {See Annexure IV} will be taken from each patient and those who will be willing to participate in study will be enrolled .All the information will be written in case report form{See Annexure V}. There will be two groups of patients, out of which one group will receive bromocriptine (Bromocriptine Group) and other group will be given pioglitazone (Pioglitazone Group ). Patients will be maintained on the same Sulfonylureas / Metformin doses as before. Bromocriptine will be given in the dose starting from 1.25 mg to 4.375 mg (MAXIMUM) along with Sulfonylureas / Metformin therapy. Bromociptine tablet 1.25 mg (1 tablet) daily will be given in first week, followed by 2.5 mg (2 tablets) in 2nd week, later 3.75 mg (3 tablets) in 3rd week and lastly 4.375 mg (31/2 tablets ) if tolerated by patient. The patient will be asked to take the tablet within 2 hours after waking from sleep with some food. Maximum tolerated dose is kept constant for the period of 6 months. This dose used in this study is different from quick release formulation. This particular dose is chosen in this study as dose of bromocriptine quick release formulation for antidiabetic effect is 0.8 mg to 4.8 mg (increased gradually), another aspect is that in India quick release formulation is not available hence have to use conventional formulation that is available as 1.25mg oral tablet.The other group (Pioglitazone Group) will be maintained on pioglitazone therapy in their maximum tolerated doses started from 15 mg daily to maximum dose of 45 mg31 for period of six months At baseline all the investigations will be carried out as follows: STUDY DESIGN FLOW CHART ENROLLMENT OF PATIENTS ON SULFONYLUREAS / METFORMIN AND Hb1Ac > 8 % BASELINE INVESTIGATIONS & RANDOM ALLOACTION IN TWO GROUPS OF PATIENTS. BROMOCRIPTINE THERAPY STARTED PIOGLITAZONE THERAPY STARTED FOLLOW UPS AT 1,2,3 AND 6 MONTHS FOLLOW UPS AT 1,2,3 AND 6 MONTHS INVESTIGATIONS FLOW CHART Both the Groups (Bromocriptine and Pioglitazone) Baseline Blood sugar-Fasting/PP, Serum lipid profile, HbA1c level, Serum insulin, Body weight, height, Blood pressure,(These investigations will be carried out to to measure the effect of Bromocriptine and Pioglitazone) Blood urea, Serum creatinine, Serum Bilirubin, SGOT,SGPT, Alkaline phoshatase, Hb % and CBC (These Investigations will be carried out to rule out hepatic or renal dysfunction ), ECG (To rule out cardiac abnormality viz, IHD, arrhythmias) 1month Blood sugar-Fasting/PP, Hb1Ac, Serum insulin, LFT, Hb % and CBC, Body weight, Blood pressure 2 months Blood sugar-Fasting/PP, Hb1Ac, Serum insulin, LFT, Hb % and CBC, Body weight, Blood pressure 3 months Blood sugar-Fasting/PP. Serum lipid profile, HbA1c level, Serum insulin, LFT, Hb % and CBC, Body weight, Blood pressure 6 months Blood sugar-Fasting/PP. Serum lipid profile, HbA1c level, Serum insulin, LFT, Hb % and CBC, Body weight, Blood pressure Inclusion Criteria: 1.Age between 30 -70 years 2.Sex: Male/ Non-lactating female 3.HbA1 > 8 4.Type 2 Diabetic patient on Sulphonylureas/ Metformin not responding adequately Exclusion Criteria: 1. Age < 30 yrs. 2. Pregnancy 3. Lactating mother 4. Patient with Insulin dependent Diabetes Mellites 5. Patient who is taking oral antidiabetic drugs other than Sulphonyureas and Metformin 6. Severe and Complicated diabetes 7. Patient with IHD 8. Patients having renal or hepatic dysfunction 9. Patient of Parkinsonism, syncopal migraine 10. Patient who is taking - Salicylates, Sulfonamides, Chloramphenicol, Probenecid, Phenithiazines, Butyrophenones, Thioxanthenes,Metoclopramide 11. Strong Inhibitors/Inducers/ Substrates of CYP 3A4 Inhibitors -sodium valproate, erythromycin, Fluroquinolones except ofloxacin, verapamil, diltiazem, propoxyphene, allopurinol, MAO inhibitors, disulfiram, tolbutamide, metronidazole,captopril, enalpril, carbidopa Inducers :Phenobarbitone, phenytoin, carbamazepine, ethanol, clofibrate, griseofulvin, Rifampcin, pyridoxine Substrates: barbiturates, dextropropoxyphene, warfarin,theophylline, paracetamol, ascorbic acid, tolbutamide, diazepam, vit D, oral contraceptives, antidepressants, quinidine, terfanidine,phenytion, carbamazepine, morphine, pethidine, 12. HIV positive patients After enrollment of patient for study, all the baseline investigations will be carried out at Central Clinical Laboratory except Hb1Ac which will be carried out at department of Pharmacology. ECG, Blood pressure recording will be carried out in Department of Medicine. Reporting of Adverse effects: All patients will be given checklist of Adverse effect of Bromocriptine (Annexure VI ) as well as Pioglitazone(Annexure VIII ). Information of ADR will be taken in next follow-up. If patients are unable to tolerate ADR, they are advised to contact any of investigators at any time. Contact numbers of investigators will be mentioned on patient information sheet. ADRs will be treated according to gradations of ADRs of Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (NIH)36. Only severe ADRs will be reported to respective company and DCGI in standard format. Treatment ADRs will be done according to grades of ADRs. Investigational drug use will be stopped if grade of ADR is 3 or more than 3. Alternative drug therapy will be made available to patient who has got ADRs due to investigational drug. General Guidelines for grading as well as treatment of ADRs are as below: Grade 1 : Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 : Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL*. Grade 3 : Severe or medically significant but not immediately life-threatening. hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL**. Grade 4 : Life-threatening consequences; urgent intervention indicated. Grade 5 : Death related to AE. Activities of Daily Living (ADL) *Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. **Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. Expected ADRs of Bromocriptine:7,12,31 Nausea, fatigue, dizziness, vomiting and headache Grading of ADRs to Bromocriptine:36 Bromocriptine Grades of ADRs 1 Symptom/ADR Nausea Fatigue 2 3 Loss of Oral intake appetite decreased Inadequate oral without without caloric or fluid alteration in significant intake; tube eating weight loss, feeding, TPN, or habits dehydration or hospitalization malnutrition indicated Fatigue not Fatigue not Fatigue relieved by rest; relieved by rest, relieved by limiting limiting self care rest instrumental ADL 4 5 ADL Mild Dizziness Moderate Severe unsteadiness unsteadiness or unsteadiness or or sensation sensation of sensation of of movement; movement; movement limiting limiting instrumental self care ADL ADL 1-2 Vomiting episodes 3 - 5 episodes >=6 episodes Life- (separated (separated by 5 (separated by 5 threatening by 5 minutes) in 24 minutes) in 24 consequences; minutes) in hrs hrs; tube feeding, urgent TPN or intervention hospitalization indicated 24 hrs Death indicated Moderate pain; Headache Mild pain limiting Severe pain; instrumental limiting self care ADL ADL Expected ADRs of Pioglitazone :31 Anaemia, weight gain, edema, and plasma volume expansion, hepatotoxicity, macular edema31 Grading of ADRs to Pioglitazone:36 Pioglitazone Grades of ADRs 1 Symptom/ADR 2 3 4 Hgb <8.0 Hemoglobin Anemia Weight gain Death g/dL; <4.9 Life-threatening (Hgb) <LLN - Hgb <10.0 - 8.0 mmol/L; consequences; 10.0 g/dL; <6.2 - 4.9 <80 g/L; urgent g/dL; <LLN - 6.2 mmol/L; <100 - transfusion intervention mmol/L; <LLN - 80g/L indicated indicated 5 - <10% from 10 - <20% from >=20% from baseline baseline baseline 100 g/L 5 Edema face Moderate Severe Localized facial localized facial swelling; edema edema; limiting limiting self instrumental care ADL ADL >10 - 30% interlimb discrepancy in Edema limbs volume or >30% inter- circumference at limb point of discrepancy 5 - 10% inter- greatest visible in limb discrepancy difference; volume; in volume or readily apparent gross circumference at obscuration of deviation point of greatest anatomic from visible architecture; normal difference; obliteration of anatomic swelling or skin folds; contour; obscuration of readily limiting self anatomic apparent care ADL architecture on deviation from close inspection normal anatomic contour; limiting instrumental ADL Symptomatic Death liver dysfunction; Hepatotoxicity fibrosis by Decompensated biopsy; liver function Asymptomatic, compensated (e.g., ascites, treatment not cirrhosis; coagulopathy, indicated reactivation encephalopathy, of chronic coma hepatitis Optic disc Decreased visual acuity (worse than Blindness 20/40); (20/200 or worse) marked visual field defect but sparing the central 20 degrees Decreased visual acuity (20/40 or better); visual field defect Asymptomatic edema present Expected ADRs of Sulfonylureas: Nausea, vomiting, hypoglycemia, cholestatic jaundice, Hypersensitivity reaction. Grading for ADRs like agranucytosis, aplastic anemia, hemolytic anemia not available.CBC and Hb % will be done at each follow up and these ADRs will be graded on the basis of general guidelines for grading of ADRs. Grades of ADRs of Sulfonylureas: Sulfonylureas Grades of ADRs 1 Symptom/ADR Nausea 2 3 Loss of appetite Oral intake Inadequate oral without decreased without caloric or fluid alteration in significant weight intake; tube eating habits loss, feeding, TPN, or dehydration or hospitalization 4 5 malnutrition Vomiting Hypoglycemia indicated >=6 episodes Life- (separated by 5 threatening 3 - 5 episodes minutes) in 24 consequences; 1 - 2 episodes (separated by 5 hrs; tube feeding, urgent (separated by 5 minutes) in 24 hrs TPN or intervention minutes) in 24 hospitalization indicated hrs indicated <LLN - 55 mg/dL; <LLN 3.0 mmol/L <55 - 40 mg/dL; <3.0 - 2.2 mmol/L <40 - 30 mg/dL; <2.2 - 1.7 mmol/ Death <30 mg/dL; Death <1.7 mmol/L; lifethreatening consequences; seizures Symptomatic Death liver Cholestatic dysfunction; Decompensat jaundice fibrosis by ed liver biopsy; function Asymptomatic, compensated (e.g., ascites, treatment not cirrhosis; coagulopathy, indicated reactivation of encephalopath chronic y, coma hepatitis Hypersensitiviy Transient Intervention or Prolonged (e.g., Life- flushing or rash, infusion not rapidly threatening drug interruption responsive to consequences; fever <38 degrees indicated; responds symptomatic urgent C (<100.4 promptly to medication intervention degrees F); symptomatic and/or brief indicated Death intervention not treatment (e.g., interruption of indicated antihistamines, infusion); NSAIDS, recurrence of narcotics); symptoms prophylactic following initial medications improvement; indicated for <=24 hospitalization hrs indicated for clinical sequelae (e.g., renal impairment, pulmonary infiltrates) Expected ADRs of Metformin : Nausea, Diarrhea, Indigestion, Abdominal cramps/bloating, Lactic acidosis Grades of ADRs of Metformin: Grading for ADRs like deficiency of Vit B12, lactic acidosis, Indigstion, Abdominal bloating not available.CBC and Hb % will be done at each follow up and these ADRs will be graded on the basis of general guidelines for grading of ADRs. Sulfonylureas Grades of ADRs 1 Symptom/ADR 2 3 Oral intake Nausea decreased Inadequate oral Loss of appetite without caloric or fluid without significant intake; tube alteration in weight loss, feeding, TPN, or eating habits dehydration hospitalization or indicated malnutrition 4 5 Increase of >=7 Death stools per day over baseline; incontinence; Increase of 4 - hospitalization Diarrhea 6 stools per indicated; Increase of <4 day severe stools per day over baseline; increase in over baseline; moderate ostomy output Life-threatening mild increase in increase in compared to consequences; ostomy output ostomy output baseline; compared to baseline compared to limiting baseline self care ADL urgent intervention indicated Sample Size Calculation and statistical analysis: Sample size of 30 for each group is calculated in the ratio of 1, power 80 %, considering 10 fold difference of drug effect in bromocriptine group and control group by using OpenEpi software. Randomization of study population will be carried out with help of randomization number table. 9) Justification for study : Newer therapeutic approach to treat Type II Diabetes with Bromocriptine will improve glycemic control as well as may be helpful in improving lipid profile as well as reducing body weight. Pioglitazone has following drawbacks :1) it has variable effect on lipid profile 2) Caution should be exercised while prescribing in hepatic disorders and heart failure patients as it causes plasma volume expansion 3) risk of developing bladder cancer. Due to these drawbacks pioglitazone, need is there to search alternative to pioglitazone. Bromocriptine is time tested drug for indications like Parkinson’s disease and hyperprolactenemia and recently in May 2009, approved for type 2 diabetes in USA. Bromocriptine causes only mild ADRs like nausea, vomiting, fatgue, giddiness, headache. Caution to be exercised in patients with syncope and hypotension. Bromocriptine use not associated with increased cardiovascular risk, infact it is found to reduce cardiovascular risk in type 2 diabetic patients and has beneficial effect over cardiovascular function. In this context, bromocriptine has beneficial features and can be used as alternative to pioglitazone in treatement of type 2 diabetes wherever pioglitazone can not be used due ADRs and limitations in form of cautions for using in hepatic dysfunction and heart failure. 10) Funding : SMT KASHIBAI NAVALE MEDICAL COLLEGE AND HOSPITAL Source of funding / Sponser Sanction letter from authorities 11) Whether informed consent of study subject is required ? 12) If study involves drug intervention Availability of drug YES - Central Pharmacy, SKNNMC & GH Pune -41 Source of procurement of drug 13) If new drug / formulation : Permission letter from DCGI - required 14) Date of submission for ethical review - 15) Remarks of the secretary: Date: Names & Signature of Principal Investigators Names(s) & Signature of Co-investigators Dr. Radha Yegnanarayan Dr. Y. D. Singh Dr. Yogendra Keche Dr. J. Sastry Prof & Head of the Department