Download Primary Endpoint

Update ESC und EuroPCR 2015
7.10.2015
Hypertonie und Herzinsuffizienz
Univ.-Prof. Dr. Burkert Pieske
Department of Internal Medicine and Cardiology
Charité University Medicine, Campus Virchow Klinikum
and
Department of Internal Medicine and Cardiology,
German Heart Center Berlin, Germany
[email protected]
www.cvk-kardiologie.de
www.dhzb.de
UNIVERSITÄTSMEDIZIN BERLIN
Hot Line Clinical Trials ESC 2015
1. Hypertonie
2. Herzinsuffizienz
Calcium Upregulation by Percutaneous Administration of
Gene Therapy in Cardiac Disease 2 (CUPID 2) study
A Phase 2b Trial Investigating the Efficacy and Safety of the
Intracoronary Administration of AAV1/SERCA2a in Patients
with Advanced Heart Failure.
SERCA2a deficiency is pivotal for the progression of Heart
Failure
J Am Coll Cardiol. 2008;51:1112-1119;
ESC London 2015 - Hotline Session; Heart Failure (Barry Greenberg, UCSD)
SERCA2a deficiency is pivotal for the progression of Heart
Failure
J Mol Cell Cardiol. 2007;42:852-861; Byrne M, et.al. Gene Ther. (24 Jul 2008); Surg Clin N Am 84 (2004) 141–159
ESC London 2015 - Hotline Session; Heart Failure (Barry Greenberg, UCSD)
CUPID 2 - Main Inclusion and Exclusion Criteria
Inclusion
• 18-80 years of age
• Diagnosis of NYHA Class II-IV chronic
HF due to ischemic or non-ischemic
cardiomyopathy
• LVEF ≥ 0.35
• Optimal tolerated stable medical
therapy for ≥30 days
• Elevated natriuretic peptide or history
of HF-related hospitalization within 6
months of enrollment
• <1:2 or equivocal anti-AAV1
neutralizing antibody
Exclusion
• Hypertrophic, restrictive and obstructive
cardiomyopathy; acute myocarditis;
amyloidosis; discrete LV aneurysm
• Cardiac surgery, PCI, valvuloplasty or IV
therapy for HF within 30 days prior to
screening
• Surgically implanted LVAD
• Significant liver or renal impairment (>3x
ULN; GFR ≤20 mL/min/1.73 m2)
• History of cancer within the past 5 years
• Active infection
Greenberg B, Yaroshinsky A, Zsebo KM, et al. J Am Coll Cardiol HF 2014;2:84.92
ESC London 2015 - Hotline Session; Heart Failure (Barry Greenberg, UCSD)
CUPID 2 - Endpoints
Primary Efficacy Endpoint: Time to recurrent HF-related hospitalizations and ambulatory WHF in
presence of terminal events (all-cause death, transplant, dMCS)
Secondary Efficacy Endpoint: Time to first terminal event (all-cause death, transplant, dMCS)
Exploratory Endpoints: NYHA class, NT-proBNP, 6MWT & KCCQ QOL
Safety Endpoints: Disposition, clinical events; AEs including procedure-related AEs; changes in
medications, vital signs & weight, physical exam, 12-lead ECG, ICD & lab parameters; time to CVrelated death
Greenberg B, Yaroshinsky A, Zsebo KM, et al. J Am Coll Cardiol HF 2014;2:84.92
ESC London 2015 - Hotline Session; Heart Failure (Barry Greenberg, UCSD)
CUPID 2 – Study design
Design of a Phase 2b Trial of Intracoronary Administration of AAV1/SERCA2a in Patients With Advanced Heart Failure: The CUPID 2
Trial (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease Phase 2b)
JCHF. 2014;2(1):84-92. doi:10.1016/j.jchf.2013.09.008
CUPID 2 – Patient population flow chart
ESC London 2015 - Hotline Session; Heart Failure (Barry Greenberg, UCSD)
CUPID 2 – Patient characteristics
ESC London 2015 - Hotline Session; Heart Failure (Barry Greenberg, UCSD)
CUPID 2 – Primary Endpoints
Of the 232 recurrent events that
qualified as primary endpoints, 128
were in the placebo group and 104
were in the AAV1/SERCA2a group
Treatment with AAV1/SERCA2a
failed to improve the rate of
recurrent events (HR, 0·93; 95%
confidence interval [CI] 0·53 to 1·65;
p=0·81)
ESC London 2015 - Hotline Session; Heart Failure (Barry Greenberg, UCSD)
CUPID 2 – Secondary Endpoints
Of the 65 terminal events that qualified
as secondary endpoints, 29 were in the
placebo group and 36 were in the
AAV1/SERCA2a group
Treatment with AAV1/SERCA2a failed to
improve time to first terminal event
(HR, 1·27; 95% CI 0·72 to 2·24; p=0·40)
ESC London 2015 - Hotline Session; Heart Failure (Barry Greenberg, UCSD)
CUPID 2 – Summary
CUPID 2 failed to support the hypothesis that
AAV1/SERCA2a at the dose used has clinical
benefits in patients with moderate to severe
heart failure and reduced ejection fraction
Effect of implanted device-based impedance monitoring with
telemedicine alerts on mortality and morbidity in heart failure: results
from the OptiLink HF study
Does Intrathoracic Impedance Monitoring with an Automatic
Wireless Telemedicine Notification Compared to Standard
Clinical Assessment Reduces All-cause Death or
Cardiovascular Hospitalizations?
OptiLink HF: Inclusion Criteria
ICD Indication according to SCD-HeFT
Chronic Heart Failure (HF), NYHA II – III, LVEF
<= 35%, Optimized Medical Therapy (OMT)
CRT-ICD Indication according to the ESC
Guidelines (2008) Chronic Heart Failure (HF),
only NYHA III, LVEF <= 35%, QRS >= 120msec ,
LVEDD >= 55mm
Optimized Medical Therapy (OMT)
ESC London 2015 - Hotline Session; Heart Failure
Additional inclusion criteria
ESC London 2015 - Hotline Session; Heart Failure
OptiLink HF Study Design
ESC London 2015 - Hotline Session; Heart Failure
Telemedicine guided intervention
Brachmann J, et al. Eur J HF. 2011;13(7):796-804.
ESC London 2015 - Hotline Session; Heart Failure
OptiLink HF: Primary endpoint all cause death or CV
hospitalisation
ESC London 2015 - Hotline Session; Heart Failure
OptiLink HF: Primary endpoint all cause death or CV
hospitalisation
ESC London 2015 - Hotline Session; Heart Failure
OptiLink HF: Primary endpoint all cause death or CV
hospitalisation
ESC London 2015 - Hotline Session; Heart Failure
OptiLink HF: Primary endpoint all cause death or CV
hospitalisation
ESC London 2015 - Hotline Session; Heart Failure
Treatment of Sleep-Disordered Breathing With Predominant Central
Sleep Apnoea by adaptive Servo Ventilation in Patients With Heart
Failure and Reduced Ejection Fraction (SERVE-HF)
Adaptive Servo-Ventilation (ASV)
• ASV is a non-invasive ventilatory therapy that supports inspiration when
breathing amplitude is reduced and ensures sufficient respiration when
respiratory effort is absent (variable IPAP)
• Upper airway patency is ensured by provision of end-expiratory pressure
(fixed or variable EPAP)
• Although algorithms employed by different ASV devices vary slightly, the
principle of treatment is the same: back-up rate ventilation with adaptive
pressure support
Cowie et al. Eur Cardiol Rev 2015.
SERVE-HF: Design
• 91 centres in 11 countries (Germany, France,
UK, Sweden, Australia,
Denmark, Norway, Czech Republic, Finland,
Switzerland, Netherlands)
• Randomized, parallel, event-driven design
• Guideline-based medical management:
– Alone (control group)
– Plus ASV (Auto Set CS™, ResMed)
• ASV titration in hospital (PG or PSG)
– Starting at default settings
– Expiratory positive airway pressure manually
increased to control
obstructive sleep apnoea (OSA) and maximum
pressure support
increased to control central sleep apnoea (CSA)
ESC London 2015 - Hotline Session; Heart Failure
SERVE-HF: Endpoints
• Primary composite endpoint:
– Time to first event of all-cause death,
life-saving cardiovascular
intervention*, or unplanned
hospitalization for worsening
chronic HF
• Secondary endpoints:
– As for primary endpoint, but cardiovascular
vs all-cause death
– As for primary endpoint, but all-cause vs
unplanned hospitalization for
worsening chronic HF
– Time to death (all-cause)
– Time to cardiovascular death
– Change in NYHA class
– Change in 6MWD
– Quality of life
ESC London 2015 - Hotline Session; Heart Failure
Inclusion Criteria
• Age ≥22 years
• Chronic stable HF (ESC guidelines,
no hospitalization within 4
weeks)
• LV systolic dysfunction
– LVEF ≤45%
• NYHA class III or IV
– Or NYHA class II with ≥1
hospitalization for HF in previous
24 months
• Predominant CSA (AHI >15/h with
≥50% central events and central
AHI ≥10/h)
ESC London 2015 - Hotline Session; Heart Failure
Exclusion Criteria
• Significant COPD
• Oxygen saturation <90% at rest
during the day
• Current use of positive airway
pressure therapy
• Cardiac surgery or
resynchronization therapy within
the previous 6 months
• TIA or stroke in previous 3
months
• Significant valvular heart disease
• Contraindications to ASV
Primary Endpoint: Neutral
Cowie et al. Eur Cardiol Rev 2015.
All cause death
Cowie et al. Eur Cardiol Rev 2015.
Cardiovascular death
Cowie et al. Eur Cardiol Rev 2015.
BENEFIT
Randomized Trial of Benznidazole
for Chronic Chagas Cardiomyopathy
BENznidazole Evaluation For Interrupting
Trypanosomiasis
(BENEFIT Trial)
Study Design
BENEFIT Trial Flow and Adherence
Baseline Characteristics
Primary Outcome
Primary Outcome Components