ABBREVIATED STATISTICAL ANALYSIS PLAN
A Phase 2b, Double-Blind, Placebo-Controlled, Multinational, Multicenter, Randomized
Study Evaluating the Safety and Efficacy of Intracoronary Administration of MYDICAR®
(AAV1/SERCA2a) in Subjects with Heart Failure
PROTOCOL No: CELL-004, Version 6, Amendment 5 (CELL-004-V6-A5)
EudraCT number 2012-001700-37
NIH OBA Protocol No: 1205-1167
STUDY NAME: Calcium Up-Regulation by Percutaneous Administration
of Gene Therapy In Cardiac Disease Phase 2b (CUPID Phase 2b Trial)
Name of Investigational Medicinal
Product:
MYDICAR® (AAV1/SERCA2a)
Development Phase:
Sponsor:
2b
Celladon Corporation
12760 High Bluff Drive, Suite 240
San Diego, CA 92130-2019
Version 3
26 November 2013
25 May 2012, Version 1
31 July 2013, Version 2
Current Version Number:
Release Date:
Version History:
Confidentiality Statement
This document contains confidential information that must not be disclosed to anyone other
than the Sponsor and Sponsor representatives, the Investigator Team, regulatory authorities,
and members of institutional review boards, ethics committees or safety review boards.
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 1 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
Table of Contents
TABLE OF CONTENTS .................................................................................................. 2
ABBREVIATIONS, ACRONYMS, AND DEFINITIONS............................................ 4
1.
PREFACE .............................................................................................................. 6
2.
PURPOSE .............................................................................................................. 6
3.
STUDY OBJECTIVES, TREATMENTS AND ENDPOINTS ......................... 6
3.1
3.2
3.3
OBJECTIVES............................................................................................................................ 6
TREATMENT GROUP COMPARISONS ....................................................................................... 7
STUDY ENDPOINTS ................................................................................................................. 7
3.3.1
3.3.2
3.3.3
4.
STUDY DESIGN ................................................................................................... 8
4.1
4.2
5.
RANDOMIZATION AND BLINDING........................................................................................... 9
SAMPLE SIZE .......................................................................................................................... 9
ANALYSIS POPULATIONS............................................................................. 10
5.1
5.2
5.3
5.4
6.
INTENT-TO-TREAT POPULATION .......................................................................................... 10
MODIFIED ITT POPULATION ................................................................................................ 10
PER PROTOCOL POPULATION ............................................................................................... 10
SAFETY POPULATION ........................................................................................................... 10
CONSIDERATIONS FOR DATA HANDLING, PRESENTATION, AND
ANALYSIS .......................................................................................................... 10
6.1
6.2
PROGRAMMING ENVIRONMENT ........................................................................................... 10
TABLES, FIGURES, AND LISTINGS ........................................................................................ 10
6.2.1
6.2.2
6.3
6.4
6.5
6.6
TABLES AND FIGURES ....................................................................................................... 10
LISTINGS ........................................................................................................................... 10
DATA ANALYSIS .................................................................................................................. 11
MISSING DATA ..................................................................................................................... 11
STUDY PERIOD AND TIME POINT DEFINITIONS .................................................................... 11
6.5.1
6.5.2
6.5.3
6.5.4
6.5.5
6.5.6
6.5.7
6.5.8
7.
EFFICACY ENDPOINTS ......................................................................................................... 7
EXPLORATORY EFFICACY ENDPOINTS ................................................................................ 8
SAFETY ENDPOINTS ............................................................................................................ 8
SCREENING PERIOD ........................................................................................................... 11
BASELINE .......................................................................................................................... 11
DAY 0 ............................................................................................................................... 11
12-MONTH ACTIVE OBSERVATION PERIOD....................................................................... 11
LTFU PERIOD ................................................................................................................... 11
PRIMARY ANALYSIS DATA CUTOFF .................................................................................. 12
EOS, SUBJECT-LEVEL ....................................................................................................... 12
EOS, STUDY-LEVEL.......................................................................................................... 12
VISIT WINDOWS ................................................................................................................... 12
STUDY POPULATION ..................................................................................... 13
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 2 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
8.
EFFICACY ANALYSES .................................................................................... 13
8.1
8.2
8.3
8.4
PRIMARY EFFICACY ANALYSIS ............................................................................................ 13
SECONDARY EFFICACY ANALYSES ...................................................................................... 14
EXPLORATORY EFFICACY ANALYSIS ................................................................................... 14
STATISTICAL METHODOLOGY FOR EFFICACY ANALYSES .................................................... 14
8.4.1
8.4.2
8.4.3
9.
SURVIVAL ANALYSES ....................................................................................................... 14
CHANGE FROM BASELINE ANALYSES ............................................................................... 19
MULTIPLICITY ................................................................................................................... 19
SAFETY ANALYSES ......................................................................................... 19
9.1
9.2
9.3
PRIMARY ANALYSIS DATA CUTOFF SAFETY PARAMETERS ................................................. 19
STUDY-LEVEL EOS SAFETY PARAMETERS .......................................................................... 20
STATISTICAL METHODOLOGY FOR SAFETY ANALYSES ....................................................... 20
10.
DATA MONITORING COMMITTEE ............................................................ 20
11.
CLINICAL ENDPOINTS COMMITTEE........................................................ 21
12.
SEQUENCE OF PLANNED ANALYSES ....................................................... 21
12.1
12.2
12.3
13.
INTERIM ANALYSES ............................................................................................................. 21
PRIMARY ANALYSIS ............................................................................................................. 21
STUDY-LEVEL EOS ANALYSES ........................................................................................... 21
REFERENCES .................................................................................................... 21
FIGURES
Figure 1. Schematic Diagram of Study ............................................................................... 9
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 3 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
Abbreviations, Acronyms, and Definitions
12-Month Active
Observation Period
Subject-level period from the day of investigational medicinal product
administration (Day 0) to completion of the 12-month visit or death,
transplant, LVAD, or permanent loss to follow-up prior to Month 12.
6MWT
6-Minute Walk Test
AAV
adeno-associated virus
AAV1
adeno-associated virus serotype 1
AE
adverse event, adverse experience
ANCOVA
analysis of covariance
βR
logarithm of the hazard ratio for recurrent events
βT
logarithm of the hazard ratio for terminal events
BNP
brain natriuretic peptide
CEC
Clinical Endpoints Committee
COMPANION
Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic
Heart Failure trial
CSR
Clinical Study Report
CUPID
Calcium Up-regulation by Percutaneous Administration of Gene
Therapy in Cardiac Disease trial
CV
Cardiovascular
DMC
Data Monitoring Committee
DNA
DRP
deoxyribonucleic acid
DNAase resistant particle
ECG
Electrocardiogram
ELISpot
enzyme-linked immunospot
EOS
End of Study
EOS, Study-Level
The point in time after the Primary Analysis Data Cutoff has been
reached and all subjects have completed a cumulative total of at least 24
months of follow-up since IMP administration
EOS, SubjectLevel
The point in time after the Primary Analysis Data Cutoff has been
reached and the subject has completed a cumulative total of at least
24 months of follow-up since Investigational Medicinal Product
Administration
exp
exponent of
HF
heart failure
HR
hazard ratio
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 4 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
Abbreviations, Acronyms, and Definitions
ICD
implantable cardioverter defibrillator
ICH
International Conference on Harmonization
IMP
investigational medicinal product
ITT
intent to treat
JFM
joint frailty model
KCCQ
Kansas City Cardiomyopathy Questionnaire
LTFU Period
Defined by subject and starts immediately after the subject completes
the 12-Month Active Observation Period and ends at the subject-level
End of Study.
LVAD
left ventricular assist device
MedDRA
Medical Dictionary for Regulatory Activities
MITT
modified intent to treat
NAb
neutralizing antibody
NT-proBNP
N-terminal prohormone brain natriuretic peptide
NYHA
New York Heart Association
PP
per protocol
Primary Analysis
Data Cutoff
The study-level point in time at which (1) all patients except those who
experienced a terminal event or were lost to follow-up have completed
the full 12-Month Active Observation Period and (2) at least 186
adjudicated HF-related hospitalizations and/or episodes of ambulatory
worsening HF have occurred. The Primary Analysis Data Cutoff is the
trigger for locking the clinical database, unblinding treatment
assignments, and performing all planned analyses.
PT
Preferred Term
SAE
serious adverse event
SAP
Statistical Analysis Plan
SERCA
sarcoendoplasmic reticulum Ca2+ ATPase
SERCA2a
2a isoform of SERCA
SOC
System Organ Class
TEAE
treatment-emergent adverse event
WHF
worsening heart failure
WHOdd
World Health Organization drug dictionary
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 5 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
1. PREFACE
This Statistical Analysis Plan (SAP) describes the planned statistical analyses and reporting
for Celladon Corporation (Celladon) Protocol Number CELL-004, entitled A Phase 2b,
Double-Blind, Placebo-Controlled, Multinational, Multicenter, Randomized Study Evaluating
the Safety and Efficacy of Intracoronary Administration of MYDICAR® (AAV1/SERCA2a) in
Subjects with Heart Failure, Version 6, Amendment 5 (CELL-004-V6-A5), dated 21 October
2013. It is a supplement to the clinical protocol, which should be referred to for details
regarding the study objectives and design.
This purpose of this phase 2b study is to assess the safety and efficacy of MYDICAR®
(AAV1/SERCA2a) in the treatment of patients with moderate to advanced heart failure due to
systolic dysfunction.
The structure and content of this SAP provides sufficient detail to meet the requirements
identified by the Food and Drug Administration (FDA) and International Conference on
Harmonisation (ICH) E9: Guidance on Statistical Principles in Clinical Trials.1,2 All work
planned and reported for this SAP will follow internationally accepted guidelines published
by the American Statistical Association for statistical practice. The following documents were
reviewed in preparation of this SAP:

Clinical Research Protocol CELL-004

ICH E9 Guidance on Statistical Principles for Clinical Trials

ICH E6 Guideline on Good Clinical Practice

ICH E8 General Considerations for Clinical Trials

ICH E3 Structure and Content of Clinical Study Reports
2. PURPOSE
The purpose of this SAP is to outline the analyses planned to support the completion of the
Clinical Study Report (CSR) for Protocol CELL-004. The planned analyses identified in this
SAP will be included in regulatory submissions and/or future manuscripts. Exploratory
analyses not identified in this SAP may be performed to support the clinical development
program. Any unplanned analyses performed but not identified in this SAP will be clearly
identified in the CSR.
3. STUDY OBJECTIVES, TREATMENTS AND ENDPOINTS
3.1 Objectives
The primary objective of this study is to determine the efficacy of a single intracoronary
infusion of 1 x 1013 DNAase resistant particles (DRP) MYDICAR® added to an optimal HF
regimen in patients with ischemic or non-ischemic cardiomyopathy and moderate to advanced
symptoms of HF by reducing the frequency of and/or delaying HF-related hospitalizations
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 6 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
and episodes of ambulatory worsening HF (WHF) (recurrent events) compared to placebotreated subjects. The target population for this study is moderate to advanced HF patients,
especially those with high risk of recurrent events. Based on published studies3-5, this
population is characterized by having either elevated N-terminal prohormone brain natriuretic
peptide (NT-proBNP)/BNP within 30 days of screening and/or a recent (within 6 months of
screening) hospitalization for HF.
Secondary objectives of the study include assessment of MYDICAR® safety.
3.2 Treatment Group Comparisons
Two treatment groups will be compared to each other: MYDICAR® and placebo.
3.3 Study Endpoints
3.3.1 Efficacy Endpoints
3.3.1.1 Primary Efficacy Endpoint
The primary efficacy endpoint is time-to-recurrent events, defined as adjudicated HF-related
hospitalizations and/or episodes of ambulatory WHF. Note: all clinical events defined as
efficacy endpoints from this point forward in the SAP refer to adjudicated events.
3.3.1.2 Secondary Efficacy Endpoint
The secondary efficacy endpoint is time to first terminal event, defined as all-cause death,
heart transplant, or left ventricular assist device (LVAD) implantation.
3.3.1.3 Efficacy Sensitivity Analyses Endpoints
3.3.1.4 Alternate Definitions of Recurrent and Terminal Events
The following alternate definitions of recurrent and terminal events will be analyzed to assess
the sensitivity of the primary and secondary efficacy analyses to the definitions of recurrent
and terminal events:

Recurrent events defined as HF-related hospitalizations, ambulatory WHF, LVAD
implantation, and/or heart transplant;

Recurrent events defined as HF-related hospitalizations only;

Recurrent events defined as all-cause hospitalizations and/or episodes of ambulatory
WHF;

Recurrent events defined as CV-related hospitalizations only;

Terminal events defined as all-cause death only;

Terminal events defined as all-cause death, urgent transplant, or LVAD.
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 7 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
3.3.1.5 Alternate Endpoints
Rather than analyzing time-to-recurrent events and time-to-first terminal event, the following
alternate endpoints will be analyzed:

Time-to-first clinical event, defined as HF-related hospitalization, episode of
ambulatory WHF, LVAD, transplant, or death;

Number of hospitalizations per patient-year;

Days of hospitalization per patient-year.
3.3.2 Exploratory Efficacy Endpoints
Exploratory efficacy endpoints will be changes from baseline in:

New York Heart Association (NYHA) class

6-Minute Walk Test (6MWT)

KCCQ

NT-proBNP
3.3.3 Safety Endpoints
Safety endpoints will include:

Subject disposition;

Time-to-cardiovascular (CV) related death;

AEs, including serious AEs (SAEs) and adjudicated clinical events;

Changes from baseline in safety laboratory evaluations, HF-related medications, vital
signs, physical examination findings, 12-lead electrocardiogram (ECG) parameters,
and implanted cardioverter defibrillator (ICD) interrogation parameters.
4. STUDY DESIGN
This is a phase 2b, multinational, multicenter, double-blind, placebo-controlled, randomized
study of a single intracoronary administration of 1 x 1013 DRP MYDICAR® versus placebo
added to an optimal HF regimen in the treatment of HF. Up to 250 adult patients with chronic
systolic HF due to ischemic or non-ischemic cardiomyopathy will be randomized in parallel
in a ratio of 1:1.
A schematic of the study design is shown in Figure 1 below.
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 8 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
The duration of long-term follow-up is variable for each subject. Each subject should be followed quarterly in the
Long-Term Follow-Up Period until End of Study. For some subjects enrolled early in the study, Long-Term FollowUp will continue past Month 24. This applies to any subject who completed or was discontinued from the 12-Month
Active Observation Period. Clinical events occurring during the Long-Term Follow-Up Period will be adjudicated
by the Clinical Endpoint Committee until End of Study.
Figure 1. Schematic Diagram of Study
Study visits will occur at Screening, Day 0 for IMP administration, and at Months 1, 3, 6, 9
and 12 for safety and efficacy assessments. After the 12-Month Active Observation Period,
subjects will be followed quarterly (e.g., Months 15, 18, 21, 24, etc.) in the Long-Term
Follow-Up (LTFU) Period for collection of information on clinical outcomes until death or
their (subject-level) EOS.
4.1 Randomization and Blinding
Subjects will be assigned in a 1:1 ratio to MYDICAR® or placebo. Randomization will be
stratified by country and the ability to walk between 150 to 425 meters in the 6MWT.
Subjects, all sponsor personnel, all site personnel performing direct care and assessments of
subjects, and the Clinical Endpoints Committee (CEC) (Section 11) will be blinded to
randomized treatment assignments until the Primary Analysis Data Cutoff is reached, all data
queries have been resolved, and the database has been locked for the primary analysis. The
DMC (Section 10) will be unblinded to treatment assignment throughout the study.
4.2 Sample Size
The sample size for this study was based on Monte-Carlo simulations. Up to 250 subjects
randomized with an estimated total of 186 recurrent events at a median follow-up time of
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 9 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
18 months will provide approximately 83% power at the 0.05 two-sided significance level to
detect at least a 45% risk reduction (hazard ratio [HR] of 0.55) based on the primary efficacy
analysis of time-to-recurrent events in the presence of terminal events. Simulation parameters
were based on 12-month and 3-year data from the previous phase 2 trial and a previously
published large HF clinical trial, COMPANION.6
5. ANALYSIS POPULATIONS
5.1 Intent-to-Treat Population
The Intent-to-Treat (ITT) Population will be all subjects who were randomized. Subjects will
be summarized and analyzed in the treatment group to which they were randomized,
regardless of the treatment they actually received.
5.2 Modified ITT Population
The Modified ITT (MITT) population will be all subjects in the ITT Population who received
the IMP.
5.3 Per Protocol Population
The Per Protocol (PP) population will be subjects in the ITT Population with no major
protocol violations (including early unblinding). The list of subjects in the PP Population will
be compiled in a blinded fashion prior to database lock.
5.4 Safety Population
The Safety Population will be the same as the MITT Population.
6. CONSIDERATIONS FOR DATA HANDLING, PRESENTATION, AND
ANALYSIS
6.1 Programming Environment
SAS® version 9.3 or higher (SAS Institute, Cary, NC) will be used for statistical analyses and
the production of tables, figures, and listings.
6.2 Tables, Figures, and Listings
6.2.1 Tables and Figures

Tables and figures will present data summaries and/or analyses for the appropriate
study population; e.g., summaries of safety parameters will be shown for the Safety
Population only.
6.2.2 Listings

Listings will present all data collected for subjects in the ITT Population.
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 10 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
6.3 Data Analysis

Categorical variables will be summarized as frequencies and percentages in each
category. Percentages will be reported to one decimal place.

Continuous variables will be summarized by numbers of subjects, means, standard
deviations, medians, and ranges.

All statistical tests will be two-sided.

All statistical hypotheses will be tested at the 0.05 significance level.
6.4 Missing Data

Listings will present data as reported.

Missing or partially missing dates that are required for date-dependent definitions
(e.g., treatment-emergent AEs, concomitant medications) will be assumed to be the
most conservative date possible.
6.5 Study Period and Time Point Definitions
6.5.1 Screening Period
The Screening Period is defined by subject as the 30 days prior to IMP administration.
6.5.2 Baseline
Baseline is defined by subject as immediately prior to IMP administration. A baseline
observation is the last non-missing observation prior to IMP administration.
6.5.3 Day 0
Day 0 is defined by subject as the day of IMP administration.
6.5.4 12-Month Active Observation Period
The 12-Month Active Observation Period is defined by subject as the period from IMP
administration (Day 0) to completion of the Month 12 study visit, terminal event during the
first 12 months, or permanent loss to follow-up during the first 12 months after IMP
administration. Subjects who are still alive and not lost to follow-up at the end of the 12Month Active Observation Period will be rolled over into the LTFU Period (see
Section 6.5.5).
6.5.5 LTFU Period
The LTFU Period is defined by subject and starts immediately after the subject completes the
12-Month Active Observation Period and ends at their subject-level EOS (see Section 6.5.7).
The purpose of the LTFU Period is to monitor for delayed toxicity that might be associated
with gene transfer. Subjects must complete a minimum cumulative total of 24 months of
observation/follow-up (time in the 12-Month Active Observation Period plus time in the
LTFU Period).
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 11 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
6.5.6 Primary Analysis Data Cutoff
The Primary Analysis Data Cutoff is declared at the study level when:
1. All subjects have completed the full 12-Month Active Observation Period; and
2. A total of at least 186 adjudicated HF-related hospitalizations and/or episodes of
ambulatory WHF have occurred.
The Primary Analysis Data Cutoff is the trigger for locking the clinical database, unblinding
the treatment assignments, and performing all planned analyses.
6.5.7 EOS, Subject-Level
EOS is declared at the subject-level after the Primary Analysis Data Cutoff has been reached
and the subject has completed a cumulative total of at least 24 months of observation/followup since IMP administration. Subjects can reach their EOS before the overall study is
completed (see Section 6.5.8).
6.5.8 EOS, Study-Level
EOS at the study level is declared after the Primary Analysis Data Cutoff has been reached
and all subjects have reached the end of their LTFU period; i.e., have each completed a
cumulative total of at least 24 months of follow-up since IMP administration.
6.6 Visit Windows
Study visits will include Screening, Baseline, Day 0 and nominal months indicated in Table 1
below. Visit windows will be used in the analysis of this study and will be based on number
of relative days, defined as:
Number of relative days = date of observation – Day 0 date + 1
Visit windows per protocol and to be used in analyses are shown in Table 1.
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 12 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
Table 1. Study Time Point Relative Day Ranges and Minimum/Maximum Days for
Analyses
Nominal Visit
(months)
1
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
Nominal
Day
31
92
183
274
366
457
548
640
731
822
914
1005
1096
1188
1279
1370
1461
Min Day Per
Protocol
24
85
176
267
359
443
534
626
717
808
900
991
1082
1174
1265
1356
1447
Max Day Per
Protocol
38
99
190
281
373
471
562
654
745
836
928
1019
1110
1202
1293
1384
1475
Min Day for
Analyses
1
63
139
230
321
409
504
595
687
778
869
961
1052
1143
1235
1326
1417
Max Day for
Analyses
62
138
229
320
408
503
594
686
777
868
960
1051
1142
1234
1325
1416
1507
7. STUDY POPULATION
The ITT Population will be used for listings and summaries of study population parameters.
Some listings and summaries may also be done for the MITT and/or PP populations. The
study population will be described in terms of subject disposition; analysis populations; dates
of screening, informed consent, randomization, and IMP administration; other details of IMP
administration; satisfaction of inclusion/exclusion criteria and inclusion/exclusion waivers
granted; demographics, HF etiology, medical history (CV and non-CV), results of chest x-ray
and angiography at Screening; dates of completion of study visits and study periods; and
protocol violations and deviations.
8. EFFICACY ANALYSES
The ITT Population will be used for listings of efficacy parameters. Efficacy summaries and
analyses will be done for the ITT, MITT and PP populations. Efficacy will be described in
terms of clinical events, hospitalization rates and duration, NYHA class, 6MWT, KCCQ, and
NT-proBNP.
8.1 Primary Efficacy Analysis
The primary efficacy analysis will be the estimation of treatment effect on the primary
efficacy endpoint, time-to-recurrent events defined as HF-related hospitalizations and/or
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 13 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
episodes of ambulatory WHF, in the ITT Population at the Primary Data Analysis Cutoff. The
null and alternative hypotheses for the primary efficacy analysis are:
Ho: βR = 0
HA: βR < 1
where exp(βR) is the recurrent event HR for MYDICAR® compared to placebo.
Occurrence, timing, and frequency of HF-related hospitalizations, episodes of ambulatory
WHF, and all other clinical events will be presented as listings, summary tables, and/or
graphical displays.
8.2 Secondary Efficacy Analyses
Secondary efficacy analyses will comprise the secondary efficacy endpoint analysis as well as
analyses of both the primary and secondary endpoints in alternate analysis populations and at
different study time points.
The secondary efficacy endpoint is time-to-first terminal event defined as all-cause death,
transplant, or LVAD implantation. The null and alternative hypotheses for analysis of the
secondary efficacy endpoint are:
Ho: βT = 0
HA: βT < 1
where exp(βT) is the terminal event HR for MYDICAR® compared to placebo.
8.3 Exploratory Efficacy Analysis
Exploratory efficacy endpoints will be change from baseline in NYHA class, 6MWT, KCCQ,
and NT-proBNP.
8.4 Statistical Methodology for Efficacy Analyses
8.4.1 Survival Analyses
The semi-parametric JFM will be used to estimate the recurrent event HR in the presence of
terminal events, i.e., informative censoring, and to simultaneously estimate the terminal event
HR. Observation ends for subjects who experience a terminal event. Subjects who do not
experience a terminal event by the analysis cutoff time point are censored at that time point.
Subjects lost to follow-up before the analysis cutoff time point are censored at the time of last
contact. A recurrent event and a terminal event cannot happen at the same time; e.g., if a
subject gets a heart transplant during a hospitalization, the heart transplant will be counted as
a terminal event and the hospitalization will not be counted. The JFM will be implemented
using the SAS® procedure NLMIXED.7
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 14 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
8.4.1.1 Statistical Model Background and Rationale
The study objective is to demonstrate the safety and efficacy of a single intracoronary
infusion of 1 x 1013 DRP MYDICAR® in patients with ischemic or non-ischemic
cardiomyopathy and moderate to advanced symptoms of HF by reducing the frequency and/or
delaying recurrent events (HF-related hospitalizations and/or ambulatory WHF) compared to
placebo-treated subjects.
Several aspects of the moderate to advanced HF patient population may complicate the
estimation of treatment effect on disease-related events. This patient population is
characterized by frequent HF-related hospitalizations, high mortality and continued worsening
of the disease, often leading to surgical interventions such as LVAD implantation and/or heart
transplant. Patients who are hospitalized or experience ambulatory WHF may be at an
increased risk of additional occurrences of these events. Therefore, recurrent events within a
patient may not be independent. Patients with high recurrent event rates may also have
increased risk of terminal events; i.e., risks of recurrent and terminal events are likely to be
correlated and may need to be jointly estimated to avoid biased estimates of treatment effect.
Further, terminal events in this context represent informative censoring, a violation of one of
the assumptions of traditional survival analysis. Other challenges include the possibility that
the impact of a treatment on the risk of recurrent events may be different than on the risk of a
terminal event, and random between-patient variations (unobserved covariates) may impact
treatment outcomes. The semi-parametric JFM addresses these challenges.
The JFM accommodates:

Multiple outcomes within subjects by accounting for the resulting within-subject
correlation through the estimation of a subject-specific frailty parameter, thereby
avoiding underestimation of the treatment effect variance.

Within-subject correlation between recurrent and terminal events by modeling the
subject-specific frailty parameter that is shared between recurrent and terminal event
processes and is further described by an estimated frailty coefficient that allows
frailties to have differing effects on recurrent and terminal events.

The competing risk of terminal events in the analysis of recurrent events (subjects who
are “censored” due to a terminal event can theoretically no longer experience a
recurrent event).

Simultaneous estimation of treatment effect on terminal events.

Differential treatment effect for recurrent and terminal events.
Following the model of Liu, et al., 20047, and as specified in Rondeau, et al., 20108, the joint
frailty model for the hazard functions for recurrent and terminal events, respectively, is:
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 15 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
𝑟𝑖 (𝑡|𝜔𝑖 ) = 𝜔𝑖 𝑟0 (𝑡) 𝑒𝑥𝑝(𝛽1′ 𝑍𝑖 (𝑡)) = 𝜔𝑖 𝑟𝑖 (𝑡)
{
𝜆𝑖 (𝑡|𝜔𝑖 ) = 𝜔𝑖𝛼 𝜆0 (𝑡)𝑒𝑥𝑝(𝛽2′ 𝑍𝑖 (𝑡)) = 𝜔𝑖𝛼 𝜆𝑖 (𝑡)
where:
𝜔𝑖 = patient-specific frailty allowing for random between-subject differences in baseline
hazards due to unobserved covariates, assumed to be independently gamma-distributed with
mean 1 and variance θ;
𝑟𝑖 = recurrent events hazard function for the i-th patient conditioned on 𝜔𝑖 (frailty is shared
between recurrent and terminal events);
𝜆𝑖 = terminal events hazard function for the i-th patient conditioned on 𝜔𝑖 ;
𝛽1′ , 𝛽2′ = covariate coefficients for recurrent and terminal events, respectively;
𝑍𝑖 = covariate value (e.g., treatment group) for the i-th patient;
α = frailty coefficient allowing for differential effects of 𝜔𝑖 on recurrent and terminal events.
8.4.1.2 Sensitivity Analyses
A series of sensitivity analyses will be conducted using the ITT population. Statistical
significance of treatment effects using alternative approaches will not be required.
8.4.1.2.1 Alternative Definitions of Recurrent and Terminal Events
The following JFM analyses will be done to evaluate the effect of alternative definitions of
recurrent and terminal events:
1. Sensitivity Analysis #1
a. Recurrent events defined as HF-related hospitalizations, ambulatory worsening
HF, LVAD implantation, and heart transplant.
b. Terminal events defined as death only.
c. Two different ending time points (subjects still alive at the ending time point
will be censored):
i. Primary Analysis Data Cutoff
ii. Study-level EOS (subjects still alive will be censored)
2. Sensitivity Analysis #2
a. Recurrent events defined as HF-related hospitalizations only.
b. All other specifications are the same as primary efficacy analysis.
3. Sensitivity Analysis #3
a. Recurrent events defined as all-cause hospitalizations and ambulatory WHF.
b. All other specifications are the same as primary efficacy analysis.
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 16 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
4. Sensitivity Analysis #4
a. Recurrent events defined as CV-related hospitalizations only.
b. All other specifications are the same as primary efficacy analysis.
5. Sensitivity Analysis #5
a. Terminal events defined as death, LVAD implantation and adjudicated urgent
heart transplant. If a subject has status other than 1A or 1B on the transplant
list or an equivalent priority system, the subject will be censored at the time of
transplant.
b. All other specifications are the same as primary efficacy analysis.
6. Sensitivity Analysis #6
a. Terminal events defined as death only. Subjects receiving heart transplants or
LVAD implantations will be censored at the time of surgery. Note: this differs
from the primary efficacy analysis in that transplant and LVAD subjects are
censored rather than terminated, meaning future clinical events may occur but
will not be observed.
b. All other specifications are the same as primary efficacy analysis.
8.4.1.2.2 Alternative Analytical Methods
All of the following analyses will be done at the Primary Analysis Data Cutoff only.
7. Sensitivity Analysis #7
a. Treatment effect on recurrent events will be analyzed using both a nonparametric approach9 and a semi-parametric marginal model10 developed by
Ghosh and Lin.
8. Sensitivity Analysis #8
a. Three “time-to-first” analyses will be done:
i. Time-to-first terminal event (all-cause death, heart transplant, or
LVAD);
ii. Time-to-first clinical event, defined as all-cause death, heart transplant,
LVAD implantation, HF-related hospitalization, or ambulatory WHF;
iii. Time-to-all-cause death.
b. Product-limit estimates of median time-to-first event, including 95%
confidence intervals, will be calculated. The log-rank test will be used to
compare treatment groups.
9. Sensitivity Analysis #9
a. Number of hospitalizations per subject-year and days of hospitalization per
subject-year from randomization to the Primary Analysis Data Cutoff will be
analyzed using an appropriate analytical method depending on the variables’
distributions (e.g., Poisson regression).
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 17 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
b. Two categories of hospitalization will be considered:
i. HF-related
ii. All-cause
10. Sensitivity Analysis #10
a. In the analysis of the primary efficacy endpoint, a log-normal rather than a
gamma distribution for the frailty random variable in the JFM will be assumed.
11. Sensitivity Analysis #11
a. An “as randomized” analysis of the primary endpoint will be done in which the
randomization strata (country and ability to walk between 150 to 425 meters in
the 6MWT) will be included in the model as fixed-effect covariates. Countries
with very few subjects (< 10) may be combined with other countries with
similar HF management.
12. Sensitivity Analysis #12
a. Univariable analyses of the following covariates will be done to assess
confounding and modifying effects in the analyses of the primary and
secondary efficacy endpoints:
i. Geography (U.S., non-U.S.);
ii. HF etiology (ischemic/non-ischemic);
iii. NYHA Class (II vs. III/IV);
iv. Age at the time of signing informed consent (continuous and
categorized);
v. Intervention (e.g., percutaneous coronary intervention, coronary bypass
artery graft) performed during the first infusion attempt;
vi. The number (nevent) of recurrent events (from the time of
randomization) preceding any given recurrent event, initially set to 0
for each subject and increased by 1 for each recurrent event (nevent = 0
for the first event, nevent = 1 for the second event, etc.).
b. Confounding effects will be assessed both by evaluating changes in HRs with
and without the potential confounder as well as by subgroup analyses.
c. Treatment effect modification will be assessed by subgroup analyses. As this
study is not powered to statistically test for significant interactions or
equivalence, we will evaluate effect modification descriptively and consider
HRs in the same direction (i.e., both > 1 or both < 1) in each subgroup as
evidence that treatment is similar across subgroups.
d. Covariate effects on the secondary efficacy endpoint will also be assessed
using a Cox proportional hazards model.
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 18 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
13. Sensitivity Analysis #13
a. As efficacy may differ depending on AAV NAb status, the primary efficacy
endpoint at the Primary Analysis Data Cutoff will be analyzed both with and
without patients with baseline AAV NAb titers > 1:2 (positive) or with titers
< 1:2 that are classified as equivocal (although titer < 1:2 is a study inclusion
criterion, some patients with positive titer at Baseline may still be infused as
results from NAb samples taken immediately before infusion are not yet
known at the time of infusion). In addition, separate summaries of primary and
secondary efficacy endpoints will be done for patients with positive or
equivocal AAV NAb titers.
b. The primary efficacy endpoint will be analyzed at the Primary Analysis Data
Cutoff both with and without patients with positive AAV NAb titers at
Baseline, and separate summaries of primary and secondary efficacy endpoints
will be done for patients with positive AAV NAb titers.
8.4.2 Change From Baseline Analyses
Change from Baseline analyses of the exploratory efficacy endpoints 6MWT, KCCQ and NTproBNP will be done using analysis of covariance (ANCOVA) with the baseline observation
as the covariate. Change in NYHA class will be analyzed by comparing distributions of
change scores between treatment groups using a chi square test of association (or Fisher’s
exact test if any change category within treatment group contains less than 5 subjects).
8.4.3 Multiplicity
Although the JFM estimates treatment effect on both recurrent and terminal events
simultaneously, this study has a single primary efficacy endpoint: time-to-recurrent events.
Therefore, no multiplicity adjustment is required.
9. SAFETY ANALYSES
The Safety Population will be used for listings, summaries and analyses of safety parameters.
Safety will be assessed at the Primary Analysis Data Cutoff and at study-level EOS.
9.1 Primary Analysis Data Cutoff Safety Parameters
Safety parameters at the Primary Analysis Data Cutoff will include subject disposition; timeto-CV-related death; AE incidence, severity, and relationship to IMP and IMP administration;
time-to-first serious AE (SAE); changes from Baseline in safety laboratory evaluations, vital
signs, physical examination findings, and 12-lead ECG parameters; ELISpot assay results
(negative/positive); concomitant medications, including changes from Baseline in HF-related
medications; concomitant medical/surgical procedures; ELISpot assay; and ICD
interrogations.
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 19 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
AEs will be coded according to MedDRA® (Medical Dictionary for Regulatory Activities).
Each reported AE will be mapped to a Preferred Term (PT) and a System Organ Class (SOC).
A treatment-emergent AE (TEAE) will be defined as an AE that began or worsened during or
after IMP administration. AEs recorded prior to IMP administration will be considered nontreatment-emergent. AEs with insufficient date or time information to determine whether or
not they were treatment-emergent will be considered treatment-emergent.
Prescription, over-the-counter, and alternative medication use will be coded to generic terms
using the World Health Organization drug dictionary (WHOdd). Medications that were
stopped before IMP administration will be considered “pre-infusion.” All other medications
will be considered “concomitant.” Medications recorded with insufficient exposure dates to
determine whether or not they were concomitant will be considered concomitant.
9.2 Study-Level EOS Safety Parameters
Safety parameters to be assessed at study-level EOS will include subject disposition,
adjudicated clinical events and responses to an in-person questionnaire designed to ascertain
new conditions and exacerbations of existing conditions.
9.3 Statistical Methodology for Safety Analyses
For all statistical analyses of safety parameters, it is understood that non-significance is not
synonymous with equality.
Time-to-CV-related death and time-to-first SAE will be compared between treatment groups
using product-limit estimates of median survival times with 95% confidence intervals and will
be graphically presented using Kaplan-Meier step function plots; p-values from log-rank tests
will be reported. In CV-related death analyses, subjects still alive at the data cutoff will be
censored at that time point and subjects who died from non-CV reasons prior to the data
cutoff will be censored at their death dates. In the SAE analysis, subjects with no reported
SAEs at the data cutoff will be censored. In both analyses, subjects lost to follow up will be
censored at the date of last contact.
10. DATA MONITORING COMMITTEE
Unblinded DMC reviews will be conducted at periodic, pre-specified milestones of the study.
The DMC will be advisory to the sponsor. The sponsor will be responsible for reviewing the
DMC recommendations promptly, to decide whether to continue or terminate the trial, and to
determine whether amendments to the protocol or changes in study conduct are required.
Study termination based on findings from the DMC can only be due to safety issues. The
study will not be terminated due to efficacy, even if recommended by the DMC, because
subject follow-up data must be acquired to fulfill the safety requirements of the study. The
DMC will be an independent multidisciplinary group consisting of at least three individuals,
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 20 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
one of whom one must be an interventional cardiologist, one a cardiologist with expertise in
HF, and one a statistician.
11. CLINICAL ENDPOINTS COMMITTEE
A blinded CEC will be established to review clinical events for adjudication in a consistent
and unbiased manner throughout the course of the study; i.e., the CEC will ensure that all
clinical events that are reported by sites are judged uniformly, using the same criteria across
all sites and throughout the study. No member from the sponsor or the sponsor’s agents,
consultants or designees will be allowed to be present during the CEC deliberations. All
policies and procedures will be specified in the written CEC Manual of Operations (or
equivalent).
12. SEQUENCE OF PLANNED ANALYSES
12.1 Interim Analyses
There are no planned interim analyses.
12.2 Primary Analysis
At the time of the Primary Analysis Data Cutoff and after the clinical database has been
quality-checked and cleaned, the database will be locked.
12.3 Study-Level EOS Analyses
Analyses that require all subjects to reach EOS (i.e., select safety and sensitivity analyses)
will be done at study-level EOS using the locked, unblinded database.
13. REFERENCES
1.
E9 Guidance on Statistical Principles in Clinical Trials. International Conference on
Harmonisation (ICH); 1998.
2.
Guidance for Industry: E9 Statistical Principles for Clinical Trials. Food and Drug
Administration: Center for Drug Evaluation and Research (CDER) and Center for
Biologics Evaluation and Research (CBER); 1998.
3.
Packer M. Effect of Carvedilol on the Morbidity of Patients With Severe Chronic
Heart Failure: Results of the Carvedilol Prospective Randomized Cumulative Survival
(COPERNICUS) Study. Circulation 2002;106:2194-9.
4.
Fonarow G, Committee. ASA. The Acute Decompensated Heart Failure National
Registry (ADHERETM): Opportunities to Improve Care of Patients Hospitalized With
Acute Decompensated Heart Failure. Rev Cardiovasc Med 2003;4:S21-30.
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 21 of 22
Celladon CUPID Phase 2b CELL-004
Abbreviated Statistical Analysis Plan Version 3, 26 November 2013
5.
Rogers J, McMurray J, Pocock SJ, et al. Eplerenone in Patients With Systolic Heart
Failure and Mild Symptoms: Analysis of Repeat Hospitalizations. Circulation
2012;126:2317-23.
6.
Anand IS, Carson P, Galle E, et al. Cardiac resynchronization therapy reduces the risk
of hospitalizations in patients with advanced heart failure: results from the
Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure
(COMPANION) trial. Circulation 2009;119:969-77.
7.
Liu L, Wolfe R, Huang X. Shared Frailty Models for Recurrent Events and a Terminal
Event. Biometrics 2004;60:747-56.
8.
Rondeau V. Statistical models for recurrent events and death: Application to cancer
events. Mathematical and Computer Modelling 2010;52:949-55.
9.
Ghosh D, Lin DY. Nonparametric analysis of recurrent events and death. Biometrics
2000;56:554-62.
10.
Ghosh D, Lin D. Marginal regression models for recurrent and terminal events.
Statistica Sinica 2002;12:663-88.
2012-2013 Celladon Corporation. Printed in USA. All rights reserved.
CELLADON CORP.
Page 22 of 22