Conditions: Heart Failure Heart Failure With Reduced Ejection Fraction Heart Failure With Preserved Ejection Fraction Cardiovascular Diseases Heart Diseases
Keywords: PDE9 Heart Failure CRD-740 HFpEF HFrEF
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: no

Brief summary:
This is a study evaluating the effectiveness of CRD-740 in patients with either Heart Failure with Reduced Ejection Fraction (HFrEF) or Heart Failure with Preserved Ejection Fraction (HFpEF) after 12 weeks of treatment. The primary objective in Part A is to assess the effect of CRD-740 compared to placebo in plasma cGMP at Week 4 in HFrEF.

Part B of the study was not conducted in favor of redesigned new studies.

Detailed description:

Arms:
arm 1: Part A: Participants in Part A randomly assigned to this arm will take CRD-740 at two ascending dose levels over 12 weeks. arm 2: Part A: Participants in Part A randomly assigned to this arm will take placebo at two ascending dose levels over 12 weeks.

Interventions: intervention 1: CRD-740 intervention 2: Placebo
Intervention descriptions: intervention 1: Tablets administered orally. intervention 2: Tablets administered orally.

Protocol document:
Prot_000.pdf: 
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Protocol 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Clinical Study to 
Assess the Effectiveness of CRD-740 in Subjects with Chronic Heart Failure  
Protocol Status: Final 
Protocol Version: 2.1, Date: 10 AUG 2022 
Investigational Product: CRD-740 
Protocol Reference Number: CRD-740-201 
IND Number: 157183 
EU CT number: 2022-500087-36-00 
 
 
Sponsor: 
Cardurion Pharmaceuticals, Inc. 
78 Blanchard Road, Suite 200 
Burlington, MA 01803 
 
 
 
 
Sponsor Signatory: 
 
Executive Director, Clinical Research 
 
Medical Monitor: 
 
Tel: +40728844418 
 
 
 
 
 
 
 
 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
 


 
 
 
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SPONSOR APPROVAL 
I have read the following and approve: 
 
 
 
 
 
 
 
 
 
Date 
Executive Director, Clinical Research 


 
 
 
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INVESTIGATOR AGREEMENT 
I have read the following protocol and agree to conduct the study as described herein. 
 
 
 
 
 
 
 
[Name, Qualification(s)] 
 
Date 
Principal Investigator 
 
















 
 
 
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7. Women of childbearing potential must use a double contraception method including a 
highly effective method of birth control from screening up to 1 month after the last 
dose. Accepted double contraception methods include the use of intrauterine device or 
hormonal contraception in addition to 1 of the following contraceptive options: (1) 
condom; or (2) diaphragm or cervical/vault cap. Female subjects who are monogamous 
with male partners who have had a documented vasectomy is also an accepted method 
of birth control. 
8. Male subjects with female partners of child bearing potential must agree to use highly 
effective contraceptive measures from the screening visit through 3 months after the 
last dose of study medication. Highly effective contraceptive measures include 
documented vasectomy, abstaining from sexual intercourse, double-barrier method 
(e.g., male using a condom and female using a diaphragm or cervical cap), or barrier 
plus hormonal contraception (e.g., male using a condom and female using hormonal 
contraception or intrauterine device). As there may be a risk of drug being secreted in 
the ejaculate, male subjects (including men who have had vasectomies) whose partners 
are currently pregnant should use barrier methods for the duration of the study and for 
3 months after the last dose of study medication. Male subjects with female partners 
that are confirmed as post-menopausal are not required to use contraceptive measures. 
Exclusion criteria: 
1. 
 
2. Recent HF exacerbation defined by hospitalization or requirement for intravenous 
diuretics within 60 days of screening.  
3. Symptomatic hypotension or uncontrolled hypertension (multiple readings with 
systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg) at the 
screening or baseline visit. 
4. History of seizure disorder or subjects considered to be at increased risk for seizures. 
5. Any ECG abnormality that, in the judgment of the investigator, poses a risk to subject 
safety or impact the validity of study results. 
6. Subjects with planned interventions (e.g., percutaneous coronary intervention, devices) 
etc. occurring during their involvement in this study.  
7. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other 
major cardiovascular surgery or carotid angioplasty within 60 days of screening. 
8. Subjects with clinical suspicion of infiltrative cardiomyopathy (e.g., amyloid, sarcoid), 
hypertrophic cardiomyopathy (obstructive or non-obstructive), or HF secondary to 
severe valvular disease, active myocarditis, active pericarditis, or clinically significant 
congenital heart disease.  
9. Prior or planned orthotopic heart transplantation. 
10. Presence of or plan for mechanical circulatory support. 
11. Chronic treatment with phosphodiesterase (PDE)-5 inhibitors (e.g., Viagra, Cialis, 
Revatio, and Adcirca). 












 
 
 
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LIST OF TABLES 
Table 1: Estimands for primary objectives for Part A ................................................................................ 30 
 
Table 3: Part A, dose ranging, sample sizes, no caps ................................................................................. 52 
 
LIST OF FIGURES 
Figure 1: Study schematic of Part A ........................................................................................................... 36 
 
 


 
 
 
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LIST OF ABBREVIATIONS 
Abbreviations 
Definitions 
ACE 
angiotensin-converting enzyme 
AE 
adverse event  
ANCOVA 
analysis of covariance 
aPTT 
activated partial thromboplastin time 
ARB 
angiotensin II receptor blocker 
AUC0-last 
area under the plasma concentration-time curve from time zero to the 
time of last measurable concentration 
AUC0-8h 
area under the plasma concentration-time curve from time zero to 8 
hours 
AUCss 
steady-state area under the plasma concentration-time curve  
AUCtau 
area under the plasma concentration-time curve over a dosing interval  
  
 
BNP 
b-type natriuretic peptide 
CFR 
Code of Federal Regulations  
cGMP 
cyclic guanosine monophosphate  
CHF 
chronic heart failure 
CHFpEF 
chronic heart failure with preserved ejection fraction  
CHFrEF 
chronic heart failure with reduced ejection fraction  
CI 
confidence interval 
CL/F 
apparent total body clearance 
Cmax 
maximum observed plasma concentration  
CNP 
c-type natriuretic peptide 
CRO 
contract research organization  
CSA 
clinical study agreement 
CSF 
cerebrospinal fluid 
CYP3A4 
cytochrome P450 3A4 
DMC 
data monitoring committee  
EAE 
emergent adverse event 
EC 
ethics committee  
ECG 
electrocardiogram 
eCRF 
electronic case report form  
EDC 
electronic data capture  


 
 
 
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Abbreviations 
Definitions 
EF 
ejection fraction  
GCP 
Good Clinical Practice  
GC-B 
guanylate cyclase type B receptor 
HF 
heart failure  
HFpEF 
heart failure with preserved ejection fraction 
HFrEF 
heart failure with reduced ejection fraction 
ICF 
informed consent form  
ICH 
International Council for Harmonisation  
IC50 
half maximal inhibitory concentration 
IMP 
INR 
investigational medicinal product  
international normalized ratio 
IRB 
institutional review board 
ITT 
Intention to Treat  
IWRS 
interactive web-based response system  
KCCQ-23 
Kansas City Cardiomyopathy Questionnaire-23  
KCCQ-23-CS 
KCCQ-23 clinical summary score 
KCCQ-23-OS 
KCCQ-23 overall summary score 
mITT 
modified Intention to Treat 
MMRM 
mixed model for repeated measures 
NO 
nitric oxide 
NP 
natriuretic pathway  
NT-proBNP  
N-terminal pro b-type natriuretic peptide 
OS 
Overall Score  
PDE 
phosphodiesterase 
PK 
pharmacokinetic(s) 
PKGI 
protein kinase GI 
PP 
per protocol  
PT 
Racc(AUCtau) 
prothrombin time 
accumulation ratio for AUCtau  
Racc(Cmax) 
accumulation ratio for Cmax 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sGC 
soluble guanylate cyclase 


 
 
 
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Abbreviations 
Definitions 
SGLT-2  
sodium-glucose transport protein 2 
TAC 
transaortic constriction 
tmax 
time to reach Cmax  
ULN 
upper limit of normal 
  


 
 
 
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1. INTRODUCTION 
CRD-740 is phosphodiesterase (PDE)-9 inhibitor being investigated for the treatment of chronic 
heart failure (CHF). Refer to the investigator’s brochure 1 for detailed information concerning the 
available pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) 
profile of this investigational medicinal product (IMP).  
1.1. 
Background and Study Rationale 
Both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved 
ejection fraction (HFpEF) are major health problems with a significant impact on morbidity, 
mortality, quality of life, and healthcare costs. They are leading global causes of hospitalizations, 
and despite treatment advances, 5-year mortality rates remain approximately 50% within 5 years 
of first diagnosis. New therapeutics that reduce morbidity and mortality in heart failure (HF) are 
needed. 
 
The cyclic guanosine monophosphate (cGMP)/protein kinase GI (PKGI) signaling pathway plays 
a critical role in cardiovascular pathophysiology. PKGI activation inhibits cardiac hypertrophy 
and remodeling and, therefore, is a rational target for potential new therapies in the treatment of 
HF 2. In the cardiomyocyte, signaling through the cGMP/PKGI pathway is achieved via 4 
hormones; nitric oxide (NO) and 3 natriuretic peptides (atrial natriuretic peptide, b-type 
natriuretic peptide [BNP], and c-type natriuretic peptide [CNP]) acting through 3 receptors 
located in different subcellular regions 3. NO acts through the soluble guanylate cyclase (sGC) 
receptor located in the cytoplasm whereas CNP acts through the guanylate cyclase type B 
receptor (GC-B) located in the cell membrane. NO and CNP are secreted by the endothelial cells. 
Atrial natriuretic peptide and BNP are produced within the cardiomyocyte and act through the 
guanylate cyclase type A receptor (GC-A) which spans the plasma membrane. Stimulation of 
guanylate cyclase results in the conversion of guanosine triphosphate to cGMP. 
 
cGMP is a second messenger molecule that transduces NO- and natriuretic-peptide-coupled 
signaling, stimulating phosphorylation changes by protein kinase G. cGMP generally has a 
protective function on the heart, attenuating adverse remodeling 3. The breakdown or hydrolysis 
of cGMP can occur under the action of 2 enzymes, PDE-5 and PDE-9. PDE-5 acts primarily in 
the vasculature and its inhibitors have been shown to be beneficial in both erectile dysfunction 
and pulmonary arterial hypertension; however, the role of PDE-5 in the myocardium is 
uncertain. The IMP, CRD-740, is a PDE-9 inhibitor. 
 
In pilot pharmacology studies in a mouse model of HF (transaortic constriction [TAC] model), 
both PDE-5 and PDE-9 were shown to be capable of reversing remodeling effects commonly 
found in HF. PDE-9 was also identified as the PDE that controls NO independent cGMP 
generated by the natriuretic peptide receptor signaling pathway 4. 
 
In studies done in the presence of an inhibitor of the NO-sGC pathway, L-NAME (which inhibits 
NO production by NO synthase and therefore, activation of the sGC), removal of the effects of 
PDE-5 and the NO-sGC pathway revealed that PDE-9 inhibition was independently efficacious 
in preventing HF. The increased oxidative stress and reactive oxygen species commonly present 
in cardiovascular disease result in uncoupling of NO synthase and low levels of bioavailable NO 












 
 
 
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• To assess the effect of CRD-740 compared to placebo on plasma cGMP to NT-proBNP 
 
 
 
 
 
 
 
 
 
2.2. 
Endpoints 
2.2.1. 
Primary Efficacy 
Part A: 
• The change from baseline (Day -1) in plasma cGMP at Week 4. 
 
 
  
2.2.2. 
Primary Safety 
Part A only: 
• AEs 
• Physical examinations 
• Vital signs 
• 12-lead ECGs 
• Laboratory safety tests (biochemistry, urinalysis, and hematology) 
 
 
 
 
 
 
 




















 
 
 
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The maximum planned dose in this clinical study is 
, which is expected to 
provide a mean Cmax of 
 
 
While it is not definitively known what the minimum percentage of enzyme inhibition is needed 
to demonstrate effectiveness of CRD-740 in HF, nonclinical data and clinical data support that 
an exposure above the half maximal inhibitory concentration (IC50) for PDE-9 will be required. 
The dose regimens of 
 of CRD-740 are expected to achieve exposures 
above the IC50 for PDE-9, providing margins above the IC50 that thoroughly explore the effect of 
PDE-9 inhibition while remaining well below a 10-fold margin to the no observed adverse effect 
level. 






 
 
 
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4.2. 
Exclusion Criteria 
Subjects will be excluded from the study if they satisfy any of the following criteria at the 
screening visit unless otherwise stated: 
 
2. Recent HF exacerbation defined by hospitalization or requirement for intravenous 
diuretics within 60 days of screening.  
3. Symptomatic hypotension or uncontrolled hypertension (multiple readings with systolic 
blood pressure >180 mmHg or diastolic blood pressure >110 mmHg) at the screening or 
baseline visit. 
4. History of seizure disorder, or subjects considered to be at increased risk for seizures. 
5. Any ECG abnormality that, in the judgment of the investigator, poses a risk to subject 
safety or impact the validity of study results. 
6. Subjects with planned interventions (e.g., percutaneous coronary intervention, devices) 
etc. occurring during their involvement in this study. 
7. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other 
major cardiovascular surgery or carotid angioplasty within 60 days of screening. 
8. Subjects with clinical suspicion of infiltrative cardiomyopathy (e.g., amyloid, sarcoid), 
hypertrophic cardiomyopathy (obstructive or non-obstructive), or HF secondary to severe 
valvular disease, active myocarditis, active pericarditis, or clinically significant 
congenital heart disease.  
9. Prior or planned orthotopic heart transplantation. 
10. Presence of or plan for mechanical circulatory support. 
11. Chronic treatment with PDE-5 inhibitors (e.g., Viagra, Cialis, Revatio, and Adcirca). 
12. Estimated glomerular filtration rate <30 mL/min/1.73m2 as measured by the simplified 
Modification of Diet in Renal Disease formula at screening. 
13. Hepatic impairment at screening defined as alanine aminotransferase/aspartate 
aminotransferase >3 x upper limit of normal (ULN) and/or total bilirubin >2 x ULN. 
14. Concomitant use of a drug that is a known, strong inhibitor or inducer of cytochrome 
P450 3A4 (CYP3A4). 
15. Concurrent participation in other clinical studies or receiving other investigational 
treatments within 30 days of randomization or within 5 half-lives of the other 
investigational treatment, whichever is longer. 


 
 
 
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16. In the judgment of the investigator, a history of alcohol or drug abuse which would 
interfere with the subject’s ability to adhere with protocol requirements. 
17. Has evidence of clinically significant cardiovascular, endocrine, gastrointestinal, 
hematologic, hepatic, immunologic, neurologic, oncologic, pulmonary, psychiatric, or 
renal disease or any other condition which, in the judgment of the investigator, is not 
explained by the diagnosis of HF and would jeopardize the safety of the subject or impact 
the validity of study results. 
18. History of malignancy, except subjects who have been disease-free for >5 years prior to 
screening or subjects whose only malignancy has been successfully treated basal or 
squamous cell skin carcinoma. 
19. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
human chorionic gonadotropin laboratory test. 
20. Women of childbearing potential, as defined in Inclusion Criterion #6, unless they are 
using contraception as defined in Inclusion Criterion #7. 
4.3. 
Discontinuation Criteria 
4.3.1. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently entered in the study because of failure to meet the inclusion/exclusion criteria, or 
any other reason. A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure subjects to meet the Consolidated Standards of Reporting Trials 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAEs. 
4.3.2. 
Re-screening 
Subjects who do not meet the criteria for participation in this study may be re-screened once if 
the reason for the original screen failure is believed not to be present again during the subsequent 
screening. Re-screened subjects will be assigned a new subject number.  
4.3.3. 
Temporary or Permanent Discontinuation of Study Treatment  
In rare instances, it may be necessary for a subject to temporarily interrupt or permanently 
discontinue the study drug. If a subject requires temporary interruption of the study drug, the 
study team should consult with the study medical monitor and sponsor. In this study, every 
attempt will be made to prevent missing data and to obtain complete follow-up of all subjects for 
the study duration. Investigators will be trained to minimize full withdrawals wherever possible. 
Subjects who permanently discontinue the study drug are not required to withdraw from the 
study. These subjects will be encouraged to remain in the study and asked to conduct the 
remaining study visits as outlined in the protocol. 


 
 
 
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4.3.4. 
Subject Discontinuation/Withdrawal from the Study  
Subjects may withdraw from the study at any time at his/her own request or may be withdrawn at 
any time at the discretion of the investigator for safety, behavioral, or administrative reasons. 
However, every effort should be made to retain the subject in the study. The reasons for subjects 
not completing the study will be recorded. 
If the subject withdraws consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. Additionally, subjects 
may request destruction of any samples taken and not tested. The investigator must document 
this in the site study records and notify the sponsor or its designee. 
Subjects who withdraw from the study will be asked to complete final study procedures (Visit 9 
for Part A 
) as described in the Schedule of Assessments (Appendix 4). All 
(S)AEs that are ongoing at the time of withdrawal will be followed up for 28 days, or until 
resolution or stabilization. 
4.3.5. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he/she repeatedly fails to attend scheduled visits 
and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to attend a required study visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of maintaining the assigned visit schedule 
and ascertain whether the subject wishes to and/or should continue in the study. 
• Before a subject is deemed lost to follow-up, the investigator or his/her designee must 
make every effort to regain contact with the subject (where possible, 3 telephone calls 
and, if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
4.3.6. 
Replacement Procedures 
Subjects who withdraw from the study will not be replaced.  
4.4. 
Study Termination 
The sponsor reserves the right to close a study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study site closure visit has been performed. Reasons for study termination may 
include, but are not limited to: 


 
 
 
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• AEs unknown to date (i.e., not previously reported in any similar investigational study 
drug clinical study with respect to their nature, severity, and/or duration) 
• Increased frequency and/or severity and/or duration of known, anticipated, or previously 
reported AEs (this may also apply to AEs defined at check-in as baseline signs and 
symptoms) 
• Medical or ethical reasons affecting the continued performance of the study 
• Difficulties in the recruitment of subjects 
• Cancelation of drug development. 
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. Reasons for the early 
closure of a study site by the sponsor or investigator may include, but are not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the institutional 
review board/ethics committee or local health authorities, the sponsor's procedures, or 
Good Clinical Practice guidelines 
• Inadequate recruitment of subjects by the investigator. 






 
 
 
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The IWRS will be programmed with blind-breaking instructions. The study blind may be broken 
if, in the opinion of the investigator, it is in the subject’s best interest to know the study drug 
assignment. If possible, the sponsor must be notified before the blind is broken unless 
identification of the study drug is required for a medical emergency in which the knowledge of 
the specific blinded study drug will affect the immediate management of the subject’s condition 
(e.g., antidote is available). In this case, the sponsor must be notified within 24 hours after 
breaking the blind. The date and reason that the blind was broken must be recorded in the source 
documentation and electronic case report form (eCRF), as applicable. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study treatment records, if any, at the site(s) to verify that randomization/dispensing has been 
done accurately. 
5.5. 
Treatment Compliance 
The study drug will be dispensed at the study visits in Parts A and B of this study, as summarized 
in the Schedule of Assessments (Appendix 4). Subjects will be instructed to follow the provided 
instructions to take the study drug. 
At the study visits in Parts A and B of this study, as summarized in the Schedule of Assessments 
(Appendix 4), subjects will be asked to return all used and unused drug supply containers.  
Accountability and subject compliance will be assessed by maintaining adequate drug dispensing 
and returning records. 


 
 
 
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6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the subject is receiving at the time of ICF signing onwards must 
be recorded along with: 
• reason for use 
• dates of administration including start and end dates 
• dosage information including dose and frequency 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Any medications, excluding those mentioned in Section 6.1.1, may be given concomitantly as 
needed for the subject’s welfare for treatment of comorbid conditions or potential AEs. 
At each visit in this study, the study staff will review use of concomitant medications with the 
subject and will record entries in the eCRF. 
6.1.1. 
Prohibited Concomitant Therapy 
Subjects may not be on the following drugs from the time of ICF signing onwards: 
• PDE-5 inhibitors (e.g., Viagra, Cialis, Revatio, and Adcirca) 
• Known strong inhibitors or inducers of CYP3A4. 
6.1.2. 
Contraception 
6.1.2.1. 
Female Subjects 
Female subjects of childbearing potential, as defined in Inclusion Criterion #6, will be required 
to follow contraception requirements as defined in Inclusion Criterion #7. 
6.1.2.2. 
Male Subjects 
Male subjects with female partners of child-bearing potential, or female partners who are 
pregnant will be required to follow contraception requirements as defined in Inclusion Criterion 
#8. 
6.1.2.3. 
Sexual Abstinence and Same-sex Relationships 
Subjects who practice true abstinence, which must be due to the subject’s lifestyle choice (i.e., 
the subject should not become abstinent just for the purpose of study participation), are exempt 
from contraceptive requirements. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 


 
 
 
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post-ovulation methods) and withdrawal are not acceptable methods of contraception. If a 
subject who is abstinent at the time of signing the ICF becomes sexually active, they must agree 
to use contraception as described previously. 
For subjects who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. If a subject who is in a same-sex relationship at the time of signing the ICF becomes 
engaged in a heterosexual relationship, they must agree to use contraception as described 
previously. 
 
 
 




 
 
 
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7.2. 
Safety and Tolerability Assessments 
7.2.1. 
Adverse Events 
AE definitions and assignment of severity and causality are detailed in Appendix 1. 
AEs will be elicited from the subject (or, when appropriate, from a caregiver, surrogate, or the 
subject’s legally authorized representative) by the study site staff using a non-leading question 
such as “How are you feeling today?” or “Have you had any health concerns since your last 
visit?” Subjects will be encouraged to voluntarily report AEs occurring at any time during the 
study. AEs will be recorded in the eCRF.  
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up on AEs 
that are serious, considered related to the study drug or the study, or that caused the subject to 
discontinue the study drug or study. For all AEs, the investigator must pursue and obtain 
information to determine the causality and outcome of the AE and to assess whether it meets the 
criteria for classification as an SAE requiring immediate notification to the sponsor or its 
designee. 
7.2.2. 
Reporting Serious Adverse Events 
Please refer to the study-specific safety guidance documents for the appropriate methods for the 
reporting and handling of SAEs. 
7.2.3. 
Pregnancy 
If a female subject becomes pregnant during the study, the study drug must be discontinued 
immediately. During the study, pregnancy events should be reported and will be followed until 
conclusion. Please refer to the study-specific safety guidance documents for details. 
7.2.4. 
Laboratory Safety Tests 
At the time-points specified in the Schedule of Assessments (Appendix 4) and at all unscheduled 
visits as applicable, blood and urine samples will be collected for laboratory safety tests, 
including hematology, biochemistry, coagulation, and urinalysis. Please refer to Appendix 2 for 
the analytes of each laboratory test. Clinically significant laboratory abnormalities, in the opinion 
of the investigator, should be reported as AEs.  
7.2.5. 
Vital Signs 
Vital signs, including heart rate, blood pressure (systolic and diastolic), respiratory rate, and 
temperature will be measured at the time-points specified in the Schedule of Assessments 
(Appendix 4) and at all unscheduled visits as applicable. Vital sign measurements will be 
recorded with the subject in a seated position and after the subject has been resting for at least 5 
minutes. All measurements will be performed singly. For any abnormal vital sign finding, further 
assessment should be performed as deemed necessary by the investigator. In case of re-
screening, all vital sign parameters will be rechecked as described above. 


 
 
 
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7.2.6. 
Physical Examination 
Physical examination will include assessment of heart, lung, extremities, body weight, and 
height. Height will only be assessed at screening. Body weight will be assessed at screening and 
on Day 85 (Visit 9 of Part A 
). All the other assessments will be performed 
at the time-points specified in the Schedule of Assessments (Appendix 4) and at all unscheduled 
visits as applicable. Clinically significant changes from the initial physical findings at screening 
observed in subsequent visits will be considered AEs and will be documented on the AE section 
of the eCRF. 
7.2.7. 
12-lead Electrocardiogram 
Resting 12-lead ECGs will be recorded after the subject has been supine and at rest for at least 
5 minutes at the time-points specified in the Schedule of Assessments (Appendix 4) and at all 
unscheduled visits as applicable. 
7.3. 
Pharmacokinetic Analysis 
7.3.1. 
Pharmacokinetic Blood Sample Collection and Processing 
Blood samples for analysis of CRD-740 concentrations will be collected by venipuncture at the 
time-points specified in the Schedule of Assessments (Appendix 4). Procedures for collection, 
processing, and shipping of PK blood samples will be detailed in the laboratory manual. PK 
samples will be assessed at a central laboratory. 
7.3.2. 
Analytical Methodology 
Plasma concentration of CRD-740 will be determined using a validated analytical procedure. 
Specifics of the analytical method will be provided in the bioanalytical report. 












 
 
 
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Adverse events  
For both Part A and Part B, global incidence of emergent adverse events (EAE) (i.e., all events 
occurring, worsening or becoming serious after the first study treatment intake) will be given by 
system organ class and preferred term according to the Medical Dictionary of Regulatory 
Activities. 
The same description will be performed for serious EAE, severe EAE, treatment related EAE, 
and EAE leading to study drug withdrawal. 
AEs leading to death will also be summarized. 
Vital signs / Physical examination 
For both Part A and Part B, descriptive statistics will be performed on observed values at each 
visit and on each change and relative change from baseline. 
Box plots will be produced for some pre-selected vital signs. 
ECG abnormalities 
For both Part A and Part B, quantitative routine 12-lead ECG results will be summarized on 
observed values at each visit and on each change and relative change from baseline. 
Box plots will be produced for some pre-selected ECGs. 
12-lead ECG data interpretations and quantitative values will be listed.  
Laboratory tests  
For both Part A and Part B, descriptive statistics will be performed on observed values at each 
visit and on each change and relative change from baseline. 
The number and percentage of subjects having a value out of reference laboratory range 
(respectively out of potentially clinically significant range) will also be provided.  
Box plots will be produced for some pre-selected lab parameters. 
8.6. 
Pharmacokinetic Analysis 
PK parameters will be calculated with plasma concentrations of CRD-740 in Part A using non-
compartmental methods.
 
 Details of PK data handling, analysis methodology, and reporting will be included in 
the SAP. 
All plasma concentrations of CRD-740 will be summarized by study part, dose, visiting day, and 
time-points. PK parameters will be summarized for Part A by dose and visiting day. 
 


 
 
 
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9. REFERENCES 
1. Cardurion Pharmaceuticals, Inc. CRD-740 - Investigator's Brochure (Version 1.0).  
2. Kong Q, Blanton RM. Protein kinase G I and heart failure: Shifting focus from vascular 
unloading to direct myocardial antiremodeling effects. Circ Heart Fail. 2013 
Nov;6(6):1268-83. 
3. Kuhn M. A big-hearted molecule. Nature. 2015; 519: 416-417. 
4. Lee D, Zhu G, Sasaki T, et al. Letter: Phosphodiesterase 9A controls nitric-oxide 
independent cGMP and hypertrophic heart disease. Nature 2015; 519: 472-476.  
5. McMurray JJ, Packer M, Desai AS, et al. PARADIGM-HF Investigators and 
Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J 
Med. 2014 Sep 11;371(11):993-1004. 
6. Solomon SD, McMurray JJV, Anand IS, et al. PARAGON-HF Investigators and 
Committees. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection 
Fraction. N Engl J Med. 2019 Oct 24;381(17):1609-1620. 
7. Besler C, Rommel KP, Kresoja KP, et al. Evaluation of phosphodiesterase 9A as a novel 
biomarker in heart failure with preserved ejection fraction. ESC Heart Fail. 2021 
Jun;8(3):1861-1872. 
8. Richards DA, Aronovitz MJ, Liu P, et al. CRD-733, a Novel PDE9 (Phosphodiesterase 9) 
Inhibitor, Reverses Pressure Overload-Induced Heart Failure. Circ Heart Fail. 2021 
Jan;14(1):e007300. 
9. ICH. Statistical Principles for Clinical Trials, Guideline E9, 1998. Available at 
https://database.ich.org/sites/default/files/E9_Guideline.pdf  
10. ICH. Addendum on Estimands and Sensitivity Analysis in Clinical Trials, Guideline 
E9(R1). Available at https://database.ich.org/sites/default/files/E9-
R1_Step4_Guideline_2019_1203.pdf 
 


 
 
 
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10. APPENDICES 
 


 
 
 
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Appendix 1 – Adverse Event Definitions 
Definitions 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. This includes the following: 
• Any clinically significant worsening of a pre-existing condition. 
• Any recurrence of a pre-existing condition. 
• An AE occurring from overdose of a sponsor study drug whether accidental or intentional 
(i.e., a dose higher than that prescribed by a health care professional for clinical reasons). 
• An AE occurring from abuse of a sponsor study drug (i.e., use for non-clinical reasons). 
• An AE that has been associated with the discontinuation of the use of a sponsor study 
drug. 
Note: A procedure is not an AE, but the reason for a procedure may be an AE. 
A pre-existing condition is a clinical condition (including a condition being treated) that is 
diagnosed before the subject signs the informed consent form and that is documented as part of 
the subject’s medical history. 
The questions concerning whether the condition existed before the start of the active phase of the 
study and whether it has increased in severity and/or frequency will be used to determine 
whether an event is a treatment-emergent AE. An AE is considered to be treatment-emergent if 
(1) it is not present when the active phase of the study begins and is not a chronic condition that 
is part of the subject’s medical history, or (2) it is present at the start of the active phase of the 
study or as part of the subject’s medical history, but the severity or frequency increases during 
the active phase. The active phase of the study begins at the time of the first dose of the study 
drug. The active phase of the study ends at the follow-up visit. 
Reporting of Adverse Events 
At each visit, the investigator, or delegate, will determine whether or not any AEs have occurred. 
Non-leading questions such as “How are you feeling today?” or “Have you had any health 
concerns since your last visit?” should be used to elicit the subject (or, when appropriate, from a 
caregiver, surrogate, or the subject’s legally authorized representative) to report any possible 
AEs. If any AEs have occurred, they will be recorded in the AE section of the electronic case 
report form (eCRF) and in the subject’s source documents. If known, the diagnosis should be 
recorded, in preference to listing the individual signs and symptoms. 
AE reporting begins from the time of informed consent and ends 28 days after the last dose of 
study drug. 


 
 
 
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Assessment of Severity 
The investigator will be asked to provide an assessment of the severity of the AE using the 
following categories:  
• Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily living. 
• Moderate: Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the subject. 
• Severe: Interrupts usual activities of daily living, significantly affects clinical status, or 
may require intensive therapeutic intervention. 
Relationship to Study Drug 
The investigator will make a determination of the relationship of the AE to the study drug using 
a binary system according to the following guidelines: 
• Related: There is a reasonable possibility that the drug causes the AE. 
• Not related: There is no reasonable possibility that the drug causes the AE. 
Action Taken for Adverse Events 
The investigator or his/her designee will record the action taken for the AE in the eCRF. Actions 
taken will include: 
• Dose not changed: The medication schedule was not changed. 
• Drug interrupted: The medication schedule was modified by temporarily terminating 
the prescribed regimen of medication. 
• Drug withdrawn: The medication schedule was modified through termination of the 
prescribed regimen of medication. 
• Not applicable 
• Unknown 
Follow-up of Adverse Events 
All AEs or serious adverse events (SAEs) that are ongoing at the time of discontinuation, or that 
develop prior to the final follow-up visit, will be followed for 28 days, or until resolution or 
stabilization. 


 
 
 
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Adverse Drug Reactions 
All noxious and unintended responses to an investigational medicinal product (IMP; i.e., where a 
causal relationship between an IMP and an AE is a reasonable possibility) related to any dose 
should be considered adverse drug reactions. 
For marketed medicinal products, a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or 
for modification of physiological function is to be considered an adverse drug reaction. 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information (e.g., investigator’s brochure for 
an unapproved IMP). 
Serious Adverse Events 
An SAE is any AE occurring at any dose that meets 1 or more of the following criteria: 
• Results in death 
• Is life threatening (see below) 
• Requires subject hospitalization or prolongation of an existing hospitalization (see below) 
• Results in a persistent or significant disability or incapacity (see below) 
• Results in a congenital anomaly or birth defect 
• Results in an important medical event (see below). 
Additionally, important medical events that may not result in death, be life threatening, or 
require hospitalization may be considered SAEs when, based on appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed above. Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias, or convulsions that do 
not require hospitalization, or development of drug dependency or drug abuse. 
A life-threatening AE is any AE that places the subject at immediate risk of death from the 
event as it occurred. A life-threatening event does not include an event that might have caused 
death had it occurred in a more severe form but that did not create an immediate risk of death as 
it actually occurred. For example, drug-induced hepatitis that resolved without evidence of 
hepatic failure would not be considered life threatening, even though drug-induced hepatitis of a 
more severe nature can be fatal. Hospitalization is to be considered only as an overnight 
admission.  
Hospitalization or prolongation of a hospitalization is a criterion for considering an AE to be 
serious. In the absence of an AE, the participating investigator should not report hospitalization 
or prolongation of hospitalization. This is the case in the following situations: 


 
 
 
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• Hospitalization or prolongation of hospitalization is needed for a procedure required by 
the protocol. Day or night survey visits for biopsy or surgery required by the protocol are 
not considered serious. 
• Hospitalization or prolongation of hospitalization is part of a routine procedure followed 
by the study center (e.g., stent removal after surgery). This should be recorded in the 
study file. 
• Hospitalization for survey visits or annual physicals fall in the same category. 
In addition, a hospitalization planned before the start of the study for a pre-existing condition that 
has not worsened does not constitute an SAE (e.g., elective hospitalization for a total knee 
replacement due to a pre-existing condition of osteoarthritis of the knee that has not worsened 
during the study).   
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions (i.e., the AE resulted in a significant, persistent, or permanent change, impairment, 
damage, or disruption in the subject’s bodily function/structure, physical activities, or quality of 
life).   
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
those situations where important medical events may not be immediately life threatening or 
result in death, hospitalization, disability, or incapacity. These include events that may jeopardize 
the subject or may require medical intervention to prevent one or more outcomes listed in the 
definition of serious. Such events should usually be considered as serious. 
 


 
 
 
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Appendix 2 – Clinical Laboratory Evaluations 
The following clinical laboratory analytes will be assessed:  
Biochemistry: 
Hematology (CBC): 
Albumin 
Hematocrit 
ALP 
Hemoglobin 
ALT 
MCH 
AST 
MCHC 
BUN 
MCV 
Calcium 
Platelet count  
Chloride 
RBC count 
Creatinine* 
WBC count 
Direct bilirubin 
WBC differential 
GGT 
(% & absolute): 
Glucose 
Basophils 
Indirect bilirubin 
Eosinophils 
Phosphorus 
Lymphocytes 
Potassium 
Monocytes 
Sodium 
Neutrophils 
Total bilirubin 
 
Total CO2 (measured as bicarbonate) 
For Females of Childbearing Potential Only: 
 
Serum Pregnancy Test  
Urinalysis: 
      Urine Pregnancy Test 
Color and appearance  
 
pH and specific gravity 
Coagulation: 
Bilirubin 
aPTT 
Glucose 
PT 
Ketones  
INR 
Leukocytes  
 
Nitrite  
 
Occult blood  
 
Protein  
 
Microscopic (including RBC and WBC) 
 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
aPTT: activated partial thromboplastin time; BUN = blood urea nitrogen; CBC = complete blood count; CO2 = 
carbon dioxide; GGT = gamma glutamyl transferase; INR = international normalized ratio; MCH = mean 
corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; 
PT = prothrombin time; RBC = red blood cell; WBC = white blood cell 
∗ Estimated glomerular filtration rate, as measured by the simplified Modification of Diet in Renal Disease formula, 
will be derived based on the level of creatinine. 


 
 
 
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Appendix 3 – Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, informed consent form (ICF), investigator’s brochure, and 
other relevant documents (e.g., advertisements) must be submitted to an institutional review 
board (IRB)/ethics committee (EC) by the investigator and reviewed and approved by the 
IRB/EC before the study is initiated.  
• Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study subjects.  
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/EC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/EC 
• Notifying the IRB/EC of serious adverse events or other significant safety findings as 
required by IRB/EC procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study drugs, procedures, and potential risks of the study. Subjects will 
be instructed that they are free to obtain further information from the investigator or his/her 
designee, that their participation is voluntary and they are free to withdraw from the study at any 


 
 
 
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time. Subjects will be given an opportunity to ask questions about the study prior to providing 
consent for participation.   
Subjects or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of local regulations, ICH guidelines, and the 
IRB/EC or study center, where applicable. The subject will be given a copy of the signed ICF, 
and the original will be maintained with the subject’s records.  
Subjects must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
Subject Data Protection 
Subjects will be assigned a unique identifier and will not be identified by name in electronic case 
report forms (eCRFs), study-related forms, study reports, or any related publications. Subject and 
investigator personal data will be treated in compliance with all applicable laws and regulations. 
In the event the study protocol, study report, or study data are included in a public registry, all 
identifiable information from individual subjects or investigators will be redacted according to 
applicable laws and regulations.  
The subject must be informed that his/her personal study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the subject. The subject must also be informed that his/her medical records may be examined by 
sponsor or contract research organization (CRO) auditors or other authorized personnel 
appointed by the sponsor, by appropriate IRB/EC members, and by inspectors from regulatory 
authorities. 
Independent Data Monitoring Committee 
An independent data monitoring committee (DMC) will be established at the beginning of the 
study. The DMC will be responsible for ensuring the safety of study subjects, study integrity, and 
validity of study results. The DMC will review study results from Part A and make a non-
binding dose recommendation for Part B to the sponsor’s representative. The DMC members 
will not be involved in any day-to-day study decisions and will remain independent from the 
study team. The DMC will review safety and efficacy data to make recommendations concerning 
study continuation, modification, and termination based on ongoing study data. The DMC will 
operate according to a DMC charter, which will describe the DMC’s membership, roles, and 
responsibilities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The investigator or 
his/her designee agrees not to disclose such information in any way without prior written 
permission from the sponsor. 


 
 
 
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Data Quality Assurance 
The following data quality steps will be implemented: 
• All subject data relating to the study will be recorded on eCRFs unless directly 
transmitted to the sponsor or its designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF.  
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The sponsor or its designee is responsible for the data management of this study 
including quality checking of the data. Pre-defined, agreed risks, monitoring thresholds, 
quality tolerance thresholds, controls, and mitigation plans will be documented in a risk 
management register. Additional details of quality checking to be performed on the data 
may be included in the data management plan. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of subjects are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator in accordance with 21 CFR 312.62(c) (US site) or in 
the study site archive for at least 5 years after the end of the study (UK site) unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor.  
Investigator Documentation Responsibilities 
All individual, subject-specific study data will be entered into a 21 CFR Part 11-compliant 
electronic data capture (EDC) system on an eCRF in a timely fashion. All data generated from 
external sources (e.g., central laboratory) and transmitted to the sponsor or its designee 
electronically will be integrated with the subject’s eCRF data in accordance with the data 
management plan. 
An eCRF must be completed for each subject who signs an ICF and undergoes any screening 
procedures, according to the eCRF completion instructions. The sponsor, or CRO, will review 
the supporting source documentation against the data entered into the eCRFs to verify the 


 
 
 
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accuracy of the electronic data. The investigator will ensure that corrections are made to the 
eCRFs and that data queries are resolved in a timely fashion by the study staff.   
The investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the investigator reviewed and approved the data on 
the eCRF, the data queries, and the site notifications. 
Publications 
If on completion of the study the data warrant publication, the investigator may publish the 
results in recognized (refereed) scientific journals subject to the provisions of the clinical study 
agreement (CSA). Unless otherwise specified in the CSA, the following process shall occur: 
The institution and investigator shall not publish or present data from an individual study center 
until the complete multicenter study has been presented in full or for 2 years after the termination 
of the multicenter study, whichever occurs first. Subsequent publications must refer to the 
multicenter findings. Thereafter, if the investigator expects to participate in the publication of 
data generated from this site, the institution and investigator shall submit reports, abstracts, 
manuscripts, and/or other presentation materials to the sponsor for review before submission for 
publication or presentation. The sponsor shall have 60 days to respond with any requested 
revisions, including (without limitation) the deletion of confidential information. The 
investigator shall act in good faith upon requested revisions, except the investigator shall delete 
any confidential information from such proposed publications. The investigator shall delay 
submission of such publication or presentation materials for up to an additional 90 days in order 
to have a patent application(s) filed. 
 
 






 
 
 
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Abbreviations: AE = adverse event; aPTT: activated partial thromboplastin time; 
 cGMP = cyclic guanosine monophosphate; 
ECG = electrocardiogram; ET = end of trial; FSH = follicle-stimulating hormone; hr = hour; INR = international normalized ratio; 
 
 PK = pharmacokinetics; PT = prothrombin time 
a. 
All assessments will be performed pre-dose unless otherwise specified. 
b. All screening laboratory tests should ideally be performed on Day -15 to ensure eligibility assessment completed during screening window. In rare 
situations, if the laboratory reporting is delayed due to unforeseen circumstances (e.g., transit delays, lost sample, or outstanding queries), up to 21 days of 
screening will be accepted. 
c. 
Women of childbearing potential only. 
d. FSH will only be measured for women <55 years of age who have not had a menstrual period for ≥12 months at screening. 
e. 
Vital signs, including heart rate, blood pressure (systolic and diastolic), respiratory rate, and temperature, will be measured at the time-points specified in the 
above table and at all unscheduled visits as applicable. Vital sign measurements will be recorded with the subject in a seated position and after the subject 
has been resting for at least 5 minutes. All measurements will be performed singly. For any abnormal vital sign finding, further assessment should be 
performed as deemed necessary by the investigator. In case of re-screening, all vital sign parameters will be rechecked as described above. 
f. 
Physical examination will include assessment of heart, lung, extremities, body weight, and height. Height will only be assessed at screening. Body weight 
will be assessed at screening and at Visit 9. All the other assessments will be performed at all the applicable time-points and at all unscheduled visits as 
applicable. 
g. Resting 12-lead ECGs will be recorded at the time-points specified in the above table and at all unscheduled visits as applicable. Resting 12-lead ECGs will 
be recorded after the subject has been supine and at rest for at least 5 minutes. 
h. The blood sample will be collected 12-24 hours after last dose of study drug. 
i. 
Laboratory safety tests will include biochemistry, urinalysis, and hematology. Please refer to Appendix 2 for the specific analytes of each test. Laboratory 
safety tests will be performed at the time-points specified in the above table and at all unscheduled visits as applicable. All laboratory safety tests will be 
analyzed at a central laboratory. 
j. 
On the days of Visit 5 and Visit 7, subjects will be instructed NOT to take their dose of study drug before the pre-dose blood and urine sampling. Subjects 
will not take the study drug at Visit 9. They will be instructed to take the study drug through the day before Visit 9. 
k. A time window of ±15 minutes applies to the time-points of 1 hour, 2 hours, 3 hours, and 6 hours. 
 
 
m. Site pharmacists blinded to treatment allocation will dispense the study drug for subjects to self-administer on an out-patient basis. Subjects will be 
instructed to follow the provided instructions to take the study drug. 
n. Subjects to return all used and unused drug supply containers. 
o. If a subject refuses to have labs collected remotely, or a country/site’s policy does not permit a 3rd party to collect blood draws off site, the subject will be 
allowed to have their visit conducted at the site instead.  





SAP_001.pdf: 
Statistical Analysis Plan 
Labcorp Drug Development Study: 000000221752 
CONFIDENTIAL 
Protocol Reference: CRD-740-201 
Final, Version 1.0, 17MAY2023 
Page 1 of 56 
ST-AD-008 version 06 
 
 
Statistical Analysis Plan 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Clinical Study 
to Assess the Effectiveness of CRD-740 in Subjects with Chronic Heart 
Failure 
 
Statistical Analysis Plan: Final 
Statistical Analysis Plan: 1.0 
Statistical Analysis Plan Date: 17MAY2023 
Investigational Product: CRD-740 
Protocol Reference: CRD-740-201 
Labcorp Drug Development Study ID: 000000221752 
Sponsor: Cardurion Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
Author: 
 
Principal Biostatistician 
Information described herein is confidential and may be disclosed only with the express written 
permission of the sponsor. 


Statistical Analysis Plan 
Labcorp Drug Development Study: 000000221752 
CONFIDENTIAL 
Protocol Reference: CRD-740-201 
Final, Version 1.0, 17MAY2023 
Page 2 of 56 
ST-AD-008 version 06 
 
 
 
Table of Contents 
Glossary of Abbreviations ........................................................................................................ 8 
1. Source Documents .............................................................................................................. 10 
2. Protocol Details .................................................................................................................. 11 
2.1. Overall Study Design................................................................................................... 11 
2.2. Study Objectives .......................................................................................................... 12 
2.2.1. Primary Objectives ................................................................................................ 12 
2.2.2. Secondary Objectives ............................................................................................ 12 
 
2.3. Sample Size and Power ............................................................................................... 13 
2.4. Primary Variables ........................................................................................................ 13 
2.4.1. Primary Efficacy Variables ................................................................................... 13 
2.4.2. Primary Safety Variables ...................................................................................... 14 
2.5. Secondary Variables .................................................................................................... 14 
2.5.1. Secondary Efficacy Variables ............................................................................... 14 
2.5.2. Secondary Safety Variables .................................................................................. 14 
No secondary safety variables are defined for Part A of the study..................................... 14 
 
2.7. Pharmacokinetics Variables ........................................................................................ 15 
3. Estimand(s) ......................................................................................................................... 16 
3.1. Part A ........................................................................................................................... 16 
3.1.1. Estimands for the primary efficacy objective ....................................................... 16 
3.1.2. Estimands for the primary safety objective ........................................................... 18 
4. Analysis Populations .......................................................................................................... 20 
4.1. All Screened Population .............................................................................................. 20 
4.2. Intention to Treat Population ....................................................................................... 20 
4.3. Modified ITT Population ............................................................................................. 20 
4.4. Per Protocol Population ............................................................................................... 20 
4.4.1. Important Protocol Deviations Leading to Exclusion from the PP Population ..... 20 


Statistical Analysis Plan 
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Page 3 of 56 
ST-AD-008 version 06 
 
 
4.5. Week 2 Analysis Population ........................................................................................ 21 
4.6. Week 4 Analysis Population ........................................................................................ 21 
4.7. Safety Analysis Population (SAF) ............................................................................... 21 
4.8. Pharmacokinetics Analysis Population (PK) ............................................................... 22 
5. Data Handling .................................................................................................................... 23 
5.1. Time Points and Visit Windows .................................................................................. 23 
5.1.1. General Definitions ............................................................................................... 23 
5.1.2. Baseline Value and Change from Baseline ........................................................... 23 
5.1.3. Screening Period ................................................................................................... 24 
5.1.4. Treatment Period ................................................................................................... 24 
5.1.5. Visit Windows ...................................................................................................... 24 
5.2. Handling of Dropouts, Missing Data, and Outliers ..................................................... 25 
5.2.1. Handling of Missing Efficacy Data ...................................................................... 25 
5.2.2. Handling of Missing Safety Data .......................................................................... 26 
5.2.3. Handling of Partial and Missing Dates for Adverse Events, Prior / Concomitant 
Medications ..................................................................................................................... 26 
5.2.4. Handling of Plasma / Blood / Serum Concentrations that are Below the Lower 
Limit of Quantification ................................................................................................... 27 
6. Statistical Methods ............................................................................................................. 28 
6.1. General Principles ........................................................................................................ 28 
6.2. Subject Disposition and Data Sets Analyzed ............................................................... 28 
6.3. Protocol Deviations ..................................................................................................... 30 
6.4. Demographic and Other Baseline Characteristics ....................................................... 30 
6.4.1. Demographic Characteristics ................................................................................ 30 
6.4.2. Baseline Characteristics ........................................................................................ 31 
6.4.3. Medical History .................................................................................................... 32 
6.4.4. Prior and Concomitant Medications ..................................................................... 32 
6.4.5. Prohibited Concomitant Therapy .......................................................................... 33 
6.5. Measurements of Treatment Compliance .................................................................... 34 
6.6. Efficacy Analysis ......................................................................................................... 35 


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6.6.1. Primary Efficacy Analysis .................................................................................... 35 
6.6.2. Sensitivity Analysis for the Primary Efficacy Endpoints ..................................... 36 
6.6.3. Secondary Efficacy Analysis ................................................................................ 37 
6.6.4. Sensitivity Analyses for the Secondary Efficacy Endpoints ................................. 37 
6.6.5. Subgroup Analysis ................................................................................................ 37 
 
6.7. Safety Analysis ............................................................................................................ 41 
6.7.1. Extent of Exposure ................................................................................................ 41 
6.7.2. Adverse Events ..................................................................................................... 42 
6.7.3. Laboratory Evaluations ......................................................................................... 45 
6.7.4. Vital Signs ............................................................................................................. 47 
6.7.5. Electrocardiograms................................................................................................ 48 
6.7.6. Physical Examination ............................................................................................ 49 
6.7.7. Interim Analysis and Data Monitoring ................................................................. 49 
6.8. Pharmacokinetic Analysis ........................................................................................... 51 
6.8.1. PK Parameters in Part A ....................................................................................... 51 
7. Changes in the Conduct of the Study or Planned Analysis ................................................ 54 
8. Appendices ......................................................................................................................... 55 
9. References .......................................................................................................................... 56 


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List of Tables 
 
Table 1 Part A, dose ranging, sample sizes, no caps .............................................................. 13 
Table 2 Handling of Intercurrent Events for the Primary Efficacy Estimand ........................ 17 
Table 3 Handling of Intercurrent Events for the Primary Safety Estimand ........................... 18 
Table 4 Definition of Visit Windows for Efficacy and Safety Assessments Part A .............. 25 
Table 5 Country and geographical locations from Subject number ....................................... 31 
 
Table 7 Laboratory Tests ....................................................................................................... 45 
Table 8 CTCAE grading ........................................................................................................ 46 
Table 9 QTcF / QTcB Interval ICH E14 Boundaries ............................................................. 48 
Table 10 PK parameters ......................................................................................................... 51 


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List of Figures 
Figure 1 Study schematic of Part A ....................................................................................... 11 












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2.2. Study Objectives 
2.2.1. Primary Objectives 
Part A: 
1. To assess the safety and tolerability of CRD-740 in subjects with CHFrEF, defined as 
heart failure (HF) with ejection fraction (EF) ≤40%. 
2. To assess the effect of CRD-740 compared to placebo in plasma cyclic guanosine 
monophosphate (cGMP) at Week 4 in subjects with CHFrEF. 
2.2.1.1. Estimands for the Primary Objectives 
Estimands for the primary objectives are described in Sections 3.1.1 and 3.1.2 for Part A in 
this SAP. 
2.2.2. Secondary Objectives 
Part A: 
• To assess the PK of CRD-740 in subjects with CHFrEF. 
 
2.2.2.1. Estimands for the Secondary Objectives 
Not applicable for Part A. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.2.3.1. Estimands for the Exploratory Objectives 
Not applicable for Part A. 
2.3. Sample Size and Power 
In Part A, approximately 60 subjects with CHFrEF will be included. 
The sample size was not determined by power calculations but by considerations to provide 
a reasonable number of subjects to assess the study objectives. Table 1 below summarizes the 
Part A sample sizes. 
Table 1 Part A, dose ranging, sample sizes, no caps 
 
EF%, Entresto 
Randomized (2:1) Treatment 
Sample Size 
≤40, Yes 
CRD-740 
⅔ n1 
≤40, Yes 
Placebo 
⅓ n1 
≤40, No 
CRD-740 
⅔ n2 
≤40, No 
Placebo 
⅓ n2 
Total N 
60 
Note: n1 + n2 = 60, where n1 and n2 are unknown and random; they denote the number of CHFrEF subjects with 
and without Entresto use, respectively. Randomization will be stratified on Entresto use (yes, no) and employ a 
2:1 randomization ratio (CRD-740: Placebo) within each stratum. 
Abbreviations: CHFrEF = chronic heart failure with reduced ejection fraction; EF = ejection fraction 
 
 
 
2.4. Primary Variables 
2.4.1. Primary Efficacy Variables 
Part A: 
• Change from baseline in plasma cGMP AUC at Week 4 


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2.4.2. Primary Safety Variables 
Part A: 
1. AEs 
2. Physical examinations 
3. Vital signs 
4. 12-lead ECGs 
5. Laboratory safety tests (biochemistry, urinalysis, and hematology) 
2.5. Secondary Variables 
2.5.1. Secondary Efficacy Variables 
Part A: 
No secondary efficacy variables are defined for Part A of the study. 
2.5.2. Secondary Safety Variables 
Part A: 
No secondary safety variables are defined for Part A of the study. 
 
 
 
 
 
 
 
 
 
 
 
 


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2.7. Pharmacokinetics Variables 
Part A: 
The PK endpoints are the following PK parameters of CRD-740: 
1. Cmax 
2. Time of Cmax (tmax) 
3. AUC0-last 
4. Area under the plasma concentration-time curve over a dosing interval (AUCtau) 
5. Apparent total body clearance (CL/F, except for Day 1) 


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3. Estimand(s) 
The ICH1 E9 (R1) addendum on estimands2 and sensitivity analysis in clinical trials to the 
guideline on statistical principles for clinical trials came into effect on 30 July 2020. This 
section addresses the construction of estimands for the primary and secondary objectives. 
Each estimand is defined according to the following five attributes: 
1) The treatment condition of interest, and as appropriate, the alternative condition to 
which comparison will be made. 
2) The population of subjects targeted by the clinical question. 
3) The variable (or endpoint) to be obtained for each subject that is required to address 
the clinical question. 
4) The clinical question of interest in respect of other intercurrent events not covered 
through the precise specifications of treatment, population and variable. 
5) A population-level summary for the variable providing a basis for comparison 
between treatment conditions. 
3.1. Part A 
3.1.1. Estimands for the primary efficacy objective 
The estimand for the primary efficacy objective (assessment of the effect of CRD-740 
compared to placebo in plasma cGMP AUC at Week 4 in subjects with CHFrEF) is defined 
through the 5 attributes described in Sections 3.1.1.1 to 3.1.1.5: 
3.1.1.1. Treatment Condition of Interest 
The primary treatment condition of interest is CRD-740 dose (either 
 
 or placebo, with or without sacubitril/valsartan, dosed as required. 
3.1.1.2. Population of Subjects Targeted by the Clinical Question 
The population targeted by the clinical question is defined through Randomized subjects with 
CHrEF (EF≤40%) who received at least one dose of CRD-740 or placebo (mITT). 
3.1.1.3. Variable Obtained from Each Subject Required to Address the Clinical 
Question 
For each subject in the study, the variable to address the clinical question is change from 
baseline in plasma cGMP AUC at Week 4. 








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4. Analysis Populations 
In accordance with ICH E3 and E93, the following analysis populations will be used for the 
analyses. 
4.1. All Screened Population 
The All Screened Population will include every subject who has signed the informed consent 
form. The All Screened Population will be used for summaries of disposition and the 
associated listing. 
4.2. Intention to Treat Population 
The Intention to Treat Population (ITT) population will consist of all randomized subjects. 
Subjects will be analyzed according to their randomized treatment, regardless of actual 
treatment received, treatment compliance, or treatment duration. The ITT population will be 
used for summaries of disposition, protocol deviations, demographics & baseline 
characteristics, medical history, and prior/concomitant medications. 
4.3. Modified ITT Population 
The modified Intention to Treat (mITT) Population will consist of all randomized subjects 
who received at least one dose of CRD-740 or placebo. Subjects will be analyzed according 
to their randomized treatment, regardless of actual treatment received, treatment compliance, 
or treatment duration. The mITT population will be used as the primary efficacy population. 
4.4. Per Protocol Population 
The Per Protocol Population (PP) will consist of all mITT subjects with no important protocol 
deviations. Subjects will be analyzed according to their randomized treatment. The PP 
Population will be used for sensitivity analyses. 
Protocol deviations are defined as any change, divergence, or departure from the study design 
or procedures defined in the study protocol. Important protocol deviations are a subset of 
protocol deviations which may significantly impact the correctness, accuracy, and / or 
reliability of the study data or that may significantly affect a subject’s rights, safety, or well- 
being. Section 4.4.1 details the deviations. 
4.4.1. Important Protocol Deviations Leading to Exclusion from the PP Population 
Deviations from the protocol, as defined in the protocol and / or protocol deviation plan, will 
be documented by the trial monitors and project management throughout the trial period. 


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Only those important protocol deviations considered to have a major effect on efficacy will 
lead to complete exclusion of the patient from the PP Population. For the purposes of this 
trial, the criteria identified as candidates for important protocol deviations leading to exclusion 
from the PP Population will be detailed in a separate protocol deviations spreadsheet, as it is 
considered that the occurrences of any of these criteria might have an important influence on 
the primary efficacy endpoint. Patients will be assessed purely by comparison of their eCRF 
data with the defined criteria; protocol waivers will not be taken into consideration (e.g., if a 
patient younger than 18 enters the trial on a protocol waiver, the patient would still be 
excluded from the PP Population). 
Criteria which require clinical or medical monitoring interpretation will be reviewed prior to 
database lock. All important protocol deviations leading to exclusion from the PP Population 
occurring during the trial will be reviewed and approved by Cardurion prior to database lock. 
4.5. Week 2 Analysis Population 
The Week 2 Analysis Population will consist of all mITT subjects with no important 
protocol deviations during the first 2 weeks. Subjects will be analyzed according to their 
randomized treatment. The Week 2 Analysis Population will be used for sensitivity analyses 
for the interim DMC. 
Important protocol deviations are defined as any change, divergence, or departure from the 
study design or procedures defined in the study protocol that may significantly confound the 
ability to detect target engagement via pharmacodynamic measures. 
4.6. Week 4 Analysis Population 
The Week 4 Analysis Population will consist of all mITT subjects with no important 
protocol deviations during the first 4 weeks. Subjects will be analyzed according to their 
randomized treatment. The Week 4 Analysis Population will be used for sensitivity analyses 
for the interim DMC. 
Important protocol deviations are defined as any change, divergence, or departure from the 
study design or procedures defined in the study protocol that may significantly confound the 
ability to detect target engagement via pharmacodynamic measures. 
4.7. Safety Analysis Population (SAF) 
The Safety population will consist of all subjects who received at least one dose of CRD-740 
or placebo. Subjects will be analyzed according to the treatment first received. The Safety 
population will be used as the primary safety population. 


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4.8. Pharmacokinetics Analysis Population (PK) 
The PK population will consist of all subjects who received at least one dose of CRD-740 and 
have no protocol deviations that are considered to impact the PK results. PK Analysis 
Population subjects are analyzed according to their randomized treatment. 


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5. Data Handling 
5.1. Time Points and Visit Windows 
5.1.1. General Definitions 
All assessment days will be related to the day of first dose of treatment. 
Day 1 is defined as first dose of treatment. Relative days after Day 1 are calculated as 
(assessment date – Day 1 date) + 1. Relative days prior to Day 1 are calculated as (assessment 
date – Day 1 date). The day prior to Day 1 is Day -1. Day 0 is not defined. 
The date of the first dose of treatment for each subject will be taken from the Study Drug 
Administration (Oral) eCRF page at Visit 3. If the date in this eCRF page is missing, 
alternatively the date of randomization + 1 will be used. 
The date of the last dose of treatment for each subject will be taken from the End of 
Treatment eCRF page. If the date in this eCRF page is missing, alternatively the Completion 
or discontinuation date of Disposition – End of Study eCRF form will be used. If the date is 
missing because the subject was lost to follow-up, the date of the last visit will be imputed, if 
appropriate. 
5.1.2. Baseline Value and Change from Baseline 
Baseline values for the primary efficacy variable in Part A (plasma cGMP) are the plasma 
cGMP values collected on Day -1 (at 0hr, 1hr, 2hr, 3hr, and 6hr) time-matched to Day 29 
values. An AUC0-6h will also be derived from those values. AUC0-6h derivation is described in 
Section 6.6.1. In addition, baseline value for 6-hour urine collection will be the value collected 
on Day -1. 
For all other variables, independently from study Part, baseline value is defined as the last 
non-missing value collected before the first dose of treatment. If assessment is performed on 
Day 1, it will be considered performed before the first dose intake unless the date/time of 
assessment confirms that it was performed after the first dose intake. 
Change from baseline at Week X will be defined as Week X value – Baseline value. 
Change from Week X to Week Y will be defined as Week Y value – Week X value. 


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5.1.3. Screening Period 
For all subjects, the screening period is defined as the period from informed consent to the 
first dose of treatment. For some variables, data from more than one assessment within the 
screening period can be collected prior to the first dose of treatment. 
5.1.4. Treatment Period 
Data collected at Day 1 will be assigned to the Treatment Period unless the time (HH:MM) 
of data collection and time (HH:MM) of first dose of treatment are both recorded and the data 
collection time is before the time of first dose of treatment. In this case, the assessment will 
be assigned to the screening period. If the time (HH:MM) of data collection is not recorded 
but the protocol and / or eCRF includes an instruction to the effect that all Day 1 assessments 
are to be performed prior to the first dose of treatment, the data collected at Day 1 will be 
assigned to the screening period. However, adverse events and medications starting on Day 1, 
will be assigned to the Treatment Period. 
 
The Treatment Period is defined as the period from the date / time of the first dose of treatment 
up to and including the date / time of the last dose of treatment. 
Treatment period in Part A comprises 3 dosing periods: 
Period 1 (dose of 
) from date of the first dose of treatment at 
 level till date 
of the first dose of treatment at 
 level; 
Period 2 (dose of 
) from date of the first dose of treatment at 
 level till day 
before Visit 7; 
Period 3 (dose of 
) from the dose of treatment on Visit 7 till the date of the last 
dose of treatment. 
If subject discontinues during Period 1 or Period 2, the date of the last dose of treatment will 
be considered as end of the respective period. 
 
5.1.5. Visit Windows 
Table 4 Definition of Visit Windows for Efficacy and Safety Assessments provides the 
relative trial day ranges to be applied to the assessment / sample collection date to derive the 
analysis visits for analyses of trial assessments. 
 
The following considerations are to be followed when deriving the analysis visit: 
• The relative day number of the assessment lies between the lower and upper boundary 
of the analysis visit window (the boundary values are included) 
• Both scheduled and unscheduled assessments are included for visit windowing 
• If there are two or more valid assessments for a defined window the following rules 
will be applied: 




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5.2.2. Handling of Missing Safety Data 
 
In general, missing clinical laboratory data, vital signs, and ECG data will not be imputed. 
Adverse event imputations for missing severity or relationship are given in Section 6.7.2. 
Unknown or partial medication and AE date imputations are given below and to be used only 
for the assessment of prior / concomitant status for medications and treatment-emergent status 
for AEs. 
 
5.2.3. Handling of Partial and Missing Dates for Adverse Events, Prior / Concomitant 
Medications 
Missing or Partial Adverse Event and Prior / Concomitant Medication Start Dates 
Missing and / or incomplete dates for medications and AEs are imputed in a manner resulting 
in the earliest onset or the longest duration during the Treatment Period, whilst ensuring that 
the start date does not occur after the stop date. The stop date will not be imputed if the 
medication or AE is “Ongoing”. Technically, this will be done as follows: 
 
For a missing / incomplete start date / time the earliest date / time of the following will be 
imputed: 
• The later date of: the earliest possible start date / time, and the date / time of first dose 
of treatment. 
• The latest possible start date / time. 
• The latest possible stop date / time. 
 
For a missing / incomplete stop date / time the later date / time of the following will be 
imputed: 
• The earlier date / time of the latest possible stop date / time and the date / time of last 
dose of treatment. 
• The earliest possible stop date / time. 
• The earliest possible start date / time. 
 
Here, the earliest possible date / time is defined as: 
• The date / time itself if available. 
• The date / time of the first day of the month at 00:00hrs, if month and year are available 
but the day / time is missing. 
• The date / time of the first day of the year at 00:00hrs, if year is available but day / 
time and month are missing. 
• 00:00hrs on the day of informed consent, if the date / time is completely missing. 
 
The latest possible date / time is defined as: 


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• The date / time itself if available. 
• The date / time of the last day of the month at 23:59hrs, if month and year are available 
but the day / time is missing. 
• The date / time of the last day of the year at 23:59hrs, if year is available but day / time 
and month are missing. 
• 23:59hrs on the date of last known date on the study for the subject plus one year, if 
the date / time is completely missing. 
 
5.2.4. Handling of Plasma / Blood / Serum Concentrations that are Below the Lower 
Limit of Quantification 
Plasma / blood / serum concentrations that are below the lower limit of quantification (BLQ) 
will be handled as follows for descriptive statistics: 
• Values that are BLQ will be set to 0 for the calculation of summary statistics. 
• Arithmetic mean or median values that are BLQ will be presented as 0. 
• If any BLQ results (treated as 0) are in a series of summarized data, geometric mean 
and coefficient of variation (CV) % of geometric mean will be reported as not 
calculated (NC). 


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6. Statistical Methods 
6.1. General Principles 
All data processing, summarization and analyses will be performed using Labcorp Drug 
Development’s SAS Environment / Version 9.4 (or later) of the SAS statistical software 
package. 
The default summary statistics for quantitative variables will be the number of observations 
(n), mean, standard deviation (SD), median, minimum (min) and maximum (max), for those 
subjects with data. 
For qualitative variables, the number (n) and percentage (%) of subjects with non-missing 
data per category will be the default summary presentation, and where appropriate and 
present, the number of missing values as a “Missing” category. Number of subjects in the 
analysis population will be used as denominator for percentages calculation, unless stated 
otherwise in TFLs mock shells. 
All statistical comparisons will be made using one sided tests at the α=0.025 significance 
level unless specifically stated otherwise. All null hypotheses will be of no treatment 
difference. All alternative hypotheses will be one-sided. 
All laboratory test results will be received from the central laboratories, and the results will 
be provided in both standard internal (SI) and conventional units. For the TFLs, the results 
will be summarized or presented in International System of Units (SI) units. Refer to 
Appendix of the TLFs mock shells for the SI unit corresponding to each laboratory test. 
Refer to Appendix of the TLF shells for the precision level in which each laboratory test is 
reported by the central laboratories. 
Specifications for table, figures and data listing formats can be found in the TFL shells 
specifications for this study. Please refer to “2. General Format Guidelines” section within 
TFL shells for more details on presentation of results. 
6.2. Subject Disposition and Data Sets Analyzed 
Subject disposition will be summarized by treatment group, and overall for Part A of the 
study, where appropriate, for the All Screened Population. The following information will be 
reported: 
• Number of subjects for the following categories: 
o Screened, 
o Treated but not randomized. 


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• Number and percentage of subjects for the following categories: 
o Randomized, 
o Treated, 
o Not Treated, 
o Discontinued the study treatment, 
o Reasons for study treatment discontinuation 
o Completed the study, 
o Ongoing in the study, 
o Discontinued the Study, 
o Reasons for study discontinuation. 
• Number and percentages of subjects completing period 1, completing period 2 and 
completing period 3 (applicable for Part A only) 
• Number and percentage of subjects included in, and excluded from, each study 
population together with the reasons for exclusion from the respective analysis 
population (this will be summarized for ITT population); 
• Number and percentage of subjects who met / did not meet all eligibility criteria, 
together with the criteria not met; 
• Number and percentage of subjects who failed screening prior to randomization, 
including the primary reason for screen failure; 
• Number and percentage of subjects at each site (this will be summarized for ITT 
population); 
• Number and percentage of subjects by stratification factors (this will be summarized 
for ITT population). Each stratification variable will be presented by the stratum 
collected in Interactive web-based response system (IWRS) and the stratum collected 
in the eCRF (if available). 
 
In Part A of this study, a subject will be considered to have completed the study if he/she has 
answered “Yes” to question “Did the subject complete the study” on Disposition – End of 
Study form in eCRF. A subject will be considered as having discontinued the study if the 
question is answered “No”. Otherwise, the subject will be considered as ongoing study. 
A subject will be considered to have discontinued the study treatment if reason of 
discontinuation is provided on End of Treatment eCRF form. 
A listing of all subjects with their treatment and study completion status, including the 
respective reasons for treatment and study discontinuation will be presented for the ITT. 
A listing of all screen failed subjects with their reasons for screen failure will be presented for 
the All Screened Population. A separate listing of subjects who failed at least one inclusion / 


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exclusion criteria including a text description of the criterion failed will be presented for the 
All Screened Population. 
A listing of all randomized subjects with their randomization details, including first dose date 
and time, and actual treatment received will be presented for the ITT. 
A listing of all subjects excluded from at least one analysis population will be presented for 
the All Screened Population. 
6.3. Protocol Deviations 
All important protocol deviations will be summarized for the ITT by treatment group and 
overall for Part A of the study as described below: 
• The number of unique subjects with at least one important protocol deviation as well 
as the number of subjects in each important protocol deviation category will be 
presented by default descriptive summary statistics for categorical variables. 
A listing of all subjects with one or more important protocol deviations will be presented for 
the ITT. In addition, a listing of the subjects affected by Coronavirus Disease of 2019 
(COVID-19) and the type of COVID-19 disruption will be provided for the ITT. 
 
6.4. Demographic and Other Baseline Characteristics 
6.4.1. Demographic Characteristics 
Demographic characteristics will be summarized for the ITT by treatment group and overall 
for Part A of the study as described below. All missing data will be presented as part of a 
missing category, if appropriate. Standard descriptive statistics will be presented for the 
continuous variables of: 
• Age (years) 
• Height (cm) at baseline 
• Weight (kg) at baseline 
• Body mass index (kg/m2) at baseline 
[calculated as (body weight / height2) where weight is in kg and height is in m] and 
presented to one decimal precision 
Total counts and percentages of subjects will be presented for the categorical variables of: 
• Age group (years): 
o ≤ 65 
o > 65 
• Sex (Male/Female) 
• Reproductive system status (Childbearing potential, menopause status) – for females 
only 
• Race 




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6.4.3. Medical History 
Medical history is defined as any condition, with the exception of the study indication, that 
the subject may have had prior to enrollment in the study, including any chronic conditions 
diagnosed prior to entry in the study. See section 5.2.3 for imputation of missing or partial 
dates for medical history. 
 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) [version 24.1 or a later version if updated during the study] and will be presented 
by System Organ Class (SOC) and Preferred Term (PT). The SOCs and PTs are to be sorted 
by Internationally Agreed order SOCs and descending PTs in the overall column. 
 
Medical history records will be summarized for the ITT population by treatment group and 
overall for Part A of the study as follows: 
• The number and percentage of subjects with at least one medical history record will 
be presented. 
• The number and percentage of subjects with at least one medical history record within 
each primary SOC and PT will be presented. The summary will be sorted using the 
internationally agreed order for SOC and using descending order of overall numerical 
counts for PT. Where terms tie, these will be sorted alphabetically. 
Medical history records will be listed by-subject and within-subject by medical history start 
date for the ITT population. 
 
6.4.4. Prior and Concomitant Medications 
All medications will be coded using the WHO Drug Global Dictionary, Format B3 [Version 
SEP 2021 (or a later version if updated during the study)], Anatomical Therapeutic Chemical 
(ATC) Classification codes. 
Prior medications and concomitant medications are defined as follows: 
• Prior medications are those taken prior to screening with a stop date and time prior to 
the start of the Treatment Period. 
• Concomitant medications are those with a start date and time on or after the start of 
the Treatment Period, or those with a start date and time before the start of the 
Treatment Period and either a stop date and time on or the start of the Treatment 
Period, or are ongoing at the end of the study. 
 
See Section 5.2.3 for imputation of missing or partial dates for medication. 
 
Prior and concomitant medications will be summarized separately for the ITT population by 
treatment group and overall for Part A of the study as follows: 


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• The number and percentage of subjects with at least one prior / concomitant 
medication will be presented. 
• The number and percentage of subjects with at least one prior / concomitant 
medication within each Anatomical Group (ATC Level 1), Therapeutic Subgroup 
(ATC Level 2), and preferred term will be presented. The summary will be sorted 
using numerical counts by descending order of Anatomical Group, then descending 
order of Therapeutic Subgroup, then descending order of preferred term in the total 
column. Where groups or terms tie these will be sorted alphabetically. 
 
Prior medications and concomitant medications will be listed separately for the ITT 
population. In the listings the relative start and stop day of prior / concomitant medication use 
will be calculated relative to the first dose date and time of treatment and will be presented 
for those subjects who received at least one dose of treatment. If the concomitant medication 
is “Ongoing” it will be indicated as such in the listing and the relative stop day will not be 
calculated. Only original dates will be presented in the listing even though the relative day 
may be based on an imputed date. 
6.4.5. Prohibited Concomitant Therapy 
Prohibited concomitant therapies are defined as he following drugs taken by subjects from the 
time of ICF signing onwards: 
• PDE-5 inhibitors (ATC codes G04BE03 and G04BE08) 
• Known strong inhibitors CYP3A4: 
o Atazanavir (J05AE08) 
o Ceritinib (L01ED02) 
o Clarithromycin (J01FA09) 
o Cobicistat and cobicistat-containing coformulations (V03AX03, J05AR14, 
J05AR15) 
o Darunavir (J05AE10, J05AR22, J05AR26) 
o Idelalisib (L01EM01) 
o Indinavir (J05AE02) 
o Itraconazole (J02AC02) 
o Ketoconazole (D01AC08, D01AC08, H02CA03, J02AB02) 
o Levoketoconazole 
o Lonafarnib (A16AX20) 
o Lopinavir (J05AR10) 
o Mifepristone (G03XB01, G03XB51) 
o Nefazodone (N06AX06) 
o Nelfinavir (J05AE04) 
o Ombitasvir-paritaprevir-ritonavir (J05AP53) 


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o Ombitasvir-paritaprevir-ritonavir plus dasabuvir (J05AP52) 
o Posaconazole (J02AC04) 
o Ritonavir and ritonavir-containing coformulations (J05AR10, J05AR23, 
J05AR26, J05AR10, J05AP53, J05AP53) 
o Saquinavir (J05AE01) 
o Telithromycin (J01FA15) 
o Tucatinib (L01EH03) 
o Voriconazole (J02AC03) 
• Known strong inducers of CYP3A4: 
o Apalutamide (L02BB05) 
o Carbamazepine (N03AF01) 
o Enzalutamide (L02BB04) 
o Fosphenytoin (N03AB05) 
o Lumacaftor (R07AX30) 
o Lumacaftor-ivacaftor (R07AX30) 
o Mitotane (L01XX23) 
o Phenobarbital (N03AA02) 
o Phenytoin (N03AB02, N03AB05, N03AB04, N03AB54, N03AB52) 
o Primidone (N03AA03) 
o Rifampin (rifampicin) (J04AB02, J04AM02, J04AM05, J04AM07, 
04AM06) 
 
Prohibited concomitant therapy will be listed for the ITT population. 
 
6.5. Measurements of Treatment Compliance 
Treatment compliance is defined as the number of tablets that were actually taken relative to 
the number of tablets that should have been taken as per the protocol for the duration of actual 
treatment exposure. 
In general, the percentage compliance, assessed by tablet count, will be calculated as follows: 
 
Compliance (%) = 
 Number of tablets dispensed – Number of tablets returned  × 100% 
Number of days on treatment x 2 x Number of tablets/dose 
Number of tablets per dose is 
 mg dosing. 
Number of days on treatment will be calculated as follows: 
(last dose date of treatment - first dose date of treatment) + 1 
The calculated percentage compliance will be categorized as: 




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The least square means of the change from baseline for each treatment group, along with the 
95% confidence intervals (CI), and the least square mean treatment difference and the 
associated 95% CI for this difference will come from the ANCOVA model. 
Observed values and absolute change from baseline at each analysis visit for plasma cGMP 
AUC will be summarized by treatment group using default summary statistics for continuous 
variables on the mITT population. 
Absolute change from baseline at each analysis visit for plasma cGMP AUC will be plotted 
by treatment group using mean and standard error for continuous variables on the mITT 
population. 
cGMP data will be listed for mITT population. 
 
6.6.2. Sensitivity Analysis for the Primary Efficacy Endpoints 
Part A 
The following sensitivity analyses of the primary efficacy endpoint will be performed: 
• Primary analysis will be repeated on the PP population. 
• Primary analysis will be repeated on the Week 2 Analysis population. This analysis 
will be performed for interim DMC purposes only. 
• Primary analysis will be repeated on the Week 4 Analysis population. This analysis 
will be performed for interim DMC purposes only. 
• Change from baseline in log-transformed plasma cGMP AUC over time will be 
analyzed in the mITT population using a mixed model for repeated measures 
(MMRM) including treatment, post-baseline visit (Visits 3, 5 and 7), Entresto use, 
treatment-by-visit interaction, treatment-by-Entresto interaction, visit-by-Entresto use 
interaction, and baseline EF as a covariate with random effects for subject, intercept, 
and slope. The covariance structure will be unstructured. No imputation of missing 
data will be performed. The least-square means of log (plasma cGMP AUC) and 
associated two-sided 95% CI for each treatment, the estimated least square mean 
treatment differences (on the log scale), and corresponding two-sided 95% CI coming 
from the MMRM will be given for all visits. 
• The MMRM analysis described above will be conducted on raw plasma cGMP AUC 
in the mITT population. 












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• > 12 weeks 
 
Duration of exposure will be summarized in two ways for the SAF by treatment group and 
overall for Part A of the study. 
• 
Descriptive statistics will be presented for duration of exposure. 
• 
Number and percentage of subjects within each of the exposure categories will be 
presented. 
A listing of overall treatment exposure data, including the first and last dates of treatment will 
be presented together with compliance for the SAF. Further, study treatment administration 
data will be listed for the SAF. 
 
6.7.2. Adverse Events 
All AEs recorded on the eCRF will be coded using the MedDRA dictionary [version 24.1 or 
a later version if updated during the study] and classified as either pre-treatment AEs or 
treatment–emergent AEs (TEAEs) as follows: 
• Pre-treatment AEs are events that start prior to the start of the Treatment Period. 
• TEAEs are either events with start date and time after the first study treatment 
administration or events with start date and time prior to the first study treatment 
administration whose severity worsening or becoming serious after the start of the 
Treatment Period. 
• The relationship between a TEAE and treatment is assessed as related, or not related. 
A treatment-related TEAE will be defined as a TEAE considered by the investigator 
as related to treatment or unknown / missing relationship to treatment. 
• The severity of and AE is assessed as Mild / Moderate / Severe according to the 
investigator. Severe TEAEs are defined as TEAEs assessed as being “Severe” and 
includes those events where the severity is missing. 
• TEAEs leading to discontinuation of study are defined as TEAEs where “Required 
Withdrawal from study” is indicated as other action taken on AE eCRF form. 
• TEAEs leading to discontinuation of study treatment are defined as TEAEs where 
“Drug Withdrawn” is indicated as action taken with study treatment on AE eCRF 
form 
• TEAEs leading to dose interruption are defined as TEAEs where “Drug Interrupted” 
is indicated as action taken on AE eCRF form 
 
For Part A, the primary safety analysis will be performed by reporting the exposure-adjusted 
incidence rates in subject-years for AE and SAE defined as the number of subjects with that 
particular AE or SAE within a system organ class or preferred term during the relevant period 
divided by the sum of the at-risk times. For a subject who does not have that particular AE or 
SAE, the at risk time is the exposure time in each period in years. For a subject who does have 


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that particular AE or SAE, the at risk time is the exposure time until the event occurs in each 
period in years. The adjusted incidence rates will be presented by system organ class and 
preferred term for Period 1, and separately for Periods 2 and 3 combined. The Hodges- 
Lehmann methodology will be used to estimate the within-subject point and interval treatment 
difference. 
Adverse events will be summarized by treatment group and overall by dose period (Period 1, 
Period 2, Period 3, pooled Period 2 and Period 3, and overall) for Part A in the SAF. 
• An overview of TEAEs including the number and percentage of subjects with at least 
one of each mentioned TEAE type: 
o Any TEAE 
 Leading to discontinuation of study 
 Leading to discontinuation of study treatment 
 Leading to death 
 Mild 
 Moderate 
 Severe 
o Any study treatment related TEAE 
 Leading to discontinuation of study 
 Leading to discontinuation of study treatment 
 Leading to death 
o Any serious TEAE 
 Leading to discontinuation of study 
 Leading to discontinuation of study treatment 
 Leading to death 
o Any serious study treatment related TEAE 
 Leading to discontinuation of study 
 Leading to discontinuation of study treatment 
 Leading to death 
 
• The number and percentage of subjects reporting each TEAE and the count of number 
of events will be summarized by SOC and PT for the following types of TEAEs: 
o All TEAEs 
o TEAEs Leading to Discontinuation of Study Treatment 
o TEAEs Leading to Dose interruption 
o TEAEs Leading to Study Withdrawal 
o TEAEs Leading to Death 
o TEAEs by Maximum Severity 
o TEAEs by Relationship to Treatment 
o TEAEs by Relationship and Maximum Severity 
o Study Treatment related TEAEs 
o Study Treatment Related TEAEs Leading to Discontinuation of Study 
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o Study Treatment related TEAEs Leading to Death 
o Serious TEAEs 
o Serious TEAEs Leading to Discontinuation of Study Treatment 
o Serious TEAEs Leading to Dose Interruption 
o Serious TEAEs Leading to Study Withdrawal 
o Serious TEAEs Leading to Death 
o Study Treatment Related Serious TEAEs 
o Study Treatment Related Serious TEAEs Leading to Discontinuation of Study 
Treatment 
o Study Treatment Related Serious TEAEs Leading to Death 
o Study Treatment Related Serious TEAEs Leading to Study Withdrawal 
• The number and percentage of subjects who died will be summarized by the primary 
reason of death (if available) 
In the above summaries, subjects with more than one TEAE within a particular SOC are 
counted only once for that SOC. Similarly, subjects with more than one TEAE within a 
particular PT are counted only once for that PT. 
For summaries by maximum severity, subjects with multiple TEAEs within a particular SOC 
or PT will be counted under the category of their most severe TEAE within that SOC or PT. 
Summaries by SOCs and PTs will be sorted by SOCs by their Internationally Agreed Order 
(MedDRA) and PTs within SOC by descending order of total incidence. Where preferred 
terms tie PTs will be sorted alphabetically. 
No statistical comparisons of AEs between treatment groups will be performed. 
All AE data will be listed and Pre-treatment AEs and TEAEs will be presented together. 
Treatment-emergence status will be flagged in the listing. The listing will present the relative 
start and stop day of the AE calculated relative to the first dose of treatment and will be 
presented for those subjects who received at least one dose of treatment. If the AE is 
“Ongoing” it will be indicated as such in the listing and the relative stop day will not be 
calculated. Only original dates will be presented in the listing even though the relative day 
may be based on an imputed date. 
In addition, the following listings will be presented: 
• Listing of Deaths 
• Listing of Serious TEAEs 
• Listing of Severe TEAEs 
• Listing of AEs Leading to Interruption of Study Treatment 
• Listing of AEs Leading to Discontinuation of Study Treatment 
• Listing of AEs Leading to Study Withdrawal 






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Laboratory data will be summarized by default descriptive summary statistics for continuous 
and categorical variables by treatment group and overall by dose period (Period 1, Period 2, 
Period 3, pooled Period 2 and Period 3, and overall) for Part A in the SAF as follows: 
•  Observed values and change from baseline at each assessed timepoint for each 
standard continuous laboratory parameter; 
• Number and percentage of subjects with categorized shift (low, normal and high) 
values relative to the reference range at baseline compared to each post-baseline 
timepoint standard continuous laboratory hematology and chemistry parameter; 
• Number and percentage of subjects with worst post-baseline NCI-CTCAE toxicity 
values; 
• Number and percentage of subjects with categorized shift NCI-CTCAE toxicity values 
at baseline compared to each post-baseline timepoint. 
 
In addition, box plots of AST, ALT, Total Bilirubin and Creatinine values at baseline and 
each post-baseline visit will be generated for the SAF. 
Listings of all clinical laboratory data including derived percentage change from baseline will 
be provided for the SAF. Within each listing, laboratory values outside the normal ranges will 
be flagged as either high or low. 
In addition, a listing of hematology and serum chemistry parameters of toxicity grade 2 and 
above will be provided. 
 
6.7.4. Vital Signs 
The analyses described below will be conducted for the following vital signs assessments 
respectively: 
• systolic blood pressure (mmHg); 
• diastolic blood pressure (mmHg); 
• pulse rate (bpm); 
• weight (kg); 
• respiration rate (breaths / min); 
• body temperature (°C). 
 
The following will be summarized by treatment group and overall by dose period (Period 1, 
Period 2, Period 3, pooled Period 2 and Period 3, and overall) for Part A in the SAF: 
•  Observed values and change from baseline at each assessed timepoint for each 
standard vital sign parameter using default summary statistics for continuous 
variables; 




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post-baseline value. 
 
Box plots of QTcF at baseline and each post-baseline visit will be generated for the SAF. A 
listing of all ECG data including derived change from baseline will be provided for the SAF. 
 
6.7.6. Physical Examination 
Abnormalities identified from physical examination are recorded in the eCRF as Medical 
History or AEs as appropriate and will be listed and summarized as such [See Sections 6.4.3 
(Medical History) and 6.7.2 (Adverse Events)]. 
 
For each physical examination body system, the number and percentage of subjects with 
abnormalities at baseline and at each assessed timepoint will be summarized by treatment 
group and overall by dose period (Period 1, Period 2, Period 3, pooled Period 2 and Period 3, 
and overall) for Part A in the SAF. 
Physical examination findings (normal / abnormal) and details of abnormalities will be listed 
for each subject at each assessed timepoint in the SAF. 
 
6.7.7. Interim Analysis and Data Monitoring 
No interim analysis (blinded or unblinded) will be performed. 
An independent DMC will be established at the beginning of the study. The DMC will be 
responsible for ensuring the safety of study subjects, study integrity, and validity of study 
results. 
The DMC will review study results from Part A. The DMC members will not be involved in 
any day-to-day study decisions and will remain independent from the study team. The DMC 
will review safety and efficacy data to make recommendations concerning study continuation, 
modification, and termination based on ongoing study data. 
The DMC will operate according to a DMC charter, which will describe the DMC’s 
membership, roles, and responsibilities. 
 
At each of the DMC meetings, the DMC will assess whether the safety profile of the 
Investigational Product (IP) is acceptable to allow the current trial to continue without 
adjustment. 
The DMC can make recommendations based on safety considerations at the DMC meetings 
that take place while subjects are still undergoing treatment. 
For all meetings, the DMC will be provided with the following data to assess the safety of 
the IP: 


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1. Summary of subject enrollment (Section 6.2) 
2. Subject disposition (Section 6.2) 
3. Demographics and baseline characteristics (Sections 6.4.1 and 6.4.2) 
4. Prior and concomitant medications (Section 6.4.4) 
5. Treatment exposure data (Section 6.7.1) 
6. Safety profile (TEAEs, treatment-related TEAEs, serious TEAEs, TEAEs 
leading to study withdrawal, TEAEs of severe intensity, laboratory values of at 
least grade 2 toxicity) (Sections 6.7.2 and 6.7.3) 
7. Deaths (Section 6.7.2) 
8. Clinical laboratory results (Section 6.7.3) 
9. Other safety information (vital sign measurements, ECG results, questionnaires) 
(Sections 6.7.4, 6.7.5, 6.7.6) 
10. Subjects randomized and not meeting eligibility criteria (Section 6.2) 
11. PK analysis (Section 6.8) 
 
The DMC can recommend stopping the trial or modifying the trial design if there are 
significant concerns regarding the safety profile of the IP. 
Efficacy analysis data will also be provided: 
For Part A: 
 
1. The change from baseline in plasma cGMP AUC at Week 2 and Week 4 (Section 
6.6.1) 
2. The change in NT-proBNP from baseline to Week 2, to Week 4, and to Week 12 
(Section 6.6.6.1) 
3. The change in BNP from baseline to Week 2, to Week 4, and to Week 12 
(Section 6.6.6.1) 
4. The change in plasma, spot urine, and 6-hour urine collection cGMP from 
baseline to Week 2, to Week 4, and to Week 12 (Section 6.6.6.2) 
5. The change from baseline at Week 12 in the KCCQ-23-CS, KCCQ-23-OS, and 7 
domains: physical limitation, symptom stability, symptom frequency, symptom 
burden, quality of life, self-efficacy, and social limitation (Section 6.6.6.4) 
6. The proportion of subjects with ≥5-point improvement from baseline in the 
KCCQ-23-CS (Section 6.6.6.4) 
 
The list of tables and listings provided for each safety data review will be a subset of the 
global TFL shells from the trial: the ones that are provided for the DMC will be flagged. 
 
The DMC will not perform any formal (based on conditional probability) futility assessment. 




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The parameters Cmax and tmax will be obtained directly from the concentration-time profiles. 
If Cmax occurs at more than 1 timepoint, tmax will be assigned to the first occurrence of Cmax. 
6.8.1.1. Criteria for Calculation and Reporting of Area Under the 
Concentration-time Curve 
The minimum requirement for the calculation of AUC will be the inclusion of at least 
3 consecutive concentrations above the lower limit of quantification. If there are only 
3 consecutive concentrations, at least 1 should follow Cmax. 
6.8.1.2. Criteria for Handling Concentrations Below the Limit of Quantification 
or Missing Concentrations for Pharmacokinetic Analysis 
Plasma concentrations below the limit of quantification (BLQ) will be assigned a value of 0 
before the first measurable concentration and thereafter BLQ concentrations will be treated 
as missing. The following rules apply to the specific situations defined below: 
● If an entire concentration-time profile is BLQ, it will be excluded from PK analysis. 
● Where 2 or more consecutive concentrations are BLQ at the end of a profile, the 
profile will be deemed to have terminated and any further quantifiable 
concentrations will be set to missing for the calculation of the PK parameters, unless 
they are considered to be a true characteristic of the profile of the drug. 
● If a predose plasma concentration is missing, it will be set to 0 by default within 
Phoenix WinNonlin for the first dosing day. 
6.8.1.3. Treatment of Outliers in Pharmacokinetic Analysis 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude the value from the PK analysis. However, the 
exclusion of any data must have strong justification and will be documented in the CSR. 
Any quantifiable predose concentration value on the first dosing day will be considered 
anomalous and set to missing for the PK analysis. This will be set to 0 by default in Phoenix 
WinNonlin. 
6.8.1.4. Presentation of Pharmacokinetic Data 
If the actual time of sample collection deviates by more than protocol window the plasma 
blood concentration may be flagged and excluded from the summary statistics at discretion 
of Pharmacokineticist. 
Individual concentrations deemed to be anomalous will be flagged in the listings and 
excluded from the summary statistics. 


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PK parameters will be reported to 3 significant figures. Summary statistics will be presented 
for all PK parameters with the following exception: 
● Geometric mean and coefficient of variation will not be calculated for tmax 
All PK concentrations and parameters will be listed for the Pharmacokinetics Analysis Set. 
Summary tables, mean (+ standard deviation [SD]) figures, overlaying individual figures, and 
individual figures dose level and by PK profile (Day 1, Week 2 and Week 4) and time postdose 
will be provided for plasma PK concentrations. All figures will be produced on both linear 
and semi-logarithmic scales. 
Summary tables dose level and by PK profile (Day 1, Week 2 and Week 4) will be provided 
for all PK parameters, with the exception of regression-related PK parameters. 
 
Additional PK outputs may be presented if appropriate. 
 
In addition, for parameters Cmax and AUC, the geometric means, the geometric mean CV% 
and the 95% CI of geometric means will be provided. 
The geometric mean CV% will be calculated according to the following formula: 
100 × sqrt(exp(s2) - 1), where s2 is the observed variance on the natural log-scale. The 
geometric mean and its 95% CI will be obtained by exponentiating the mean and 95% CI of 
the mean on the natural log-scale 
Scatter plots will be also performed presenting changes from baseline in plasma cGMP (time- 
matched 1-hour, 2-hour, 3-hour and 6-hour), cGMP AUC and 6-hour urine collection cGMP 
versus CRD-740 concentrations (2-hour concentration for cGMP AUC and 6-hour urine 
cGMP, and time-matched concentration for plasma cGMP) by dose period (Period 1, Period 
2, Period 3, pooled Period 2 and Period 3) and overall on the Pharmacokinetics Analysis Set, 
including Pearson and Spearman correlation coefficient values 


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7. Changes in the Conduct of the Study or Planned Analysis 
Baseline calculation for cGMP (that is collected at several timepoints) in Part A has been 
defined using time-matched values and using AUC0-6. 
Baseline calculation for spot urine cGMP in Part A has been defined as the last non-missing 
value collected before the first dose of treatment rather than the Day -1 value noted in the 
protocol. 
Analysis (ANCOVA) of change from baseline in cGMP AUC at Week 2 has been added for 
Part A. 
Racc(AUC0-6) and Racc(Cmax) have been removed from PK endpoints and parameters to 
analyse, as only approximations of these parameters can be retrieved: AUCtau can only be 
calculated on Day 29, hence we would have to base accumulation ratio on AUC0-6. In addition, 
there are different doses between day 29 and Day 1 which is problematic for the calculation. 
Only a dose adjustement could be used (if the compound displays linear PK over dose) to 
provide approximate Racc parameters. 
Any deviations from the approved SAP will be described and justified in the CSR. 




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9. References 
 
1ICH. Statistical Principles for Clinical Trials, Guideline E9, 1998. Available at 
https://database.ich.org/sites/default/files/E9_Guideline.pdf 
 
2ICH. Addendum on Estimands and Sensitivity Analysis in Clinical Trials, Guideline E9(R1). 
Available at 
https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf 
 
3ICH. Structure and Content of Clinical Study Reports, Guideline E3, 1995. Available at 
https://database.ich.org/sites/default/files/E3_Guideline.pdf 
 
4Brown H and Prescott R. Applied Mixed Models in Medicine. John Wiley & sons 
(Chichester), 1999. 
 
5Katz D, D’Argenio DZ. Experimental design for estimating integrals by numerical 
quadrature, with application to pharmacokinetic studies. Biometrics. 1983;39:621–628. 
 
6Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_60 
 
7ICH. E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-Antiarrhythmic Drugs. 12 May 2005. Available at 
https://database.ich.org/sites/default/files/E14_Guideline.pdf