A Phase 2, Randomized, Double-Blind, Placebo-Controlled Clinical Study to Assess the Effectiveness of CRD-740 in Subjects With Chronic Heart Failure (CARDINAL-HF)
Phase: PHASE2
Conditions: Heart Failure, Heart Failure With Reduced Ejection Fraction, Heart Failure With Preserved Ejection Fraction, Cardiovascular Diseases, Heart Diseases
Sponsor: Cardurion Pharmaceuticals, Inc.

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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.