Clinical trial NCT03554291
Conditions: Pulmonary Arterial Hypertension Right Heart Failure
Keywords: famotidine H2 blocker H2 antagonist
Sponsor: University of Washington
Start date: 2019-05-01; Completion date: 2023-07-11
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, single-center, randomized placebo controlled trial of famotidine (an H2 receptor antagonist) in adults with pulmonary arterial hypertension. The study will evaluate the safety and clinical efficacy of a 24-week course of famotidine.

Detailed description:
Pulmonary arterial hypertension (PAH) is one of many conditions that put stress and strain on the right side of the heart. This stress and strain can cause right heart failure. Although there are medications to treat PAH, there are currently no medications that act directly on the heart to improve right heart function. This is different than left heart failure where one of the cornerstones of treatment is medication targeted at the heart to improve left heart function.

Famotidine is a well-tolerated, over-the-counter, and inexpensive medication. Preliminary results suggest that famotidine may help the right heart to adapt and strengthen when stressed instead of fail; however, these results are suggestive and not definitive. A randomized controlled trial is required to evaluate the possibility that famotidine can impact right heart function.

Participants in the study will take famotidine or placebo for 24 weeks. They will have three study visits at 0, 12, and 24 weeks. These visits will add 20-30 minutes to the standard clinic visits at those time points and there will be an echocardiogram at weeks 0 and 24. There will also be one phone visit at 4 weeks to check-in. Some participants may elect to participate in exercise testing and/or right heart catheterization at weeks 0 and 24; however, this is not required to participate in the trial.

Arms: arm 1: 20mg of oral famotidine (pill) daily

Other names: Pepcid arm 2: Daily oral placebo (pill)
Interventions: intervention 1: Famotidine 20 MG intervention 2: Placebo
Intervention descriptions: intervention 1: Famotidine 20 mg capsule taken daily for 24 weeks. intervention 2: Placebo capsule taken daily for 24 weeks.

Protocol documents:
SAP_002.pdf: 
  
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Protocol REHAB-PH 
 
Repurposing a histamine antagonist to benefit patients with pulmonary 
hypertension 
Protocol Number: 
(Version Date) 
NCT03554291  
Protocol Version 1.8 (12-DEC-2022) 
Name of Test Drug: 
Famotidine  
Phase: 
2 
Methodology: 
Single-center, randomized, double-blinded, placebo 
controlled, parallel design 
Sponsor: 
University of Washington 
1959 NE Pacific St. 
Seattle, WA 98195 
(206) 685-2484 
Sponsor Representative: 
Peter Leary, M.D., Ph.D. 
 
Document Date: 
30 AUGUST 2023 
Document Version: 
1.00 
 
 
 


  
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SIGNATURE PAGE 
 
Protocol Title: 
Repurposing a histamine antagonist to benefit patients 
with pulmonary hypertension 
Sponsor: 
University of Washington 
Sponsor Address, Telephone 
Protocol Number: 
NCT03554291 
Document Date/Version: 
30-AUG-2023 / Version 1.00 
Cytel, Inc. Author: 
Alexander Karpov, Ph.D. 
Cytel, Inc. 
675 Massachusetts Avenue 
Cambridge, MA 02139 
 
 
Signature:___________________________________ 
 
Date:_______________________________________ 
Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein.  I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidance’s and guidelines. 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author. 
I also understand that any subsequent changes to the planned statistical analyses, as 
described herein, may have a regulatory impact and/or result in timeline adjustments.  All 
changes to the planned analyses will be described in the clinical study report (CSR). 
Sponsor Signatory: 
Peter Leary, M.D., Ph.D. 
University of Washington 
1959 NE Pacific St. 
Seattle, WA 98195 
 
 
Signature:___________________________________ 
 
Date:_______________________________________ 
 
 
Signature:
Email:
Signature:
Email:
Electronically signed by: Alexander
Karpov
Reason: Approve
Date: Aug 30, 2023 14:48 EDT
30-Aug-2023
alexander.karpov@cytel.com
Electronically signed by: Peter Leary
Reason: Approve
Date: Aug 30, 2023 12:03 PDT
30-Aug-2023
learyp@uw.edu


  
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MODIFICATION HISTORY 
Current 
Version 
Date 
Amended by 
Summary of Changes from 
previous version 
Reason 
1.00 
 
 
Original document  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
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Table of Contents 
1 
INTRODUCTION AND OBJECTIVES OF ANALYSIS ................................................................... 8 
1.1 
INTRODUCTION .................................................................................................................... 8 
1.2 
OBJECTIVES ........................................................................................................................ 8 
2 
STUDY DESIGN ............................................................................................................................. 9 
2.1 
INTRODUCTION .................................................................................................................... 9 
2.2 
RANDOMIZATION METHODOLOGY ........................................................................................ 11 
2.3 
STOPPING RULES .............................................................................................................. 11 
2.4 
BLINDING ........................................................................................................................... 11 
2.5 
INTERIM ANALYSES ............................................................................................................ 12 
3 
STUDY ENDPOINTS ................................................................................................................... 13 
3.1 
EFFICACY VARIABLES ......................................................................................................... 13 
3.2 
PHARMACOKINETIC VARIABLES ........................................................................................... 15 
3.3 
SAFETY VARIABLES ............................................................................................................ 15 
4 
ANALYSIS SETS .......................................................................................................................... 16 
4.1 
ANALYSIS SET DEFINITIONS ................................................................................................ 16 
4.2 
PROTOCOL DEVIATIONS ..................................................................................................... 16 
5 
DATA HANDLING ........................................................................................................................ 18 
5.1 
COMPUTING ENVIRONMENT ................................................................................................ 18 
5.2 
DATA CONVENTIONS .......................................................................................................... 18 
5.3 
METHODS OF POOLING DATA ............................................................................................. 19 
5.4 
WITHDRAWALS, DROPOUTS, LOSS TO FOLLOW-UP .............................................................. 19 
5.5 
VISIT WINDOWS ................................................................................................................. 19 
6 
STATISTICAL METHODS ............................................................................................................ 20 
6.1 
SAMPLE SIZE JUSTIFICATION .............................................................................................. 20 
6.2 
GENERAL STATISTICAL METHODS ....................................................................................... 21 
6.2.1 
General Methods ......................................................................................................... 21 
6.2.2 
Definition of Baseline ................................................................................................... 22 
6.2.3 
Adjustments for Covariates ......................................................................................... 22 
6.2.4 
Multiple Comparisons/Multiplicity ................................................................................ 22 
6.2.5 
Subgroups ................................................................................................................... 22 
6.2.6 
Missing, Unused, and Spurious Data .......................................................................... 22 
6.3 
STUDY POPULATION ........................................................................................................... 23 
6.3.1 
Subject Disposition ...................................................................................................... 23 
6.3.2 
Demographic and Baseline Characteristics ................................................................. 24 
6.3.3 
Prior Medication .......................................................................................................... 24 
6.3.4 
Exposure and Compliance .......................................................................................... 25 


  
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6.4 
EFFICACY EVALUATION ...................................................................................................... 25 
6.4.1 
Primary efficacy analysis ............................................................................................. 25 
6.4.2 
Secondary analysis ..................................................................................................... 27 
6.4.3 
Sub-study analysis ...................................................................................................... 29 
6.4.4 
Exploratory analysis .................................................................................................... 30 
6.5 
PHARMACOKINETIC EVALUATIONS ....................................................................................... 30 
6.6 
SAFETY EVALUATIONS ....................................................................................................... 31 
6.6.1 
Adverse Events ........................................................................................................... 31 
6.6.2 
Laboratory Data ........................................................................................................... 32 
6.6.3 
Vital Signs and Physical Examinations ........................................................................ 32 
6.6.4 
Electrocardiogram ....................................................................................................... 32 
7 
CHANGES TO PLANNED ANALYSES ........................................................................................ 33 
8 
REFERENCES ............................................................................................................................. 34 
9 
APPENDICES............................................................................................................................... 35 
9.1 
SCHEDULE OF ASSESSMENTS ............................................................................................. 35 
9.2 
ESTIMANDS ....................................................................................................................... 38 
9.3 
LABORATORY CONVERSION FACTORS ................................................................................. 39 
10 
LIST OF STATISTICAL OUTPUTS .............................................................................................. 40 
 
 
 
 


  
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List on in-text Tables                                                             
 
               Page 
Table 3-1: Study objectives and endpoints ............................................................................................... 13 
Table 5-1: Evaluation Intervals for Efficacy Analysis ................................................................................. 19 
Table 6-1: Power to detect a minimally important difference in 6MWD (31.9 meters) .............................. 20 
Table 9-1: Schedule of assessments ........................................................................................................ 35 
Table 9-2: Laboratory parameters ............................................................................................................. 39 
 
 
 
List on in-text Figures                                                              
 
               Page 
Figure 2-1: Study design ........................................................................................................................... 10 
 
 
 


  
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ABBREVIATIONS 
Abbreviation 
Definition 
6MWD 
Six-minute walk distance 
AE 
Adverse event 
ATC 
Anatomic Therapeutic Class  
BNP 
Brain natriuretic peptide 32 
CMH 
Cochran-Mantel-Haenszel  
CPET 
Cardiopulmonary exercise testing  
CRO 
Contract research organization  
CSR 
Clinical study report 
DSMB 
Data and safety monitoring board  
ECG 
Electrocardiogram 
FAS 
Full Analysis Set  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice  
ICEs 
Intercurrent events  
ICH 
International Council on Harmonization 
IWRS 
Interactive web response system  
MCMC 
Markov Chain Monte Carlo  
MedDRA 
Medical Dictionary for Regulatory Activities 
MVN 
Multivariate normal distribution  
PAH 
Pulmonary arterial hypertension 
PK 
Pharmacokinetic 
PPS 
Per Protocol Set  
PT 
Preferred Term 
RHC 
Right heart catheterization  
SAE 
Serious adverse event  
SAF 
Safety analysis set  
SAP 
Statistical analysis plan 
SOC 
System Organ Class 
TAPSE 
Tricuspid Annular Plane of Systolic Excursion  
TEAE 
Treatment-emergent adverse event  
WCS 
Worst case scenario  
 
 
 
 
 


  
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1 INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1 Introduction 
This statistical analysis plan (SAP) is designed to outline the methods to be used in the 
analysis of study data to answer the study objective(s).  The statistical analyses and summary 
tabulations described in this SAP will provide the basis for the results sections of the clinical 
study report (CSR) for this trial. 
 
1.2 Objectives  
 
Primary Objective:   
To determine whether famotidine increases six-minute walk distance at 24 weeks in 
men and women with pulmonary arterial hypertension. 
 
Secondary Objectives:  
• 
To determine whether famotidine reduces BNP at 24 weeks  
• 
To determine whether famotidine improves New York Heart Association (NYHA) 
functional class at 24 weeks 
• 
To determine whether famotidine improves right ventricular morphology at 24 weeks 
including improved right ventricular dilation and TAPSE 
• 
To determine whether famotidine improves health related quality of life as estimated by 
the emPHasis-10 score 
• 
To determine whether famotidine decreases the need to escalate PAH focused care 
(increased diuretics, escalating doses of pulmonary vasodilators, and/or adding an 
additional pulmonary vasodilator) 
 
Exercise sub-study: 
• 
To determine whether famotidine increases maximal oxygen uptake in individuals with 
pulmonary arterial hypertension at 24 weeks 
• 
To explore changes in other metrics of the exercise response (oxygen uptake, 
Ve/VCO2 ratio, total achieved wattage) with famotidine relative to placebo over 24 
weeks.  
 
Right heart catheterization sub-study  
• 
To determine whether famotidine increases stroke volume index at 24 weeks  
• 
To explore whether famotidine is associated with differences in wedge pressure, right 
atrial pressure, and/or pulmonary vascular resistance at 24 weeks 
 
 


  
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2 STUDY DESIGN  
2.1 Introduction 
Pulmonary arterial hypertension (PAH) is one of many conditions that put stress and strain on 
the right side of the heart. This stress and strain can cause right heart failure. Although there 
are medications to treat PAH, there are currently no medications that act directly on the heart to 
improve right heart function. This is different than left heart failure where one of the 
cornerstones of treatment is medication targeted at the heart to improve left heart function. 
Famotidine is a well-tolerated, over-the-counter, and inexpensive medication. Preliminary 
results suggest that famotidine may help the right heart to adapt and strengthen when stressed 
instead of fail; however, these results are suggestive and not definitive. A randomized 
controlled trial is required to evaluate the possibility that famotidine can impact right heart 
function. 
This study is a Phase II, single-center, double-blinded, randomized, placebo controlled trial 
designed to test whether famotidine improves functional capacity and metrics of right heart 
failure relative to placebo in participants with pulmonary arterial hypertension over 24 weeks. In 
addition, there are two sub-studies. One sub-study involves cardiopulmonary exercise testing 
and the other sub-study involves invasive hemodynamic evaluation using right heart 
catheterization. 
Approximately 80 participants, male or female, age 18 to 80 with WHO Group 1 Pulmonary 
Arterial Hypertension and NYHA Functional Class II, III, or IV at screening will be randomized 
to receive placebo or famotidine, 20 mg daily, per oral, and will be assessed for efficacy and 
safety for 24 weeks as described in the Schedule of Assessments of the protocol. The 
Schedule of Assessments is provided in Table 9-1, further details are available in the study 
protocol. 
The study will consist of the following periods: 
• 
Screening period: up to 21 days 
• 
Treatment period: up to 24 weeks  
The study design is shown in Figure 2-1. 
There are two sub-studies proposed for this trial. One sub-study involves cardiopulmonary 
exercise testing (CPET) and the other sub-study involves invasive hemodynamic evaluation 
using right heart catheterization (RHC). Understanding the relationship between therapy, 
exercise response, and invasive hemodynamic assessment is important for all pulmonary 
arterial hypertension (PAH) therapies and such studies are very common in trials of PAH-
specific therapy. To date, nearly all therapeutic trials for participants with PAH have focused on 
medications intended to lower pulmonary vascular resistance and right heart afterload. Few 
studies have evaluated therapies intended to improve right heart fitness in the absence of 
changes in right heart afterload (“right heart targeted therapy”). Targeting myocardial histamine 
H2 receptors is one such therapy that is hypothesized to impact right heart fitness without 


  
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changing right heart afterload. While the two proposed sub-studies are powered to detect 
plausible, but large differences in exercise response or invasive hemodynamic markers, these 
studies are not powered to detect small to moderate differences. The co-primary intent of these 
sub-studies is to begin to understand appropriate end-points in trials of right heart targeted 
therapy. This more exploratory motivation is intended to complement but not supplant primary 
and secondary outcome measures including six-minute walk distance, BNP, and right 
ventricular structure and function by echocardiography in the current trial. Lessons learned 
from resting, exercise, and invasive measures will be used to inform subsequent trials of right 
heart targeted therapy using famotidine and/or other compounds. Exercise response and 
invasive hemodynamic differences in participants with pulmonary hypertension with and without 
exposure to famotidine will be studied.  
 
Figure 2-1: Study design 
 
 
All patients in the pulmonary vascular disease clinic are pre-screened using the electronic 
medical record.  
Those interested in participation and eligible will be consented at their baseline visit. For most 
participants in the main study, all study assessments will occur during one study visit; however, 
sub-study participants and occasional main study participants may have study assessments on 
two or more different days. If this occurs then randomization will occur following the last 
baseline study assessment. Individuals who appear to violate inclusion or exclusion criteria as 
Day -21 to Day -1 
Pre-Screening 
Day -14 to Day -1 
Baseline including 
sub-study 
assessments / 
Randomization 
Day 0 – Week 24 
Maintenance 
Week 24 
End of Study Assessments (EOS) 
Intervention N= 40 
Placebo N= 40 
2 in-clinic 
visits and 
1 telephone 
contact 


  
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a result of baseline assessments before randomization will be considered screen failures and 
not randomized.  
Study drug will be dispensed on the day of the last study assessment and will be started the 
day following the last baseline assessment. All baseline assessments must be completed over 
the 14 days before study drug is started. Study drug start date will be considered Day 0.  
 
2.2 Randomization Methodology 
A total of 80 subjects are to be randomly assigned in a 1:1 ratio to one of two arms using 
permuted block randomization: (1) placebo or (2) famotidine. Subject randomization will be 
stratified by NYHA/WHO Functional Class (NYHA/WHO Functional Class II versus Class III/IV) 
to ensure balanced representation of this important marker of severity. A randomization code 
will be computer-generated by contract research organization (CRO) Axio Research, LLC. 
Subjects meeting study entry criteria will be randomized via an interactive web response 
system (IWRS). The randomization schedule will be generated by the randomization statistician 
at Axio Research (who is not on the project team) or designee and maintained in a secure and 
limited-access location separate from the study investigator and members of the project team. 
The study subject, investigative staff, the Sponsor, the Sponsor study team (includes 
contractors and vendors), excluding the unblinded study site pharmacist will be blinded to 
treatment assignments during the study. 
 
2.3 Stopping Rules  
Not applicable, see Section 2.5. 
 
2.4 Blinding 
This is a double-blind study in which all participants, Investigators, and study personnel 
involved in the conduct of the study, including data management, are blinded to treatment 
assignment except for: 
• 
An unblinded independent statistician or designee who will prepare and have access to 
the randomization code 
• 
The unblinded pharmacist at study site  
Although unblinded to treatment assignment, none of the above roles will have access to 
unblinded summaries of efficacy or safety data. 


  
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The following personnel will have access to unblinded efficacy and safety data in order to 
discharge their roles for data analysis and periodic safety review meetings: 
• 
The unblinded statistical programming team and independent DSMB support statistician 
who will prepare the unblinded reports for review 
Other than the above-mentioned personnel, all other individuals involved in the study conduct, 
statistical analysis and reporting will remain blinded until the after official study unblinding at the 
end of the study. The DSMB will review masked data by treatment arm with the option to 
unmask during the meeting. One DSMB member asking for unmasking is sufficient for 
unmasking of the DSMB to occur. The DSMB also has the option to unmask only for a single 
individual safety event (e.g., a death).  
 
2.5 Interim Analyses 
Reports to the Data and Safety Monitoring Board (DSMB) will focus on trial integrity 
(recruitment, protocol deviations/violations, completeness of follow-up and adherence) and 
safety. Comprehensive safety interim reports will be provided semi-annually to the DSMB. 
Comprehensive, safety reports will include detailed summaries of all SAEs, AEs, laboratory 
parameter listings, drug discontinuations and withdrawals as well as other pertinent safety data. 
The DSMB will recommend continuation or discontinuation of the study based on these interim 
reviews. Because of the length, size, and scope of the proposed study interim analyses for 
efficacy or futility will not be performed.   
 
 


  
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3 STUDY ENDPOINTS 
3.1 Efficacy Variables 
The study objectives and efficacy endpoints are summarized in Table 3-1. 
Table 3-1: Study objectives and endpoints 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To determine whether famotidine 
increases six-minute walk distance 
at 24 weeks in men and women 
with pulmonary arterial 
hypertension. 
 
The primary endpoint is the change 
in six-minute walk distance (6MWD) 
between baseline and 24 weeks. This 
will be compared between treatment 
groups.  
The six-minute walk 
distance is simple, 
reproducible, and well 
tolerated in patients 
with PAH. The 6MWD 
has been the primary 
outcome measure for 
the majority of pivotal 
trials of PAH 
therapeutics because 
of its relationship to 
hemodynamic 
parameters, treatment 
outcome, and survival. 
Secondary 
 
 
To determine whether famotidine 
reduces BNP at 24 weeks 
 
To determine whether famotidine 
improves New York Heart 
Association (NYHA) functional class 
at 24 weeks 
 
To determine whether famotidine 
improves right ventricular 
morphology at 24 weeks including 
improved right ventricular dilation 
and TAPSE 
 
To determine whether famotidine 
improves health related quality of 
Secondary endpoints include the 
change in BNP, NYHA functional 
class, right ventricular basal 
diameter, TAPSE, emPHasis-10 score, 
and the frequency with which 
routine therapies for patients with 
PAH are escalated during the trial. 
Secondary outcomes 
were chosen to better 
understand the impact 
of the intervention on 
various aspects of the 
treatment response 
including health-
related quality of life 
using disease specific 
validated tools. 


  
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life as estimated by the emPHasis-
10 score 
 
To determine whether famotidine 
decreases the need to escalate 
PAH focused care (increased 
diuretics, escalating doses of 
pulmonary vasodilators, and/or 
adding an additional pulmonary 
vasodilator) 
 
Tertiary/Exploratory  
 
 
Exercise sub-study: 
 
To determine whether famotidine 
increases maximal oxygen uptake 
in individuals with pulmonary 
arterial hypertension at 24 weeks 
 
To explore changes in other 
metrics of the exercise response 
(oxygen uptake, Ve/VCO2 ratio, 
total achieved wattage) with 
famotidine relative to placebo over 
24 weeks.  
 
Right heart catheterization sub-
study:  
 
To determine whether famotidine 
increases stroke volume index at 
24 weeks  
 
To explore whether famotidine is 
associated with differences in 
wedge pressure, right atrial 
pressure, and/or pulmonary 
vascular resistance at 24 weeks 
The primary analyses will be the 
change in oxygen consumption (VO2) 
for the exercise sub-study and the 
change in stroke volume index (SVi) 
for the right heart catheterization 
sub-study conducted using the FAS.  
 
Qualitative descriptions of other 
exercise and hemodynamic markers 
including mean, median, and 
distribution will be presented 
stratified by treatment group. 
While the two 
proposed sub-studies 
are powered to detect 
plausible, but large 
differences in exercise 
response or invasive 
hemodynamic 
markers, these studies 
are not powered to 
detect small to 
moderate differences. 
The co-primary intent 
of these sub-studies is 
to begin to understand 
appropriate end-points 
in trials of right heart 
targeted therapy. This 
more exploratory 
motivation is intended 
to complement but not 
supplant primary and 
secondary outcome 
measures. 


  
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3.2 Pharmacokinetic Variables 
Not applicable. 
 
3.3 Safety Variables 
Safety assessments performed during the study included physical examinations, measurement 
of vital signs (includes height, blood pressure, heart rate, oxygen saturation), weight, symptom 
assessment, clinical laboratory evaluations including comprehensive metabolic panel, complete 
blood count, pregnancy test (if premenopausal), and monitoring of adverse events. 
 


  
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4 ANALYSIS SETS 
4.1 Analysis Set Definitions 
The following Analysis sets will be evaluated and used for presentation and analysis of the 
data: 
• 
Screening Analysis Set: Includes all subjects who signed the informed consent form. 
• 
Enrolled Analysis Set: Includes all subjects in the Screening Analysis Set who were 
assigned a randomized treatment. 
• 
Full Analysis Set (FAS): Includes all randomized subjects who received at least 1 dose 
of study medication.  Subjects will be analyzed according to their randomized treatment. 
• 
Per Protocol (PP) Set 1 (PPS1): Includes all subjects in the FAS whose famotidine 
medication reconciliation suggest adherence to study drug for 80% or more of 
administered doses.  Subjects will be analyzed according to their randomized treatment. 
• 
Per Protocol (PP) Set 2 (PPS2): Includes all subjects in the FAS who (1) were 
randomized to famotidine for whom H2 receptor antagonists are detected by mass 
spectrometry at the final visit and (2) those randomized to placebo for whom H2 receptor 
antagonists are not detected at the final visit.  Subjects will be analyzed according to 
their randomized treatment. 
• 
Safety Analysis Set (SAF): Includes all randomized subjects who received at least 1 
dose of study medication.  Subjects will be analyzed according to their actual treatment. 
Actual treatment is defined as the treatment received for most of the days during the 
treatment phase of the study.   
 
Per ICH-E9 [1] and ICH-E9-R1 [2] guidelines, will use FAS instead of intention-to-treat. The 
FAS will be the primary analysis set for the analysis of the primary and secondary efficacy 
endpoints. 
The PPS1 and PPS2 will be used in the sensitivity analyses of the primary and secondary 
efficacy endpoints. 
The SAF will be the primary set for the analysis of the safety parameters.  
 
4.2 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or International Council 
on Harmonization Good Clinical Practice (ICH GCP). The noncompliance may be either on the 
part of the participant, the investigator, or the study site staff. As a result of deviations, 
corrective actions are to be developed by the site and implemented promptly.  


  
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It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations.  All deviations must be addressed in study source documents and entered into the 
IBM Clinical Development system.  Protocol deviations must be sent to the reviewing 
Institutional Review Board (IRB) per their policies. The site investigator is responsible for 
knowing and adhering to the reviewing IRB requirements.  
All protocol deviations will be listed. 
 


  
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5 DATA HANDLING 
5.1 Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software 
(Version 9.4 or later), unless otherwise noted. Medical comorbidities and adverse events 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 
24.0 or later. Prior and concomitant medications will be coded using World Health 
Organization (WHO) Drug version Global B3 (March 2021 or later). The actual version of 
the dictionary used will be noted in the footnote of the respective output. 
5.2 Data Conventions 
The following conventions will be used: 
• 
Period definition: 
o Screening Period: The period prior to the date of first dose of study drug (Day 0) 
o On-Treatment Period: The period from date of first dose of study drug through the 
Week 24 study visit  
• 
Study day 0: The date of first dose of study drug 
• 
End of Treatment Visit: End of treatment/early withdrawal visit 
• 
End of Study Visit: The last recorded visit date 
• 
Unscheduled or repeated visits: Unscheduled visits results will be listed, but not included 
in tables or graphs.   
• 
Conversion factors: 
o 1 month = 30.4375 days  
o 1 year = 365.25 days  
o 1 week = 7 days  
o °C = (°F - 32)/1.8 
• 
Additional rules 
o Age (years) = (date of informed consent – date of birth + 1) / 365.25, rounded to the 
lowest whole number.  
o Weight values recorded in pounds will be converted to kilograms using the following 
formula: kilograms = pounds/2.2046.  
o Height values recorded in inches will be converted to centimeters using the following 
formula: centimeters = inches*2.54.  


  
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o Duration on study (weeks) = (Last visit date – randomization date + 1) / 7.   
o Duration on treatment (weeks) = (Last study drug intake date – first study drug intake 
date + 1) / 7.  
o (Absolute) Change from baseline = Value at the time point – Baseline value.  
o Relative change from baseline = [(Value at the time point – Baseline value) / Baseline 
value] x 100. 
5.3 Methods of Pooling Data 
Not applicable. 
5.4 Withdrawals, Dropouts, Loss to Follow-up 
Discontinued subjects will not be replaced whether they received or did not receive the study 
drug. The multiple imputation approach is included in Section 6.4. 
Follow-up of subjects who discontinued the study drug early will continue until Week 24 and the 
study procedures will be assessed as per the schedule of assessment (see Table 9-1). 
5.5 Visit Windows 
All visits (scheduled, unscheduled or withdrawal) will be mapped to an analysis visit as defined 
in Table 5-1, where Day 0 is defined as the date of first dose of study treatment.  All safety and 
efficacy analyses will be based on the analysis visit.  In cases where a subject has more than 
one particular analysis visit, the visit with non-missing data closest to the protocolled visit will 
be selected for analysis. 
Table 5-1: Evaluation Intervals for Efficacy Analysis 
Scheduled Visit 
Protocol-Specified Interval 
Interval for Analysis Visit 
Baseline 
Day –14 to Day –1 
Day –14 to Day -1 
Week 12 
Day 77 to Day 91 
Day 0 to Day 125 
Week 24 
Day 161 to Day 175 
Day 126 to Day 175 
 


  
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6 STATISTICAL METHODS 
6.1 Sample Size Justification 
The primary endpoint is the change in six-minute walk distance (6MWD). The study was 
powered to detect a difference of 31.9 meters. A 31.9 meter improvement in 6MWD is well 
aligned with established thresholds for a minimally important difference in patient reported 
outcomes (Mathai SC, et al. Am J Respir Crit Care Med, 2012; 186(5):428-433). The 6MWD 
was chosen because it is a surrogate for patient-centered outcomes and was the primary 
endpoint in labeling trials for most of the medications used to treat pulmonary arterial 
hypertension (PAH).  
Standard deviation in 6MWD among PAH participants with NYHA functional class II, III, or IV 
symptoms is 37.6 meters (national Pulmonary Hypertension Association Registry; unpublished 
data). As shown, the proposed sample size has adequate power (0.96) to detect a minimally 
important different in 6MWD even with 10% attrition in the study sample (power, 0.94).   
Table 6-1: Power to detect a minimally important difference in 6MWD (31.9 
meters) 
Alpha 
Sample size per 
group 
Power for the 
total sample size 
Sample size per 
group with ~10% 
attrition 
Power with 
attrition 
0.05 
20 
0.74 
18 
0.69 
0.05 
40 
0.96 
36 
0.94 
0.05 
60 
0.99 
54 
0.99 
The field is appropriately shifting toward larger event driven trials; however, we did not feel a 
larger event driven trial of famotidine was warranted at this juncture. The current proposal is the 
first randomized evaluation of this drug and this pathway in individuals with right heart failure 
and/or PAH and a smaller Phase II trial was felt to be a more appropriate next step. 
 
 
 
 
 
 


  
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For the RHC sub-study, the initial sample size was set at 10 participants based on the following 
power to detect large differences.  
Size of difference 
SV index (mL/m2) 
Total sample 
size 
n per group 
power 
Large  
20 
10 
5 
0.87 
Medium-high 
15 
10 
5 
0.67 
Medium-low 
10 
10 
5 
0.36 
Small 
5 
10 
5 
0.13 
For the exercise sub-study, the initial sample size was set at 10 participants based on the following power 
to detect large differences.  
Size of difference 
VO2 (mL/min/kg) 
Total sample 
size 
n per group 
power 
Large  
8 
10 
5 
0.96 
Medium 
4 
10 
5 
0.46 
Low 
2 
10 
5 
0.15 
 
6.2 General Statistical Methods  
6.2.1 General Methods 
All outputs will be incorporated into Microsoft Excel or Word files, sorted and labeled according 
to the International Conference on Harmonization (ICH) recommendations, and formatted to 
the appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, efficacy and safety 
parameters.  For categorical variables, summary tabulations of the number and percentage 
within each category (with a category for missing data) of the parameter will be presented.  For 
continuous variables, the mean, median, standard deviation, minimum and maximum values 
will be presented.   
Formal statistical hypothesis testing will be performed with all tests conducted at the 2-sided, 
0.05 level of significance.  Summary statistics will be presented, as well as 95% confidence 
intervals on selected parameters, as described in the sections below.  


  
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6.2.2 Definition of Baseline 
Baseline is defined as the last non-missing assessment prior to the first dose of study 
treatment.  On the day of randomization all participants will be randomized, and study drug will 
be dispensed at this visit. Participants will be instructed to take one tablet daily (20 mg of 
famotidine or placebo) the day following randomization and dispensing of the study drug. All 
baseline assessments need to be completed within 14 days prior to the start of study drug (not 
inclusive of the date the first dose of study drug is taken). The day study drug is taken will be 
considered day 0. See Section 5.5 for details of the visit window for baseline. 
 
6.2.3 Adjustments for Covariates 
Subject randomization will be stratified by NYHA/WHO Functional Class (NYHA/WHO 
Functional Class II versus Class III/IV) to ensure balanced representation of this important 
marker of severity. 
For continuous outcome variables, baseline values of the dependent variable and NYHA 
functional class (as a binary stratification variable) will be included in the statistical model .  
6.2.4 Multiple Comparisons/Multiplicity 
No adjustments for multiplicity will be made.  
6.2.5 Subgroups 
No subgroups analyses are planned. 
6.2.6 Missing, Unused, and Spurious Data 
The handling of intercurrent events (ICEs) and sensitivity analyses are described in Section 
6.4. No other imputation of missing efficacy endpoints will be used. 
In all listings, missing or incomplete dates in safety data will be left as they have been 
recorded. However, for calculation and sorting based on dates and for consideration in 
summary tables, the following method will be used: 
For partial or missing adverse event (AE) start dates the following imputation will be applied: 
1.      If year is not missing and is after the year of first dose: 
a.       If month is missing, then month will be imputed as January. 
b.      If day is missing, then day will be imputed as the first of the month. 


  
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2.      If year is not missing and is the same as the year of the first dose: 
a.       If month is missing, then impute the month as the month of the first dose 
date. 
b.      If day is missing, and the month is the same as the month of the first dose 
date, then impute day as the day of the first dose date. 
c.       If day is missing but month is after the month of first dose date, then 
impute day as the first day of the month. 
3.      If year is missing then impute the year as the year of the first dose date: 
a.       If month is missing, then impute the month as the month of the first dose 
date. 
b.      If day is missing, then impute the day as the day of the first dose date. 
4.      If the start date is completely missing, but the AE is either ongoing or the stop 
date is after the first dose date then impute the start date as the first dose date. 
5.      For any cases involving the rules above, if the AE end date is before the AE start 
date, then do not impute the AE start date and assume that the AE is treatment 
emergent for the purpose of the analysis. Further, if the AE stop date occurs prior to the 
first dose date, do not impute the AE start date, and assume that the AE 
is not treatment emergent. 
No imputations will be applied to AE stop dates. 
A missing/incomplete date of medical comorbidities or disease diagnosis will be assumed to 
have occurred before any study treatment. 
Missing AE relationship data will be assigned the ‘related’ category for treatment emergent AE. 
 
6.3 Study Population 
6.3.1 Subject Disposition 
Subject disposition will be presented, including the number screened, the number dosed, the 
number that withdrew from study treatment and from the study along with the reasons.  The 
number of subjects in each analysis set will also be presented. 
The summaries will be presented by treatment group and overall. The denominator for all 
percentages will be the total number of subjects in each treatment group. 
The following by-subject listings will be presented.  
• 
Study completion information, including the reason for premature study withdrawal. 
• 
Inclusion/exclusion criteria 


  
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• 
Inclusion in study analysis sets 
• 
Protocol deviations 
• 
Reasons for exclusion from the per protocol sets 
 
6.3.2 Demographic and Baseline Characteristics 
Treatment groups will be described for the FAS and compared with respect to baseline 
demographic and clinical characteristics such as age, gender, race, ethnicity, height, weight, 
body mass index, use of concomitant medications, and markers of pulmonary hypertension 
disease severity (e.g., right ventricular structure and function, BNP, 6-minute walk distance, 
NYHA functional class). The preference will be to present these baseline results without formal 
statistical testing; however, journal preference, editorial preference, and reviewer preference on 
this issue vary widely despite published CONSORT guidance. On request, continuous 
measures will be analyzed using t-tests and categorical variables will be analyzed using chi-
square, Fisher’s exact, or Cochran-Mantel-Haenszel tests. The analyses may be repeated for 
other subject subsets (e.g., PPS1, PPS2) if some risks of imbalance are revealed during the 
data analysis. 
Medical comorbidities will be coded using MeDRA dictionary (see Section 5.1) and summarized 
by System Organ Class (SOC) and Preferred Term (PT). No formal statistical comparisons will 
be performed.  
Demographic and baseline data will be provided in data listings. 
6.3.3 Prior Medication 
Prior and concomitant medications will be coded using the WHO Drug dictionary (see Section 
5.1).  
Prior medications will be defined as any medication with a start date before the date of first 
dose of study medication.  
Medications with a start date on or after the date of first dose of study medication and not after 
the last dose of study medication will be considered concomitant. Medications taken prior to the 
first dose of study medication and continuing after the first dose of study medication will be 
considered both prior and concomitant. 
If a medication date or time is missing, or partially missing, and it cannot be determined 
whether it was taken on or after start of treatment, it will be considered both prior and 
concomitant medication. 
Results will be tabulated by Anatomic Therapeutic Class (ATC) and preferred term. 
The use of prior and concomitant medications will be included in by-subject data listing. 


  
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6.3.4 Exposure and Compliance 
Summary statistics of the duration of exposure, number of doses and the percent compliance 
will be presented.  Percentage compliance will also be summarized by category (<=60%, 
>60%-80%, >80-100%, >100%-120%, >120%, and >=80%). The number and percentage of 
participants who reported taking the study drug as directed and the primary reasons for not 
taking the study drug as directed will be summarized by visit. 
Duration of exposure (days) will be defined as Last Dose Date – Start Dose Date + 1. 
Percentage compliance will be defined as Number of doses taken/ Number of doses expected 
*100. 
Number of doses taken will be defined as the number of tablets dispensed – number of tablets 
returned. 
Number of doses expected will be defined as duration of exposure (days)*planned daily dose. 
6.4 Efficacy Evaluation 
Primary Efficacy Endpoint(s): The primary endpoint is the difference in 6-minute walk distance.  
Secondary Efficacy Endpoint(s): The secondary endpoint is the difference between treatment 
groups in BNP, NYHA functional class, TAPSE, right ventricular basal diameter, emPHasis-10 
score, and number of participants with an escalation of routine clinical treatments for PAH for 
each visit. 
 
6.4.1 Primary efficacy analysis 
The primary endpoint is the difference between treatment groups in the change of 6-minute 
walk distance (6MWD) between baseline and 24 weeks. Linear regression will be performed for 
the FAS with the change in 6MWD between baseline and 24 weeks as outcome and treatment 
group as the primary predictor of interest, adjusted for baseline 6MWD and baseline NYHA 
functional class as the stratification variable. The estimate of the treatment effect will be 
provided with associated 95% confidence interval (CI).  
Missing 6MWD at 24 weeks will be imputed as follows. Subjects known to be dead before the 
24 week assessment will have zero imputed for their 24 week 6MWD. Missing 24 week 6MWD 
for subjects who are alive will be imputed using multiple imputation. The imputation model will 
have prognostic variables as the predictor variables. Prognostic variables will include age, 
gender, and etiology of pulmonary hypertension, baseline six minute walk test distance, 
baseline right ventricular diameter, and baseline BNP. The multiple imputation will use Markov 
Chain Monte Carlo (MCMC), which assumes that the variables in the imputation model have a 
joint multivariate normal distribution (MVN). The number of imputations to be performed will be 
100. One hundred is selected because it is not too large that it requires heavy computations 


  
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and is not too small (such that the Monte Carlo error is still small enough at around 0.1 times 
the standard deviation). The “proc mi” procedure in SAS will be used to impute the missing 
observations.  
PAH etiology in the analysis will be as follows: 
• 
Idiopathic 
• 
Familial 
• 
Congenital Heart Disease 
• 
Collagen Vascular Disease 
• 
Toxin 
• 
Portopulmonary Hypertension 
6.4.1.1 Sensitivity analysis 
Sensitivity analyses will be performed using the PPS1 and PPS2 analysis sets instead of FAS. 
Although every effort will be made to avoid missing data, a range of approaches to missing 
6MWD will be considered as sensitivity analyses representing a range of conservative and anti-
conservative biases to describe the range of possible differences.  
Sensitivity analyses of the primary endpoint will include:  
1) • a linear regression model using a worst case scenario (WCS) method of imputation  
2) • a linear regression model of the 24 week 6MWD without imputation (complete case 
analysis)  
(1) The worst case scenario method of imputation will impute zero for all missing 6MWD at 
week 24.  
(2) The linear regression method will model the 24 week 6MWD on treatment assignment, 
adjusting for baseline 6MWD and baseline NYHA functional class using least squares and 
robust standard error estimates.  
For all methods, treatment effect estimates and 95% CIs will be presented. 
6.4.1.2 Additional analyses 
Additional analyses of the relative change in 6MWD will include the proportion of participants 
who achieve a minimally important change in 6MWD of 31.9 meters or greater. To test the null 
hypothesis that there is no difference between the treatment groups, logistic regression 
adjusted for the NYHA functional class (stratification variable) will be used. The odds ratio 
between treatment groups will be provided with associated 95% CI. Subjects missing the 24 
week 6MWD will not be counted as having achieved a minimally important change.  


  
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6.4.2 Secondary analysis 
Secondary endpoints include the change in BNP, NYHA functional class, right ventricular basal 
diameter, TAPSE, emPHasis-10 score, and the number of participants with an escalation of 
routine clinical treatments for PAH during the trial. 
The main analysis for each secondary endpoint will be performed for the FAS. Sensitivity 
analyses will be performed using the PPS1 and PPS2 analysis sets instead of FAS. Sensitivity 
analyses using worst case scenario and complete case analysis will be performed for the FAS. 
 
6.4.2.1 BNP 
Summary statistics (mean, standard deviation, median and range) of BNP (untransformed and 
log-transformed) and change from baseline for each visit will be presented by treatment group. 
Change in log-transformed value will be evaluated between the treatment groups using linear 
regression adjusted for the value at baseline and NYHA functional class (stratification variable). 
The difference with 95% CIs will be reported.  
The BNP is expected to vary by NYHA functional class. An additional sensitivity analysis will be 
performed with the difference of log-transformed BNP between baseline and week 24 as the 
outcome, with the predictor variables being baseline log-transformed BNP, treatment group, 
baseline NYHA functional class, and an interaction term between treatment group and baseline 
NYHA functional class.  
Missing data will be imputed in an analogous fashion to the primary outcome including 
sensitivity analyses to define the range of uncertainty imposed by missing data (worst case 
scenario and complete case analysis). The worst case scenario for BNP will be set to the 
highest value in the observed population.  
6.4.2.2 NYHA functional class 
Summary tabulations of the number and percentage of participants within each NYHA 
functional class for each visit will be presented by treatment group. NYHA functional class will 
be evaluated between the treatment groups using ordinal logistic regression adjusted for the 
baseline NYHA functional class (stratification variable). The odds ratio with 95% CIs will be 
reported.  
Missing data will be imputed in an analogous fashion to the primary outcome including 
sensitivity analyses to define the range of uncertainty imposed by missing data (worst case 
scenario and complete case analysis) but for categorical variables [3]. The worst case scenario 
for NYHA functional class will be assumed to be IV.  


  
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6.4.2.3 Right ventricular basal diameter 
Summary statistics (mean, standard deviation, median and range) of right ventricular basal 
diameter and change from baseline for each visit will be presented by treatment group. Change 
from baseline will be evaluated between the treatment groups using linear regression adjusted 
for the value at baseline and NYHA functional class (stratification variable). The difference with 
95% CIs will be reported.  
Missing data will be imputed in an analogous fashion to the primary outcome including 
sensitivity analyses to define the range of uncertainty imposed by missing data (worst case 
scenario and complete case analysis). The worst case scenario for right ventricular basal 
diameter will be set to the highest value in the observed population.  
6.4.2.4 TAPSE 
Summary statistics (mean, standard deviation, median and range) of TAPSE and change from 
baseline for each visit will be presented by treatment group. Change from baseline will be 
evaluated between the treatment groups using linear regression adjusted for the value at 
baseline and NYHA functional class (stratification variable). The difference with 95% CIs will be 
reported.  
Missing data will be imputed in an analogous fashion to the primary outcome including 
sensitivity analyses to define the range of uncertainty imposed by missing data (worst case 
scenario and complete case analysis). The worst case scenario for TAPSE will be assumed to 
be zero.  
6.4.2.5 EmPHasis-10 score 
Summary statistics (mean, standard deviation, median and range) of emPHasis-10 score and 
change from baseline for each visit will be presented by treatment group. Change from 
baseline will be evaluated between the treatment groups using linear regression adjusted for 
the value at baseline and NYHA functional class (stratification variable). The difference with 
95% CIs will be reported.  
Missing data will be imputed in an analogous fashion to the primary outcome including 
sensitivity analyses to define the range of uncertainty imposed by missing data (worst case 
scenario and complete case analysis). The worst case scenario for emPHasis-10 score will be 
assumed to be 50.  
6.4.2.6 Escalation of routine clinical treatments for PAH 
Summary tabulations of the number and percentage of participants with an escalation of 
routine clinical treatments for PAH for each visit will be presented by treatment group.  


  
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Escalation of routine clinical treatments for PAH will be analyzed as a categorical variable (yes 
/ no escalation). A Cochran-Mantel-Haenszel (CMH) test with adjustment for the stratification 
factor baseline NYHA functional class will be used to test the null hypothesis of no treatment 
effect during the trial for famotidine vs. placebo with regards to the proportion of subjects with 
an escalation of routine clinical treatments for PAH.   
Odds ratios will be estimated from the CMH test together with the associated 95% confidence 
intervals (CIs) and corresponding p-values. The proportion per treatment arm will be displayed 
together with exact Clopper-Pearson 95% CIs. In addition, the common risk difference between 
famotidine and placebo will be provided, along with 95% confidence interval (stratified 
Newcombe confidence limits).  
Missing data will be imputed in an analogous fashion to the primary outcome including 
sensitivity analyses to define the range of uncertainty imposed by missing data (worst case 
scenario and complete case analysis) but for categorical variables [3]. The worst case scenario 
for a participant will be assumed to have escalated PAH specific care.  
 
6.4.3 Sub-study analysis 
There are two sub-studies proposed for this trial. One sub-study involves cardiopulmonary 
exercise testing and the other sub-study involves invasive hemodynamic evaluation using right 
heart catheterization. 
 
6.4.3.1 Cardiopulmonary exercise testing (CPET) sub-study 
Summary statistics (mean, standard deviation, median and range) of CPET sub-study results 
and change from baseline for each visit will be presented by treatment group. The following 
metrics of the exercise response will be summarized: 
• 
Peak VO2 (mL/min) 
• 
Peak Weight adjusted VO2 (mL/kg/min) 
• 
Ve/VCO2 slope 
• 
Achieved watts (watt) 
 
6.4.3.2 Right heart catheterization (RHC) sub-study 
Summary statistics (mean, standard deviation, median and range) of RHC sub-study results 
and change from baseline for each visit will be presented by treatment group. The following 
results will be summarized: 


  
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• 
Thermodilution stroke volume Index (mL/m2) 
• 
Right atrial pressure (mmHg) 
• 
Pulmonary Arterial Pressure Systolic (mmHg)  
• 
Pulmonary Arterial Pressure Diastolic (mmHg) 
• 
Mean Pulmonary Arterial Pressure (mmHg) 
• 
Pulmonary capillary wedge pressure (mmHg) 
• 
Thermodilution pulmonary vascular resistance (wood units) 
 
6.4.4 Exploratory analysis 
Pre-planned exploratory analysis: Etiology of PAH or sex may lead to effect modification in the 
relationship between study drug and outcomes. A subgroup analysis will be repeated for any 
group with at least 10 participants (e.g., men, women, toxin-induced PAH, idiopathic PAH, etc). 
The primary purpose of these analyses will be to inform subsequent trial design; however, if 
these individual analyses are reported it will be with the tempered inference informed by the 
fact that these sub-groups may not be balanced between active drug and placebo, are meant 
to be hypothesis generating only, and are underpowered as shown in the following table 
depicting the power to detect a minimally important difference in six-minute walk distance 
(assuming balanced groups which may not be true). 
 
Alpha  
Group size  
Power  
0.05  
10  
0.22  
0.05  
12  
0.27  
0.05  
14  
0.31  
0.05  
16  
0.35  
0.05  
20  
0.39  
 
6.5 Pharmacokinetic Evaluations 
Not applicable.  


  
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6.6 Safety Evaluations  
Safety analyses will be conducted using the Safety Analysis Set.   
6.6.1 Adverse Events 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), see Section 5.1, and displayed in tables and listings using System/Organ/Class 
(SOC) and Preferred Term (PT). 
Analyses of adverse events will be performed for those events that are considered treatment 
emergent, where treatment emergent is defined as any adverse event with onset after the 
administration of study medication through the end of the study (see Section 5.2) or any event 
that was present at baseline but worsened in intensity or was subsequently considered drug-
related by the investigator through the end of the study.   
Adverse events are summarized by subject, therefore, in any tabulation, a subject contributes 
only once to the count for a given adverse event (SOC or preferred term). 
The number and percentage of subjects with any treatment-emergent adverse event (TEAE), 
any treatment-emergent adverse event by severity, with any treatment-emergent adverse event 
by relationship to study drug, with any treatment-emergent adverse event leading to withdrawal 
from study drug, and with any treatment-emergent serious adverse event (SAE) will be 
summarized by treatment group and overall.  In these tabulations, each subject will contribute 
only once (i.e., the most related occurrence or the most intense occurrence), regardless of the 
number of episodes. The number of events and the average number of events will also be 
provided in tabulations of TEAEs and serious TEAEs.  
Adverse events with definite, probable, and possible relationship are considered related to 
study drug. Adverse events with unrelated and unlikely relationship are considered unrelated to 
study drug. 
Histograms showing the frequency of the number of treatment-emergent AEs and SAEs in 
each treatment group will be included. 
Exposure-adjusted event rates by treatment group and overall will be provided for participants 
with TEAEs, and with serious TEAEs. Each summary will present by decreasing incidence of 
PT per 100 subject years of exposure, calculated as (number of subjects with event/total 
patient-years). Years of exposure is either a) time from first treatment until start date of TEAE 
type or b) duration of exposure for subjects without a TEAE type. Poisson regression modeling 
will be used to derive rate ratios and 95% CIs for each SOC. Rate ratios will be compared 
using a two-sided 0.05 level test for Poisson count data. 


  
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The number and percentage of subjects with TEAE with hospitalization required will be 
summarized by treatment group and overall, including the number of events, the average 
number of events and the exposure-adjusted event rates.  Poisson regression modeling will be 
used to derive rate ratios and 95% CIs to compare hospitalization rates between treatment 
groups. 
All adverse events occurring on study will be listed in subject data listings. 
By-subject listings also will be provided for the following: subject deaths; serious adverse 
events; adverse events leading to withdrawal and adverse events with hospitalization required.  
6.6.2 Laboratory Data 
Safety laboratory data at each study visit and changes from baseline will be summarized by 
treatment group. Laboratory parameters will be reported in original units without conversion, 
see Table 9-2. 
In addition, clinical laboratory summaries will be presented by treatment group including: (i) 
incidence of significant abnormalities by visit; (ii) tables summarizing the frequencies of 
subjects below, within, and above the normal reference ranges at baseline and end of study; 
and (iii) tables displaying baseline to end of study shifts in each laboratory value (shifts 
between below, within or above normal range). 
All laboratory data will be provided in data listings. 
A subset listing will be presented for all abnormal laboratory values. 
 
6.6.3 Vital Signs and Physical Examinations 
The actual value and change from baseline to each on study evaluation will be summarized for 
vital signs.   
By-subject listings of vital sign measurements will be presented in data listings. 
 
6.6.4 Electrocardiogram 
Not applicable.  
 


  
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7 CHANGES TO PLANNED ANALYSES 
The following are changes between the protocol-defined statistical analyses and those 
presented in this statistical analysis plan: 
The FAS will be the primary analysis set for the analysis of the primary and secondary efficacy 
endpoints rather than ITT. FAS includes all randomized subjects who received at least 1 dose 
of study medication. Subjects will be analyzed according to their randomized treatment. 
Safety analysis set will be the primary set for the analysis of the safety parameters and it 
includes all randomized subjects who received at least 1 dose of study medication.  Subjects 
will be analyzed according to their actual treatment. Actual treatment is defined as the 
treatment received for most of the days during the treatment phase of the study.   
The data of NYHA functional class will be considered to be ordinal categorical values in the 
analysis. Change from baseline in NYHA functional class will be evaluated between the 
treatment groups using logistic regression adjusted for the baseline NYHA functional class 
(stratification variable). Missing data will be imputed in an analogous fashion to the primary 
outcome including sensitivity analyses to define the range of uncertainty imposed by missing 
data (worst case scenario and complete case analysis) but for categorical variables.  
The data of escalation of routine clinical treatments for PAH will be analyzed as a binary 
categorical variable (yes / no escalation). A Cochran-Mantel-Haenszel (CMH) test with 
adjustment for the stratification factor baseline NYHA functional class will be used to test the 
null hypothesis of no treatment effect during the trial for famotidine vs. placebo with regards to 
the proportion of subjects with an escalation of routine clinical treatments for PAH.  Missing 
data will be imputed in an analogous fashion to the primary outcome including sensitivity 
analyses to define the range of uncertainty imposed by missing data (worst case scenario and 
complete case analysis) but for categorical variables.  
 
 


  
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8 REFERENCES 
1. International Council on Harmonization, Statistical Principles for Clinical Trials (ICH E9) 
2. International Council on Harmonization, Statistical Principles for Clinical Trials Addendum 
(ICH E9 R1) 
3. Imputation of Categorical Variables with PROC MI. Paul D. Allison, University of 
Pennsylvania, Philadelphia, PA.  
 
 


  
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9 APPENDICES 
9.1 Schedule of Assessments 
Table 9-1: Schedule of assessments 
  
Baseline 
Randomization 
 
Phone Visit 
Week 4 
Week 12 
Week 24 
Visit # 
1 
 
Non-visit 
PH 
2 
3 
Day # 
-14 to -1  
-1 
0 
28 ± 7 
84 ± 7 
168 ± 7 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
History and physical exam 
  
 
 
 
  
  
  Demographics 
X 
 
 
 
 
 
  Medical history 
X 
 
 
 
 
 
  Symptom assessment 
X 
 
 
 
X 
X 
  Concomitant medications 
X 
 
 
 
X 
X 
  Vital Signs & Weight 
X 
 
 
 
X 
X 
  Physical Examination 
X 
 
 
 
X 
X 
Safety laboratories 
  
 
 
 
  
  
  Laboratory Draw 
X 
 
 
 
 
X 
  Comprehensive metabolic panel 
X 
 
 
 
 
X 
  Complete blood count 
X 
 
 
 
 
X 
  Mass-Spectrometry for H2 
antagonists 
X 
 
 
 
 
X 


  
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  Pregnancy test if premenopausal 
X 
 
 
 
 
X 
Endpoint assessment 
  
 
 
 
  
  
  6 minute-walk distance (primary) 
X 
 
 
 
X 
X 
  echocardiogram 
X 
 
 
 
 
X 
  emPHasis-10 score 
X 
 
 
 
X 
X 
  BNP 
X 
 
 
 
 
X 
  NYHA functional class 
X 
 
 
 
X 
X 
Study Procedures 
  
 
 
 
  
  
  Dispense study drug 
 
X 
 
 
X 
 
  Start study drug 
 
 
X 
 
 
 
  Study drug adherence 
 
 
 
X 
X 
X 
  Study drug compliance 
 
 
 
X 
X 
X 
  Adverse events 
X 
 
 
X 
X 
X 
  Study Termination 
 
 
 
 
 
X 
Sub-study components 
  
 
 
 
  
  
Right heart catheterization (n=20) 
X 
 
 
 
 
X 
Cardiopulmonary Exercise Test 
(n=10) 
X 
 
 
 
 
X 
Miscellaneous  
 
 
 
 
  
  
Data Safety Monitoring Board  
 
 
Semi-annually  
As per clinical practice guidelines, patients will be seen every three months with blood work and six-minute walk testing. These 
elements (visit, laboratory draw, comprehensive metabolic panel, complete blood count, BNP, pregnancy test, 6 minute-walk 
distance, and NYHA functional class) will be collected as part of routine medical care and abstracted from the medical record as 
research endpoints. Echocardiograms are often part of routine medical care and will be abstracted from the medical record as 
research endpoints; however, the frequency may be influenced by the study. To avoid any concern about overlap, any 


  
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echocardiogram occurring more frequently than annually will be considered research. It is anticipated that 1 of the 2 
echocardiograms will fit this research definition. Other research elements include mass spectrometry for H2 antagonists, the 
emPHasis-10 score, study procedures, and sub-study components.  
 


  
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9.2 Estimands 
Not applicable.  
 


  
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9.3 Laboratory Conversion Factors 
Laboratory parameters will be reported in original units without conversion, see Table 9-2. 
 
Table 9-2: Laboratory parameters 
Parameter (unit) 
Sodium (mEq/L) 
Potassium (mEq/L) 
BUN (mEq/L) 
Creatinine (mEq/L) 
WBC (thou/uL) 
Hemoglobin (g/dL) 
Platelets (thou/uL) 
BNP (pg/mL) 
Calcium (mg/dL) 
 
 


  
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10 LIST OF STATISTICAL OUTPUTS  
The list of statistical outputs is provided in a separate file. This avoids duplication since it will be 
part of the mock shells.  
 


UW REHAB-PH Statistical Analysis Plan Final
Version 1.00 2023-08-30
Final Audit Report
2023-08-30
Created:
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Prot_001.pdf: 
Study Title: Repurposing a histamine antagonist to benefit patients with 
pulmonary hypertension (REHAB-PH) 
 
National Clinical Trial (NCT) Identified Number: NCT03554291 
 
PI Name: Peter Leary, MD PhD 
 
IRB Approval Dates: 
Initial approval: 8/9/2018 
Current version of the protocol reviewed/approved: 1/20/2023 
Current version of the consent reviewed/approved: 1/20/2023 
Most recent continuing review approval: 4/25/2024 3 4/24/2025  


  
CONFIDENTIAL 
 
 
 
Clinical Trial Protocol: REHAB-PH 
 
Study Title: Repurposing a histamine antagonist to benefit patients with 
pulmonary hypertension 
(REHAB-PH) 
 
National Clinical Trial (NCT) Identified Number:  NCT03554291 
 
Principal Investigator: Peter Leary, M.D., Ph.D. 
 
Funded by: National Heart, Lung, and Blood Institute 
 
Version Number:  v.1.8 
 
12 December 2022 
 
 


  
CONFIDENTIAL 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................ 1 
1 
PROTOCOL SUMMARY .............................................................................................................................. 1 
1.1 
Synopsis ............................................................................................................................................... 1 
1.2 
Schema ................................................................................................................................................ 4 
1.3 
Schedule of Activities (SoA) .............................................................................................................. 5 
2 
INTRODUCTION ........................................................................................................................................... 6 
2.1 
Study Rationale ................................................................................................................................... 6 
2.2 
Background .......................................................................................................................................... 7 
2.3 
Risk/Benefit Assessment ................................................................................................................... 7 
2.3.1 
Potential Risks ................................................................................................................. 7 
2.3.2 
Potential Benefits ............................................................................................................ 7 
3 
OBJECTIVES AND ENDPOINTS ............................................................................................................... 8 
4 
STUDY DESIGN ............................................................................................................................................ 9 
4.1 
Overall Design ..................................................................................................................................... 9 
4.2 
Scientific Rationale for Study Design ........................................................................................... 109 
4.3 
Justification for Dose ........................................................................................................................ 10 
4.4 
End of Study Definition ..................................................................................................................... 10 
5 
STUDY POPULATION ............................................................................................................................ 1110 
5.1 
Inclusion Criteria ........................................................................................................................... 1110 
5.2 
Exclusion Criteria .............................................................................................................................. 11 
5.3 
Lifestyle Considerations ............................................................................................................... 1211 
5.4 
Screen Failures ................................................................................................................................. 12 
5.5 
Strategies for Recruitment and Retention ..................................................................................... 12 
6 
STUDY INTERVENTION ........................................................................................................................ 1312 
6.1 
Study Intervention(s) Administration .......................................................................................... 1312 
6.1.1 
Study Intervention Description ................................................................................ 1312 
6.1.2 
Dosing and Administration ........................................................................................... 13 
6.2 
Preparation/Handling/Storage/Accountability ............................................................................... 13 
6.2.1 
Acquisition and accountability ..................................................................................... 13 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ........................................... 1413 
6.2.3 
Product Storage and Stability ...................................................................................... 14 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................................... 14 
6.4 
Study Intervention Compliance ....................................................................................................... 14 
6.5 
Concomitant Therapy ....................................................................................................................... 14 
6.5.1 
Rescue Medicine ........................................................................................................... 15 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................................................................... 15 
7.1 
Participant Discontinuation/Withdrawal from the Study .............................................................. 15 
7.2 
LosS to Follow-Up ............................................................................................................................. 16 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 16 
8.1 
Efficacy AND SAFETY Assessments ............................................................................................ 16 
8.2 
Adverse Events and Serious Adverse Events .......................................................................... 1918 
8.2.1 
Definition of Adverse Events (AE) ........................................................................... 1918 
8.2.2 
Definition of Serious Adverse Events (SAE) ......................................................... 1918 
8.2.3 
Classification of an Adverse Event ............................................................................. 19 
8.2.4 
Time Period and Frequency for Event Assessment and Follow-Up ...................... 20 


  
CONFIDENTIAL 
8.2.5 
Adverse Event Reporting ............................................................................................. 20 
8.2.6 
Reporting Events to Participants ................................................................................. 21 
8.2.7 
Events of Special Interest ............................................................................................ 21 
8.2.8 
Reporting of Pregnancy ................................................................................................ 21 
9 
STATISTICAL CONSIDERATIONS ...................................................................................................... 2221 
9.1 
Statistical Hypotheses .................................................................................................................. 2221 
9.2 
Sample Size Determination ......................................................................................................... 2322 
9.3 
Populations for Analyses ............................................................................................................. 2423 
9.4 
Statistical Analyses ....................................................................................................................... 2423 
9.4.1 
General Approach ..................................................................................................... 2423 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ........................................................ 2423 
9.4.3 
Analysis of the Secondary Endpoint(s) .................................................................. 2524 
9.4.4 
Safety Analyses ......................................................................................................... 2524 
9.4.5 
demographic and Baseline Descriptive Statistics ................................................. 2625 
9.4.6 
DSMB Review of ongoing data ............................................................................... 2625 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......................... 2726 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ...................................................... 2726 
10.1.1 
Informed Consent Process ...................................................................................... 2726 
10.1.2 
Study Discontinuation and Closure ......................................................................... 2726 
10.1.3 
Confidentiality and Privacy ....................................................................................... 2827 
10.1.4 
Future Use of Stored Specimens and Data ........................................................... 2928 
10.1.5 
Key Roles and Study Governance .......................................................................... 2928 
10.1.6 
Safety Oversight ........................................................................................................ 2928 
10.1.7 
Clinical Monitoring ..................................................................................................... 3029 
10.1.8 
Quality Assurance and Quality Control .................................................................. 3029 
10.1.9 
Data Handling and Record Keeping ....................................................................... 3029 
10.1.10 
Protocol Deviations ................................................................................................... 3130 
10.1.11 
Publication and Data Sharing Policy ...................................................................... 3130 
10.1.12 
Conflict of Interest Policy .......................................................................................... 3231 
11 
REFERENCES ......................................................................................................................................... 3332 
12 
APPENDIX 1: EMPHASIS-10 QUESTIONNAIRE .............................................................................. 3837 
13 
APPENDIX 2: FUNCTIONAL CLASS DECISION AID ....................................................................... 3938 
 


REHAB-PH PROTOCOL 
Version 1.8 
 
20 Jan 2023 
 
CONFIDENTIAL 
 
1 
STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP) and the following:  
 
" 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Repurposing a histamine antagonist to benefit patients with pulmonary 
hypertension (REHAB-PH) 
  
Study Description: 
Pulmonary arterial hypertension (PAH) is one of many conditions that put 
stress and strain on the right side of the heart. This stress and strain can 
cause right heart failure. Although there are medications to treat PAH, 
there are currently no medications that act directly on the heart to 
improve right heart function. This is different than left heart failure where 
one of the cornerstones of treatment is medication targeted at the heart 
to improve left heart function. 
 
Famotidine is a well-tolerated, over-the-counter, and inexpensive 
medication. Preliminary results suggest that famotidine may help the right 
heart to adapt and strengthen when stressed instead of fail; however, 
these results are suggestive and not definitive. A randomized controlled 
trial is required to evaluate the possibility that famotidine can impact right 
heart function. 
 
Objectives: 
 
 
Primary Objective:   
To determine whether famotidine increases six-minute walk 
distance at 24 weeks in men and women with pulmonary arterial 
hypertension. 
 
Secondary Objectives:  


REHAB-PH PROTOCOL 
Version 1.8 
 
20 Jan 2023 
 
CONFIDENTIAL 
 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sub-study Objectives: 
" 
To determine whether famotidine reduces BNP at 24 weeks  
" 
To determine whether famotidine improves New York Heart 
Association (NYHA) functional class at 24 weeks 
" 
To determine whether famotidine improves right ventricular 
morphology at 24 weeks including improved right ventricular 
diameter and TAPSE 
" 
To determine whether famotidine improves health related quality 
of life as estimated by the emPHasis-10 score 
" 
To determine whether famotidine decreases the need to escalate 
PAH focused care (increased diuretics, escalating doses of 
pulmonary vasodilators, and/or adding an additional pulmonary 
vasodilator) 
" 
To explore changes in invasive hemodynamics with famotidine 
" 
To explore changes in gas exchange, maximal oxygen uptake, 
metabolism, and myocardial reserve with famotidine 
 
 
Exercise sub-study: 
" 
To determine whether famotidine increases maximal oxygen 
uptake in individuals with pulmonary arterial hypertension at 24 
weeks 
" 
To explore changes in other metrics of the exercise response 
(oxygen uptake, Ve/VCO2 ratio, total achieved wattage) with 
famotidine relative to placebo over 24 weeks.  
" 
In a <right heart targeted therapy= trial, to explore the relationship 
between markers of the exercise response and other standard 
markers of treatment response including BNP, New York Heart 
Association functional class, quality of life, and need to escalate 
PAH-specific therapy.  
 
Right heart catheterization sub-study  
" 
To determine whether famotidine increases stroke volume index 
at 24 weeks  
" 
To explore whether famotidine is associated with differences in 
wedge pressure, right atrial pressure, and/or pulmonary vascular 
resistance at 24 weeks 
" 
In a <right heart targeted therapy= trial, to explore the relationship 
between markers of the exercise response and other standard 
markers of treatment response including BNP, New York Heart 
Association functional class, quality of life, and need to escalate 
PAH-specific therapy.  
 
 
  
Endpoints: 
Primary endpoint: The difference between treatment groups in 6-minute 
walk distance (6MWD) at 24 weeks.  
 


REHAB-PH PROTOCOL 
Version 1.8 
 
20 Jan 2023 
 
CONFIDENTIAL 
 
3 
Secondary endpoint: The difference between treatment groups in BNP, 
NYHA functional class, TAPSE, right ventricular basal diameter, emPHasis-
10 score, and number of participants with an escalation of routine clinical 
treatments for PAH for each visit. 
  
Study Population: 
Approximately 80 participants, male or female, age 18 to 80 with 
 WHO Group 1 Pulmonary Arterial Hypertension and NYHA Functional 
Class II, III, or IV at screening.  
  
Phase: 
II  
Description of 
Sites/Facilities Enrolling 
Participants: 
 
All potential subjects for the REHAB-PH Trial will be recruited from the 
University of Washington Pulmonary Vascular Disease Program. 
 
Description of Study 
Intervention: 
Famotidine, 20 mg daily, per oral 
  
Study Duration: 
60 months 
 
Participant Duration: 
Participants will be evaluated and participate over 24 ± 1 weeks. 
 
 




REHAB-PH PROTOCOL 
Version 1.8 
 
20 Jan 2023 
 
CONFIDENTIAL 
 
5 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
  
Baseline 
Randomization 
 
Phone 
Visit 
Week 4 
Week 
12 
Week 
24 
Visit # 
1 
 
Non-
visit 
PH 
2 
3 
Day # 
-14 to -1  
-1 
0 
28 ± 7 
84 ± 7 
168 ± 7 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
History and physical exam 
  
 
 
 
  
  
  Demographics 
X 
 
 
 
 
 
  Medical history 
X 
 
 
 
 
 
  Symptom assessment 
X 
 
 
 
X 
X 
  Concomitant medications 
X 
 
 
 
X 
X 
  Vital Signs & Weight 
X 
 
 
 
**X 
X 
  Physical Examination 
X 
 
 
 
**X 
X 
Safety laboratories 
  
 
 
 
  
  
  Laboratory Draw 
X 
 
 
 
 
X 
  Comprehensive metabolic panel 
X 
 
 
 
 
X 
  Complete blood count 
X 
 
 
 
 
X 
  Mass-Spectrometry for H2 antagonists 
X 
 
 
 
 
X 
  Pregnancy test if premenopausal 
X 
 
 
 
 
X 
Endpoint assessment 
  
 
 
 
  
  
  6 minute-walk distance (primary) 
X 
   
 
 
       ** X 
X 
  echocardiogram 
X 
 
 
 
 
X 
  emPHasis-10 score 
X 
 
 
 
X 
X 
  BNP 
X 
 
 
 
 
X 
  NYHA functional class 
X 
 
 
 
X 
X 
Study Procedures 
  
 
 
 
  
  
  Dispense study drug 
 
X 
 
 
X 
 
  Start study drug 
 
 
X 
 
 
 
  Study drug adherence 
 
 
 
X 
X 
X 
  Study drug compliance 
 
 
 
X 
X 
X 
  Adverse events 
X 
 
 
X 
X 
X 
  Study Termination 
 
 
 
 
 
X 
Sub-study components 
  
 
 
 
  
  
Right heart catheterization (n=20) 
X 
 
 
 
 
X 
Cardiopulmonary Exercise Test (n=10) 
X 
 
 
 
 
X 
Covid testing for exercise test 
 (as required per lab requirement) 
X 
 
 
 
 
X 
Miscellaneous    
 
 
 
 
  
  


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Data Safety Monitoring Board  
 
 
Semi-annually  
As per clinical practice guidelines, patients will be seen every three to six months with blood work and 
six-minute walk testing. These elements (visit, laboratory draw, comprehensive metabolic panel, 
complete blood count, BNP, pregnancy test, 6 minute-walk distance, and NYHA functional class) will be 
collected as part of routine medical care and abstracted from the medical record as research endpoints. 
The pregnancy test can be performed as either a blood or urine test. A blood-based pregnancy test is 
preferred; however, if a urine test is used then it must be performed by  study personnel  and 
documented in the medical record. Echocardiograms are often part of routine medical care and will be 
abstracted from the medical record as research endpoints; however, the frequency may be influenced 
by the study. To avoid any concern about overlap, any echocardiogram occurring more frequently than 
annually will be considered research. It is anticipated that 1 of the 2 echocardiograms will fit this 
research definition. Other research elements include mass spectrometry for H2 antagonists, the 
emPHasis-10 score, study procedures, and sub-study components.  
 
** These procedures will not be performed if the visit is done remotely. 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Although there has been substantial progress in the development of medications to lower pulmonary 
vascular resistance in pulmonary arterial hypertension, there are currently no therapies that have been 
shown to have benefit for right heart failure in the absence of changes in right ventricular afterload.  
 
We are pursuing a novel approach that targets histamine H2 receptors in patients with pulmonary 
arterial hypertension. Previous animal studies suggest that myocardial H2 receptors contribute to 
myocardial fibrosis and are important mediators of heart failure. Our work has shown a lower incidence 
of heart failure in community dwelling adults who use H2 receptor antagonists and a lower all-cause 
mortality in veterans with pulmonary hypertension who use H2 receptor antagonists. A previous 
randomized controlled trial showed that famotidine improved b-natriuretic peptide, left ventricular 
morphology, and New York Heart Association Functional Class in participants with Heart Failure and 
Reduced Ejection Fraction (left heart failure). H2 receptor antagonism is an appealing therapeutic target 
that is well aligned with current NIH priorities of repurposing existing, inexpensive, and well-tolerated 
medications for novel use in other disease states.  
 
We will study intermediate range clinical efficacy of famotidine in participants with pulmonary 
hypertension. We will also assess the safety of famotidine in participants with pulmonary hypertension.  
 
There are two sub-studies proposed for the REHAB-PH trial. One sub-study involves cardiopulmonary 
exercise testing and the other sub-study involves invasive hemodynamic evaluation using right heart 
catheterization. Understanding the relationship between therapy, exercise response, and invasive 
hemodynamic assessment is important for all pulmonary arterial hypertension (PAH) therapies and such 
studies are very common in trials of PAH-specific therapy. To date, nearly all therapeutic trials for 
participants with PAH have focused on medications intended to lower pulmonary vascular resistance 
and right heart afterload. Few studies have evaluated therapies intended to improve right heart fitness 
in the absence of changes in right heart afterload (<right heart targeted therapy=). Targeting myocardial 


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histamine H2 receptors is one such therapy that is hypothesized to impact right heart fitness without 
changing right heart afterload. While the two proposed sub-studies are powered to detect plausible, but 
large differences in exercise response or invasive hemodynamic markers, these studies are not powered 
to detect small to moderate differences. The co-primary intent of these sub-studies is to begin to 
understand appropriate end-points in trials of right heart targeted therapy. This more exploratory 
motivation is intended to complement but not supplant primary and secondary outcome measures 
including six-minute walk distance, BNP, and right ventricular structure and function by 
echocardiography in the current trial. Lessons learned from resting, exercise, and invasive measures will 
be used to inform subsequent trials of right heart targeted therapy using famotidine and/or other 
compounds. We will study exercise response and invasive hemodynamic differences in participants with 
pulmonary hypertension with and without exposure to famotidine.  
2.2 
BACKGROUND  
H2 receptor antagonists were used successfully as a treatment for left heart failure and we showed a 
lower incidence of heart failure and differences in cardiac morphology with H2 receptor antagonist use 
in a large observational cohort. We have also shown H2 receptor antagonist use is associated with 
improved mortality in a cohort of veterans with pulmonary hypertension. This raises the strong 
possibility that H2 receptor antagonism is important in heart failure and likely alters the natural history 
of right heart failure. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 POTENTIAL RISKS  
 
Protection of participant identity is important and will be safeguarded by the use of study identifiers 
whenever possible, a secure comprehensive data management system, and safeguards for electronic 
data including password protection and encryption. In addition, all study staff will be trained in the 
importance and proper safeguards for participant9s privacy and confidentiality. All study personnel will 
be required to sign a confidentiality agreement as per our institutional review board requirements.  
 
All other study procedures including venipuncture, six-minute walk test, echocardiography, right heart 
catheterization, and cardiopulmonary exercise testing are part of the routine care for patients with PAH 
and will be familiar to all participants in the trial. Covid testing may be required prior to exercise testing 
and presents minimal risk and discomfort to most people. Procedures with a small, but extant risk of 
serious complications including right heart catheterization and cardiopulmonary exercise testing are 
optional sub-studies for this trial. These risks will be described and procedures will be done only in the 
setting of adequate staffing and resuscitation equipment to include at a minimum a registered nurse 
and cardiac catheterization technologist in the Catheterization Laboratory and a respiratory therapist or 
exercise physiologist in the Exercise Laboratory. 
 
Famotidine is very well tolerated and available over-the-counter where it is commonly marketed as 
Pepcid. Headaches and gastrointestinal upset have been reported and very rare instances of allergic 
reactions to the medication (e.g. hives or difficulty breathing). Adverse events will be collected and 
reviewed by a data safety monitoring board. 
 
Pregnant women and prisoners are excluded from study. 
 
2.3.2 POTENTIAL BENEFITS  


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Participants in this trial have the potential to benefit from the intervention. If the hypothesis is 
confirmed than participants using famotidine may experience fewer signs and symptoms of right heart 
failure over the course of the study. The proposed trial also has the potential to benefit the pulmonary 
arterial hypertension community at-large given the possibility that the REHAB-PH trial will identify a 
readily available medication that is the first of its kind to target right heart failure directly. Results from 
this trial could inform future trials that benefit the larger community of patients with a range diseases 
complicated by right heart failure (not related to PAH). Finally, results from the trial have the potential 
to benefit the health care system by providing a low cost adjunctive therapy for PAH patients, whose 
therapy currently represents a major expense for the health care system. These benefits may outweigh 
any risk associated with study procedures both for the study participant and the larger community. 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To determine whether famotidine 
increases six-minute walk distance 
at 24 weeks in men and women 
with pulmonary arterial 
hypertension. 
 
The primary end-point is the change 
in six-minute walk distance (6MWD) 
between baseline and 24 weeks. This 
will be compared between treatment 
groups.  
The six-minute walk 
distance is simple, 
reproducible, and well 
tolerated in patients 
with PAH. The 6MWD 
has been the primary 
outcome measure for 
the majority of pivotal 
trials of PAH 
therapeutics because 
of its relationship to 
hemodynamic 
parameters, treatment 
outcome, and survival. 
Secondary 
 
 
To determine whether famotidine 
reduces BNP at 24 weeks 
 
To determine whether famotidine 
improves New York Heart 
Association (NYHA) functional class 
at 24 weeks 
 
To determine whether famotidine 
improves right ventricular 
morphology at 24 weeks including 
improved right ventricular dilation 
and TAPSE 
 
Secondary endpoints include the 
change in BNP, NYHA functional class, 
right ventricular basal diameter, 
TAPSE, emPHasis-10 score, and the 
frequency with which routine 
therapies for patients with PAH are 
escalated during the trial. 
Secondary outcomes 
were chosen to better 
understand the impact 
of the intervention on 
various aspects of the 
treatment response 
including health-
related quality of life 
using disease specific 
validated tools. 


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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
To determine whether famotidine 
improves health related quality of 
life as estimated by the emPHasis-
10 score 
 
To determine whether famotidine 
decreases the need to escalate PAH 
focused care (increased diuretics, 
escalating doses of pulmonary 
vasodilators, and/or adding an 
additional pulmonary vasodilator) 
 
Tertiary/Exploratory  
 
 
Exercise sub-study: 
 
To determine whether famotidine 
increases maximal oxygen uptake 
in individuals with pulmonary 
arterial hypertension at 24 weeks 
 
To explore changes in other metrics 
of the exercise response (oxygen 
uptake, Ve/VCO2 ratio, total 
achieved wattage) with famotidine 
relative to placebo over 24 weeks.  
 
 
Right heart catheterization sub-
study:  
 
To determine whether famotidine 
increases stroke volume index at 24 
weeks  
 
To explore whether famotidine is 
associated with differences in 
wedge pressure, right atrial 
pressure, and/or pulmonary 
vascular resistance at 24 weeks 
The primary analyses will be the 
change in oxygen consumption (VO2) 
for the exercise sub-study and the 
change in stroke volume index (SVi) 
for the right heart catheterization 
sub-study conducted using the 
intent-to-treat (ITT) population.  
 
Qualitative descriptions of other 
exercise and hemodynamic markers 
including mean, median, and 
distribution will be presented 
stratified by treatment group. 
While the two 
proposed sub-studies 
are powered to detect 
plausible, but large 
differences in exercise 
response or invasive 
hemodynamic markers, 
these studies are not 
powered to detect 
small to moderate 
differences. The co-
primary intent of these 
sub-studies is to begin 
to understand 
appropriate end-points 
in trials of right heart 
targeted therapy. This 
more exploratory 
motivation is intended 
to complement but not 
supplant primary and 
secondary outcome 
measures. 


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This study is a Phase II, single-center, blinded, randomized, placebo controlled trial designed to test 
whether famotidine improves functional capacity and metrics of right heart failure relative to placebo in 
participants with pulmonary arterial hypertension over 24 weeks. In addition, there are two sub-studies. 
One sub-study involves cardiopulmonary exercise testing and the other sub-study involves invasive 
hemodynamic evaluation using right heart catheterization.  
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
The central aim of the proposed study is to determine whether famotidine improves right heart failure 
for participants with PAH. This includes the impact on functional outcomes (six-minute walk distance 
and CPET), patient-reported outcomes (emPHasis-10 questionnaire, Appendix 1), and metrics of right 
heart stress and strain (echocardiography, BNP, and invasive hemodynamics). Right heart failure is the 
key driver of morbidity and mortality for patients with PAH. Treatments for pulmonary vascular disease 
have been developed over the last twenty years; however, there are no cardiac-targeted therapies for 
this or any other form of right heart failure. Our work and the work of others strongly suggests that H2 
receptor signaling is important in the pathogenesis and progression of heart failure and antagonism of 
the H2 receptor may improve the natural history of heart failure and pulmonary hypertension. The 
potential importance of this approach is augmented by the fact that famotidine is an extremely well-
tolerated and inexpensive over-the-counter medication for gastro-esophageal reflux. Inexpensive and 
well-tolerated medications are important for all diseases; however, are particularly needed for patients 
with pulmonary vascular disease where current medications targeting the pulmonary vasculature are 
notable for their extreme expense and high side effect profile. 
  
4.3 
JUSTIFICATION FOR DOSE 
 
Participants will receive either 20mg of famotidine or placebo and will take one tablet, once daily for 24 
weeks. This dose was chosen because it is a standard clinically available dose resulting in effective 
antagonism of the H2 receptor. This dose was included in a previous observational study evaluating 
famotidine in heart failure with reduced ejection fraction.  
 
Famotidine is widely available, inexpensive, and has relatively few side effects. This belies an 
intervention that is well tolerated with minimal impact on the health care system. If we show efficacy, 
this represents a high value addition for patients and society. 
 
The choice of 24 weeks was not arbitrary. A previous randomized controlled trial showed that 
famotidine relative to an active control (teprenone) improved b-natriuretic peptide, left ventricular 
morphology, and New York Heart Association Functional Class over 24 weeks in participants with Heart 
Failure and Reduced Ejection Fraction (left heart failure). 
 
To avoid contamination of the placebo arm by participants taking over-the-counter H2 receptor 
antagonists for acid reflux, we will provide all participants with a comprehensive list of H2 receptor 
antagonists to avoid during the trial. We will also provide Calcium Carbonate and Omeprazole for acute 
and chronic control of acid reflux symptoms during the trial. This will help to minimize inadvertent 
contamination of the control arm through self-treatment of acid reflux. 
 
4.4 
END OF STUDY DEFINITION 


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A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit shown in the Schedule of Activities (SoA), Section 1.3. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Male or female, age 18 to 80 
2. WHO Group 1 Pulmonary Arterial Hypertension 
3. NYHA Functional Class II, III, or IV at screening* (See Appendix 2 for Functional Class Decision 
Aid)  
4. Stable dose of pulmonary vasodilators for 30 days prior to randomization 
5. Right heart catheterization within five years demonstrating a mean pulmonary arterial pressure 
of g 25 mmHg, an occlusion pressure of f 15 mmHg, and a pulmonary vascular resistance of g 3 
wood units  
o Participants with a right heart catheterization within five years demonstrating a mean 
pulmonary arterial pressure of g 25 mmHg and occlusion pressure of 15 - 20 mmHg will 
be considered for inclusion if the pulmonary vascular resistance g 9 wood units and they 
are being treated with pulmonary arterial hypertension specific therapy 
6. Able to walk with/without a walking aid for a distance of at least 50 meters 
 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. Pregnant or lactating 
2. Non-group 1 pulmonary hypertension or veno-occlusive disease 
3. History of interstitial lung disease, unless subject has collagen vascular disease and has 
pulmonary function testing conducted within 12 months demonstrating a total lung capacity or 
vital capacity of g 60 % 
4. Has received or will receive an investigational drug, device, or study within 30 days or during the 
course of study 
5. Left sided myocardial disease as evidenced by left ventricular ejection fraction < 40% 
6. Any other clinically significant illness or abnormal laboratory values (measured during the 
Screening period) that, in the opinion of the Investigator, might put the subject at risk of harm 
during the study or might adversely affect the interpretation of the study data 
7. Anticipated survival less than 1 year due to concomitant disease  
8. Regularly taking an H2 receptor antagonist within 30 days of enrollment  
9. Creatinine clearance of < 30 mL/min 
10. History of bariatric surgery 
11. Current treatment for HIV 
 
Individuals with thrombocytopenia (<20,000/microliter), coagulopathy (INR >3), hyperkalemia (>6), 
hypokalemia (<2.5), or hyponatremia (125) cannot participate in the RHC sub-study. In addition, 
participants with known anatomic barriers to IJ placement, a latex allergy, or infection at the insertion 
site will be excluded from this sub-study.  


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Individuals with known, recent exercise associated syncope will be exclude from the cardiopulmonary 
exercise testing sub-study. In addition, individuals with recent myocardial infarction, unstable angina, 
uncontrolled arrhythmia, severe valvular stenosis, decompensated heart failure, active endocarditis, 
acute myocarditis or pericarditis, acute aortic dissection, or marked electrolyte abnormalities will be 
excluded from the CPET sub-study.  
 
5.3 
LIFESTYLE CONSIDERATIONS 
Not applicable. 
 
 
 
 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. This includes 
participants who undergo baseline studies, but who have not been randomized, and for whom the 
baseline evaluation inform clinical concern that they are not appropriate for the study as evidenced by 
meeting an exclusion criteria or failing to meet an inclusion criteria. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
All potential subjects for the REHAB-PH Trial will be recruited from the University of Washington 
Pulmonary Vascular Disease Program. 
 
Potential participants seen in the UW Pulmonary Vascular Disease Clinic will be pre-screened using the 
electronic medical record. Potentially eligible participants will be recruited at the time of their clinic visit 
or if time permits, they will receive a one page letter via mail describing the study and/or a phone call 
from the study coordinator in anticipation of their next visit to clinic. During the potential participant9s 
clinic visit, they will be approached and invited to participate in the REHAB-PH study by the study team 
at the UW Pulmonary Vascular Disease Clinic. A research coordinator will follow-up with any patient 
who is willing or considering participation in the study. This may include scheduling a baseline visit in-
person at the clinic visit and/or following up by telephone. 
 
Retention is a vital consideration for the success of the study. As we have done in other studies, we will 
maximize retention by careful training of clinical research staff on best practices for retaining 
participants. Staff conducting adherence and retention efforts will be trained to conduct effective 
informed consent to assure that participants fully understand the demands and nature of the study 
before they enroll. Clinical center staff will carefully review study requirements with the subjects, 
explain the concept of random assignment and what each treatment involves, and stress the importance 
of follow-up assessment even if they are not adhering to their assigned treatment. Participants will be 
nominally remunerated for their participation to offset travel and parking costs. Clinic staff will, at each 
visit, convey our appreciation for their participation in the study.  Concerns about individual participants 


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will be raised with direct involvement, such as phone calls, by the PI and study center staff as needed to 
facilitate retention. 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
The study drug is Famotidine, a histamine H2-receptor antagonist. Participants will receive either 20mg 
of famotidine or placebo. H2 receptor antagonists are widely available, over-the-counter medications 
and acid reflux (their current indication) is common. Over-dose with an H2 receptor antagonists has not 
been described; however, to avoid contamination of the placebo arm by participants taking over-the-
counter H2 receptor antagonists for acid reflux, we will provide all participants with a comprehensive list 
of H2 receptor antagonists to avoid during the trial. We will also provide Calcium Carbonate and 
Omeprazole for acute and chronic control of acid reflux symptoms during the trial. This will help to 
minimize inadvertent contamination of the control arm through self-treatment of acid reflux. We will 
employ adherence and retention principles and procedures that are standard in the cardiology trials unit 
at the University of Washington. In addition, the degree to which this approach is effective will be 
evaluated through a mass-spectrometry based assay for the presence of any H2 receptor antagonist in 
the blood of study participants at the end of the trial. Ideally H2 receptor antagonists will be seen in 
100% of the assays in the active arm and 0% in the control arm. Significant deviation from this expected 
finding will be considered in the inference on results. 
 
The placebo contains an inactive excipient powder and to preserve study blinding, the placebo tablets 
will be identical in size, shape, color, and appearance to the famotidine tablets.  
 
Famotidine and matching placebo tablets will be in bottles containing 91 tablets. Following enrollment 
and randomization, each subject will receive one bottle to cover the first 12 weeks of the study, which 
will be subject-specific. The site staff will instruct the subject to take one tablet daily. At Week 12, 
subjects will receive another bottle to cover the last 12 weeks of the study.   
6.1.2 DOSING AND ADMINISTRATION 
 
Participants will be randomized to either take a placebo or a 20 mg tablet of famotidine, per oral, once a 
day for 24 weeks.  
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
Harborview Medical Center Investigational Drug Services (HMC IDS) will distribute famotidine and 
placebo tablets for the University of Washington Medical Center Investigational Drug Services (UWMC 
IDS) to dispense. UWMC IDS will store the famotidine and placebo and dispense the pills to the study 
coordinator who will then give them to the subjects. The subjects will self-administer the pills at home 


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and bring any unused pills back to the study coordinator. Returned pills will be logged and then disposed 
of by UWMC IDS.  
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Kirkland Signature will manufacture Famotidine 20 mg tablets. HMC IDS will provide famotidine 20mg 
placebo capsules (Placebo) and over-encapsulation of famotidine 20 mg tablets (Famotidine) to the 
University of Washington Medical Center Investigational Drug Services (UWMC IDS). UWMC IDS will 
place the tablets in 91 count bottles and will label the bottles with blinded prescription labels prior to 
distribution.  
 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
The bottles of famotidine and matching placebo should be stored at controlled room temperature of 
15°C 3 30°C (59°F 3 86°F). Each bottle will have an expiration date.  
 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Subjects will be randomly assigned in a 1:1 ratio to one of two arms using permuted block 
randomization: (1) placebo or (2) famotidine. Subject randomization will be stratified by NYHA/WHO 
Functional Class (NYHA/WHO Functional Class II versus Class III/IV) to ensure balanced representation of 
this important marker of severity. A randomization code will be computer-generated by contract 
research organization (CRO) Axio Research, LLC. Subjects meeting study entry criteria will be randomized 
via an interactive web response system (IWRS). The randomization schedule will be generated by the 
randomization statistician at Axio Research (who is not on the project team) or designee and maintained 
in a secure and limited-access location separate from the study investigator and members of the project 
team. The study subject, investigative staff, the Sponsor, the Sponsor study team (includes contractors 
and vendors), excluding the unblinded study site pharmacist will be blinded to treatment assignments 
during the study. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Study drug counts will be conducted at all study visits. Per protocol cohorts include 80% compliance with 
the once daily intervention. A total of 91 tablets will be provided at each study visit. A count of unused 
medications at the 12 and 24-week follow-up visit will be logged in a drug accountability log and used to 
determine compliance with the intervention. 
 
6.5 
CONCOMITANT THERAPY 
 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, over-the-counter medications and supplements. 
 
Participants are prohibited to take H2 receptor antagonists during the trial. 


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Research pharmacists will review the study participant9s medications listed in their medical record and 
advise them about the timing of administration of their current medications with famotidine and the 
acid reflux concomitant medications provided. This will occur at the initial visit and as needed for any 
follow-up visits that have any new medications added between the visits.  
 
According to pharmacokinetic analyses, single doses of famotidine 20mg raised intragastric pH to mean 
values of 5.0 (similar for when doses were given in the evening or after breakfast). There were no 
cumulative effects with repeated doses. However, there are many studies that have shown 
tachyphylaxis with repeated doses of H2RAs occurring after approximately a week of therapy. Repeated 
doses of H2RAs are associated with decreased time of gastric pH maintained above 4.0.   
 
The impact on the availability of pulmonary vasodilators is as follows:  
 
" 
Sildenafil: no interaction known; delayed rate of absorption with high-fat meals but not antacids 
(time delay 1 hr, reduced maximum concentration by 29%) 
" 
Tadalafil: no significant interaction known; antacids reduced rates of absorption with no change in 
overall exposure; no significant effects observed with the co-administration of nizatidine 300mg 
" 
Riociguat: no information available specifically with H2RAs; however, concurrent use with antacids 
is associated with up to 50% reduction in riociguat maximum serum concentration and 25% 
reduction in exposure; recommended to separate the administration of antacids and riociguat by 
at least 1 hr; specific mechanisms for these interactions are unknown but riociguat solubility is pH-
dependent, and therefore, increases in gastric pH may be partially responsible 
" 
Bosentan: no interaction 
" 
Ambrisentan: no interaction 
" 
Macitentan: no interaction 
" 
Oral treprostinil: no interaction; bioavailability is increased by high fat, high calorie meals by up to 
49% but not known to be impacted by acid suppression  
" 
Selexipag: no interaction; time to peak concentration may be delayed with food but not known to 
be impacted by acid suppression.  
 
References:  
Famotidine [package insert]. Morgantown, WV: Mylan Pharmaceuticals Inc.; 2018. 
McRorie JW, Kirby JA, Miner PB. Histamine2-receptor antagonists: rapid development of tachyphylaxis 
with repeat dosing. World J Gastrointest Pharmacol Ther. 2014; 5(2):57-62. 
Adempas (riociguat) [package insert]. Whippany, MJ: Bayer HealthCare Pharmaceuticals Inc., 2013. 
Interactions. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. 
Accessed March 2019. 
 
6.5.1 RESCUE MEDICINE 
Not applicable.  
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 


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An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
" 
Pregnancy 
" 
Serious Adverse event(s) related to the trial medication  
" 
Any relevant deterioration in the health of the subject (AEs, vital signs, laboratory parameters). 
" 
Protocol violation 
" 
Subject9s inability to stay on the study drug or off other H2 blockers 
" 
Subject withdrew consent 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF).  
 
7.2 
LOSS TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for a scheduled visit and is 
unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
" 
The site will attempt to contact the participant and reschedule the missed visit within a week 
and counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study. 
" 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant9s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant9s study file.  
" 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY AND SAFETY ASSESSMENTS  
 
At the baseline visit participants will be consented and inclusion and exclusion criteria will be assessed 
for eligibility. Participants will then undergo a standardized clinical assessment with medical history, 
symptom assessment including NYHA functional class, vital signs (includes height, blood pressure, heart 
rate, oxygen saturation), weight, and physical examination. Demographics will be collected. A blood 
draw will include safety laboratories including comprehensive metabolic panel, complete blood count, 
BNP, and pregnancy test (for pre-menopausal women). The pregnancy test can be performed as either a 
blood or urine test. A blood-based pregnancy test is preferred; however, if a urine test is used then it 
must be performed by  study personnel and documented in the medical record. All participants will have 
serum collected for mass-spectrometry at the end of the study to evaluate for contamination of the 
study design by individuals taking over-the-counter H2 receptor antagonists. Serum, plasma, and blood 


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for RNA isolation will be collected and stored for participants. Subjects will have an option to opt-out of 
this additional research blood sample. All participants will have a transthoracic (TTE) echocardiogram 
and emPHasis-10 measure of health-related quality of life. They will also complete a 6 minute walk 
distance (6MWD) at their baseline visit. Distance, BORG dyspnea scores, peak heart rate, oxygen 
saturation, and heart rate recovery at one minute will be collected to characterize the walk.  
 
Participants who are not participating in the right heart catheterization or exercise sub-studies will be 
randomized and study drug will be dispensed at this visit. Participants will be instructed to take one 
tablet daily (20 mg of famotidine or placebo) the following day which will represent day zero and entry 
into the study. An antacid (Calcium Carbonate) and proton pump inhibitor (Omeprazole), both over-the-
counter medications, will be provided by a study physician to participants as needed for short and long 
term heartburn control in an effort to try and minimize contamination of the study question by 
inadvertent H2 receptor antagonist use by participants attempting to self-treat heartburn with over-the-
counter medications. 
 
Individuals who are participating in the right heart catheterization or exercise sub-studies will be 
randomized and study drug will be dispensed at their last baseline study assessment. These participants 
will also be instructed to take one tablet daily (20mg of famotidine or placebo) the day following 
randomization and dispensing of the study drug.  
 
Regardless of the participation in sub-studies, all baseline assessments need to be completed within 14 
days prior to the start of study drug (not inclusive of the date the first dose of study drug is taken). The 
day study drug is taken will be considered day 0.   
 
Week 4 phone call will be on day 28 ± 7. This visit will address study drug adherence and adverse events.  
 
Week 12 visit will occur at day 84 ± 7. This visit will include a standard clinical assessment with a 
symptom assessment including NYHA Functional Class, vital signs, weight, and physical examination. 
Participants will also have a 6-minute walk distance, emPHasis-10 score, evaluation for adverse events, 
evaluation for medication and study drug compliance, and dispensation of study drug. Due to the 
COVID-19 pandemic, this visit can be done as telehealth or in-person based on current COVID-19 levels 
in the community and patient preference. If visit is done as telehealth it will include a symptom 
assessment including NYHA Functional Class, emPHasis-10 score, evaluation for adverse events, and 
evaluation for medication and study drug compliance. The UWMC Investigational Drug Service will ship 
the next supply of study medication to the subject via FedEx overnight shipping to coincide with this 
visit. In person visits will be encouraged.  
 
Week 24 visit will occur at day 168 ± 7 and will include all components included in the baseline visit: a 
standard clinical assessment with a symptom assessment including NYHA Functional Class, vital signs, 
weight, and physical examination. Participants will also have a 6-minute walk distance, an 
echocardiogram, emPHasis-10, evaluation for adverse events, evaluation for medication and study drug 
compliance, and a blood draw including a comprehensive metabolic panel, complete blood count, BNP, 


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and pregnancy test if indicated. The pregnancy test can be performed as either a blood or urine test. A 
blood-based pregnancy test is preferred; however, if a urine test is used then it must be performed by 
study personnel  and documented in the medical record. All participants will have serum collected for 
mass-spectrometry at the end of the study to evaluate for contamination of the study question by 
individuals taking over-the-counter H2 receptor antagonists. Serum, plasma, and blood for RNA isolation 
will be collected and stored for participants. 
  
Adverse events and concomitant medications will be assessed and collected at all visits.  
 
Optional Right Heart Catheterization (RHC) Evaluation: Subjects will have the option to take part in the 
RHC portion of the study that will be performed within 14 days of the Baseline Visit and within 7 days of 
the Week 24 Visit. The baseline visit must be done while not taking study drug and the week 24 visit 
must be done while taking study drug. This is a procedure which is performed for all patients with PAH. 
The purpose of this optional evaluation is to track changes in the measurements of the subjects9 heart 
and lungs that might be related to study treatment with famotidine. 1% lidocaine local anesthesia will 
be used.  It will take 3-4 hours to complete the right heart catheterization. On the day of the right heart 
catheterization, subjects will check into the cardiac catheterization laboratory at the University of 
Washington Medical Center. A nurse will check the subject9s vital signs and basic bloodwork to make 
sure that the procedure is safe to perform. Once this is done, subjects will go into the cardiac 
catheterization laboratory where Dr. Leary will numb the area for the procedure with lidocaine. This will 
typically be the right side of the neck. After numbing the area, Dr. Leary will place a catheter into a vein, 
the right atria, right ventricle, and pulmonary artery and measure pressures at each position and check 
to see how much blood the heart is pumping. The process of inserting the catheter and taking 
measurements normally takes approximately 20-30 minutes. After these measurements, the catheter 
will be removed, a nurse will hold pressure on the area to ensure that there is no bleeding, and the 
subject will then be free to go. 
 
Optional Cardiopulmonary Exercise Test (CPET) Evaluation: Subjects will have the option to take part in 
the CPET portion of the study that will be performed within 14 days of the Baseline Visit and within 7 
days of the Week 24 Visit. The baseline visit must be done while not taking study drug and the week 24 
visit must be done while taking study drug. CPET will be done via bicycle ergometry and will be 
performed in the Exercise Testing Laboratory of the UW Lung Function Testing Center. This is a routine 
clinical test used by pulmonologists and cardiologists, but is not routinely done for all individuals with 
PAH. This test measures how the body tolerates physical activity. Due to the Covid 19 Pandemic, the 
Lung Function Testing department at UWMC is requiring Covid testing prior to any procedures done in 
the lab. As long as this requirement is in place, you will be given a phone number to call to arrange 
testing at a drive through testing site within 72 hours of your appointment. At the drive through site, 
you will stay in your car and a nurse will use a nasal swab (like a long Q-tip) inserted into your nose and 
back of throat to collect cells which will be sent to the lab. You will be notified in the event of a 
positive test result. 
On the day of the test, subjects will check into the Lung Function Testing Center at the University of 
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check the subject9s vital signs and conduct breathing tests. After this they will hook up an EKG, monitor 
the subject9s oxygen via a probe on their finger, and place a neoprene mask over their nose and mouth. 
These will measure a number of important exercise characteristics. Subjects will then ride a stationary 
bicycle in the exercise lab. The test is variable in length and designed to push the subject to exercise as 
hard as they can tolerate in a highly supervised setting. Most participants exercise for 5-15 minutes with 
increasing resistance on the stationary bicycle. This is followed by a <cool-down= period on the bicycle. 
When the subject is done, a respiratory therapist will continue to monitor the subject for 5-10 minutes 
at rest. After this time, subjects will be free to go.    
 
Participants in the invasive hemodynamic and cardiopulmonary exercise testing (CPET) sub-studies will 
have the option to do both tests on the same day or separate days, but within the 3 days of the final 
visit.    
 
8.2 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.2.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease 
temporally associated with the use of a medical treatment or procedure, regardless of whether it is 
considered related to the medical treatment or procedure. 
 
8.2.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
Any AE that results in any of the following outcomes:  
" Death  
" Life-threatening  
" Event requiring inpatient hospitalization or prolongation of existing hospitalization  
" Persistent or significant disability/incapacity  
 
8.2.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.2.3.1 
SEVERITY OF EVENT 
 
AEs are graded according to the following scale:  
Mild: An experience that is transient, & requires no special treatment or intervention. The 
experience does not generally interfere with usual daily activities. This includes transient 
laboratory test alterations.  
Moderate: An experience that is alleviated with simple therapeutic treatments. The experience 
impacts usual daily activities. Includes laboratory test alterations indicating injury, but without 
long-term risk.  
Severe: An experience that requires therapeutic intervention. The experience interrupts usual 
daily activities. If hospitalization (or prolongation of hospitalization) is required for treatment it 
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8.2.3.2 
RELATIONSHIP TO STUDY INTERVENTION 
 
The study uses the following AE attribution scale: 
Definite: AE is clearly related to study drug or a study procedure  
Probable: AE is likely related to study drug or a study procedure  
Possible: AE is possibly related to study drug or a study procedure  
Unlikely: AE is doubtfully related to study drug or a study procedure  
Unrelated: AE is clearly not related to study drug or a study procedure 
 
8.2.3.3 EXPECTEDNESS  
 
Expected AEs associated with famotidine include: 
Headaches 
 
Although expected AEs associated with right heart catheterization are uncommon, they include: 
Pain/discomfort, nausea, vomiting, redness, irritation, bruising, or development of a small 
hematoma/bleeding, allergic reactions in rare instances (e.g. hives or difficulty breathing from lidocaine 
or catheters), infection, damage to nearby structures (artery, vein, nerve, lung), hypertensive crisis, 
hypotension, chest pain, bronchospasm, arrhythmia, dizziness/syncope, or death (Hoeper et al., 
Complications of right heart catheterization procedures in patients with pulmonary hypertension in 
experienced centers, J Am Coll Cardiol; 48: 2546-52, 2006). 
 
Although expected AEs associated with exercise testing are uncommon, they include: 
Changes in blood pressure and heart rate, fatigue, discomfort, musculoskeletal injury, syncope, 
arrhythmia, heart attack, or stroke (Skalski et al. The safety of cardiopulmonary exercise testing in a 
population with high-risk cardiovascular diseases, Circulation; 126:2465-72, 2012). 
 
Expected AEs associated with the underlying natural history of pulmonary arterial hypertension or PAH 
therapies over a 24-week study include: 
Dizziness, syncope, leg swelling, abdominal swelling, chest pain, shortness of breath, hypoxemia, 
hemoptysis, nausea, vomiting, diarrhea, jaw pain, flushing, joint pain, muscle pain, infection, arrhythmia, 
heart failure, pericardial effusion/tamponade, cirrhosis, thrombosis or embolus, stroke, cardiac arrest, 
or sudden cardiac death. 
8.2.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The study team will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 14 days (for SAEs) after the last day of study 
participation.  AEs are identified at any of the three in-person visits, during a phone visit, during a study-
based procedure (e.g. heart catheterization or cardiopulmonary exercise test) or when notified outside 
of the normal visit structure by a participant or surrogate.  Events will be followed until resolution or 
stabilization. 
 
8.2.5 ADVERSE EVENT REPORTING  
 


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Deaths and unexpected, but definite, probable, or possibly-related SAEs are reported to the PI and 
DSMB within 48 hours through the use of an e-mail transmitted SAE report form copied to the PI, 
executive secretary of the DSMB, and DSMB Chair.  
 
In addition, all events that meet the definition of an unanticipated problem (in the PI9s opinion) should 
be reported to the UW IRB within 10 days using the Zipline Online portal.  
 
An unanticipated problem is a problem or event that meets all of the following criteria:  
" 
Unexpected 3 The harm (or potential harm) is inconsistent with risk information previously 
reviewed and approved by the Institutional Review Board (IRB) in terms of nature, severity, or 
frequency as well as the characteristics of the study population. 
" 
Related or probably related to participation in the research; 
o 
Probably related: There is a reasonable probability (more likely than not) that the 
incident, experience or outcome may have been caused by the procedures involved in 
the research, or that it is associated with the use of any drug, biologic, or medical device 
that is part of the research. 
" 
Suggests that the research places (or did place) one or more subjects or others at a greater risk 
of harm than was previously known or recognized. This includes physical, psychological, 
economic, educational advancement, or social harm. 
Reports are required within 24 hours for qualifying medical problems covered by the UW Human 
Subjects Assistance Program (HSAP), a breach of confidentiality, or inappropriate use of protected 
health information.  
In addition, the IRB requires a report within 10 days for serious non-compliance, continuing non-
compliance (serious or non-serious), emergency deviation from IRB approved procedures to eliminate 
an apparent hazard to subjects or others, complaints that cannot be resolved by the research team, 
audit notification from a federal agency, information that indicates a new potential risk (e.g. new 
publication), and all DSMB reports.  
 
Expected S(AE)s are not required to be reported to the UW IRB outside of continuing review.  
 
 
8.2.6 REPORTING EVENTS TO PARTICIPANTS  
 
Participants will be updated with any learned information during the study that may affect their 
willingness to participate.  
8.2.7 EVENTS OF SPECIAL INTEREST  
Not applicable.  
 
8.2.8 REPORTING OF PREGNANCY  
 
Pregnancy and the post-partum period is a highly dangerous and volatile time for women with 
pulmonary arterial hypertension and as a result participants who are pregnant, lactating, or have 


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evidence of dynamic disease with pulmonary vasodilator adjustment within 30 days of randomization 
will not be included. It is also possible that harmful side effects that are not yet known could happen to 
both the mother and unborn or breast-feeding child.   
 
The investigator must be notified immediately if the subject becomes pregnant and they will be 
withdrawn from the study. This is anticipated to occur uncommonly if ever. The clear clinical 
recommendation in pulmonary arterial hypertension is dual-method contraception and the risk of death 
with pregnancy is prohibitive. Unintended or intended pregnancy is a very rare event in the pulmonary 
vascular disease clinic.  
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
Primary Efficacy Endpoint(s): The primary endpoint is the difference in 6-minute walk distance.  
 
Secondary Efficacy Endpoint(s): The secondary endpoint is the difference between treatment groups in 
BNP, NYHA functional class, TAPSE, right ventricular basal diameter, emPHasis-10 score, and number of 
participants with an escalation of routine clinical treatments for PAH for each visit. 
 
We hypothesize that famotidine use in individuals with PAH will improve 6-minute walk distance over 24 
weeks relative to placebo.  
 
We further hypothesize that over 24 weeks famotidine use in individuals with PAH will lower BNP, 
improve the NYHA functional class, increase the TAPSE, diminish the right ventricular basal diameter, 
improve the emPHasis-10 score, and minimize the need to escalate routine treatment for PAH (diuretics 
and pulmonary vasodilators).  
 
 


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9.2 
SAMPLE SIZE DETERMINATION 
 
The primary endpoint is the change in six-minute walk distance. The study was powered to detect a 
difference of 31.9 meters. A 31.9 meter improvement in 6MWD is well aligned with established 
thresholds for a minimally important difference in patient reported outcomes. The 6MWD was chosen 
because 6MWD is a surrogate for patient-centered outcomes and was the primary endpoint in labeling 
trials for most of the medications used to treat pulmonary arterial hypertension (PAH).  
 
The field is appropriately shifting toward larger event driven trials; however, we did not feel a larger 
event driven trial of famotidine was warranted at this juncture. The current proposal is the first 
randomized evaluation of this drug and this pathway in individuals with right heart failure and/or PAH 
and a smaller Phase II trial was felt to be a more appropriate next step. 
 
For the RHC sub-study, the initial sample size was set at 10 participants based on the following power to 
detect large differences.  
 
Size of difference 
SV index (mL/m2) 
Total sample size 
n per group 
power 
Large  
20 
10 
5 
0.87 
Medium-high 
15 
10 
5 
0.67 
Medium-low 
10 
10 
5 
0.36 
Small 
5 
10 
5 
0.13 
 
As the study progressed, recruitment into this invasive arm appeared to be more feasible and the 
sample size was increased to 20 participants. 
Size of difference 
SV index (mL/m2) 
Total sample size 
n per group 
power 
Large  
20 
20 
10 
0.99 
Medium-high 
15 
20 
10 
0.95 
Medium-low 
10 
20 
10 
0.68 
Small 
5 
20 
10 
0.23 
 
 
 


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9.3 
POPULATIONS FOR ANALYSES 
Intent-to-Treat Population: All subjects who are randomized will comprise the intent-to-treat (ITT) 
population. The ITT population will be analyzed for the primary and secondary endpoint analyses and will 
comprise the safety population used for all safety analyses.  
Per Protocol Population: Subjects in the ITT population whose famotidine medication reconciliation 
suggest adherence to study drug for 80% or more of administered doses will be evaluated as the per 
protocol population. The per-protocol population will be used in the sensitivity analyses of the primary 
and secondary endpoints. A second per protocol population will include participants for whom H2 
receptor antagonists are detected by Mass Spectrometry at the final visit relative to those for whom H2 
receptor antagonists are not detected.  
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
Except where otherwise noted, all tests will be two-sided and statistical significance will be determined at 
the 0.05 level.  
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The primary endpoint is the difference between treatment groups in the change of 6-minute walk 
distance (6MWD) between baseline and 24 weeks. Linear regression will be performed with the change 
in 6MWD between baseline and 24 weeks as outcome and treatment group as the primary predictor of 
interest, adjusted for baseline 6MWD and baseline NYHA functional class as the stratification variable. 
The estimate of the treatment effect will be provided with associated 95% confidence interval (CI).  
 
Missing 6MWD at 24 weeks will be imputed as follows. Subjects known to be dead before the 24 week 
assessment will have zero imputed for their 24 week 6MWD. Missing 24 week 6MWD for subjects who 
are alive will be imputed using multiple imputation. The imputation model will have prognostic variables 
as the predictor variables. Prognostic variables will include age, gender, and etiology of pulmonary 
hypertension, baseline six minute walk test, baseline right ventricular diameter, and baseline BNP. The 
multiple imputation will use Markov Chain Monte Carlo (MCMC), which assumes that the variables in 
the imputation model have a joint multivariate normal distribution (MVN). The number of imputations 
to be performed will be 100. One hundred is selected because it is not too large that it requires heavy 
computations and is not too small (such that the Monte Carlo error is still small enough at around 0.1 
times the standard deviation). The <proc mi= procedure in SAS will be used to impute the missing 
observations. 
 
Although every effort will be made to avoid missing data, a range of approaches to missing 6MWD will 
be considered as sensitivity analyses representing a range of conservative and anti-conservative biases 
to describe the range of possible differences. 
 
Sensitivity Analyses of the Primary Endpoint 
Sensitivity analyses of the primary endpoint will include: 


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" 
a linear regression model using a worst case scenario (WCS) method of imputation  
" 
a linear regression model of the 24 week 6MWD without imputation (complete case analysis) 
 (1) The worst case scenario method of imputation will impute zero for all missing 6MWD at week 24.     
 (2) The linear regression method will model the 24 week 6MWD on treatment assignment, adjusting for 
baseline 6MWD and baseline NYHA class using least squares and robust standard error estimates. For all 
methods, treatment effect estimates and 95% CIs will be presented. 
 
Additional Analyses of the Primary Endpoint 
Additional analyses of the relative change in 6MWD will include the proportion of participants who 
achieve a minimally important change in 6MWD of 31.9 meters or greater. To test the null hypothesis 
that there is no difference between the treatment groups, logistic regression adjusted for the NHYA 
functional class (stratification variable) will be used. The difference between treatment groups will be 
provided with associated 95% CI. Subjects missing the 24 week 6MWD will not be counted as having 
achieved a minimally important change. 
 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Summary statistics (mean, standard deviation, median and range) of BNP (untransformed and log-
transformed), NYHA functional class, right heart strain, TAPSE, right ventricular basal diameter, 
emPHasis-10 score, and number of participants with an escalation of routine clinical treatments for PAH 
for each visit will be presented by treatment group. Change in these parameters (log-transformed value 
for BNP) will be evaluated between the treatment groups using linear regression adjusted for the value 
at baseline and NYHA functional class (stratification variable). The difference with 95% CIs will be 
reported. 
 
The BNP is expected to vary by NYHA functional class. An additional sensitivity analysis will be 
performed with the difference of log-transformed BNP between baseline and week 24 as the outcome, 
with the predictor variables being baseline log-transformed BNP, treatment group, baseline NYHA 
functional class, and an interaction term between treatment group and baseline NYHA functional class. 
 
Missing data in the secondary outcomes will be imputed in an analogous fashion to the primary 
outcome including sensitivity analyses to define the range of uncertainty imposed by missing data 
(worst case scenario and complete case analysis). The worst case scenario is different by variable. BNP 
and right ventricular basal diameter will be set to the highest value in the observed population. TAPSE 
will be assumed to be zero, emPHasis-10 score will be assumed to be 50, NYHA functional class will be 
assumed to be IV, and a participant will be assumed to have escalated PAH specific care.  
 
 
9.4.4 SAFETY ANALYSES 
 
All reported (S)AEs will be coded using MedDRA and grouped by body system. (S)AEs will be tabulated 
by treatment group using standard coding terms. Incidence of AEs by treatment arm will be tabulated by 
seriousness, severity, and relationship to study drug. If an AE is reported more than once for a given 
subject, the greatest severity and the worst-case relationship will be presented in tables. The number of 
SAEs and AEs will be summarized for each treatment group as follows: (i) The proportion of subjects 
with at least one (S)AE, (ii) The average number of (S)AEs per subject, and (iii) The rate of (S)AEs per 


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subject week of follow-up. Histograms showing the frequency of the number of (S)AEs in each treatment 
group will be included. Rates of (S)AEs by System Organ Class (SOC) will be presented by treatment 
group. Poisson regression modeling will be used to derive rate ratios and 95% CIs for each SOC. Rate 
ratios will be compared using a two-sided 0.05 level test for Poisson count data.  
 
Safety lab data at each study visit and changes from baseline will be summarized by treatment group. In 
addition, clinical laboratory summaries will be presented by treatment group including: (i) incidence of 
significant abnormalities by visit; (ii) tables summarizing the frequencies of subjects below, within, and 
above the normal reference ranges at baseline and end of study; and (iii) tables displaying baseline to 
end of study shifts in each laboratory value (shifts between below, within or above normal range).  
 
Although drug discontinuation is anticipated to be infrequent, the proportion of subjects permanently 
discontinuing study drug will be tabulated by treatment group. Drug discontinuation events will be 
categorized as: (1) Permanently discontinued study drug and (2) Permanently discontinued study drug 
and withdrew from study. The reason for permanent drug discontinuation will be summarized. The 
number of hospitalization events and proportion of subjects hospitalized from baseline to study 
termination will be summarized and compared by treatment group. Poisson regression modeling will be 
used to derive rate ratios and 95% CIs to compare hospitalization rates between treatment groups.  
 
9.4.5 DEMOGRAPHIC AND BASELINE DESCRIPTIVE STATISTICS 
Treatment groups will be described and compared with respect to baseline demographic and clinical 
characteristics such as age, gender, race, ethnicity, height, weight, body mass index, use of concomitant 
medications, and markers of pulmonary hypertension disease severity (e.g., right ventricular structure 
and function, BNP, 6-minute walk distance, New York Heart Association (NYHA) functional class). 
Continuous measures will be analyzed using t-tests and categorical variables will be analyzed using chi-
square, Fisher9s exact, or Cochran-Mantel-Haenszel tests. 
 
9.4.6 DSMB REVIEW OF ONGOING DATA  
 
Reports to the DSMB will focus on trial integrity (recruitment, protocol deviations/violations, 
completeness of follow-up and adherence) and safety. Comprehensive safety interim reports will be 
provided semi-annually to the DSMB. Comprehensive, safety reports will include detailed summaries of 
all SAEs, AEs, laboratory parameter listings, drug discontinuations and withdrawals as well as other 
pertinent safety data. The DSMB will recommend continuation or discontinuation of the study based on 
these interim reviews. Because of the length, size, and scope of the proposed study interim analyses for 
efficacy or futility will not be performed.   
 
 


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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to administering study 
intervention.   
 
All participants will be given a list of H2 receptor antagonists to avoid during the trial. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual9s agreeing to participate in the 
study and continues throughout the individual9s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. A 
study team member will explain the research study to the participant and answer any questions that 
may arise. A verbal explanation will be provided in terms suited to the participant9s comprehension of 
the purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants will be given adequate opportunity to consider all options by allowing 
subjects to take the consent form home and to contact the study team at a later time if they would like 
to participate. The participant will sign the informed consent document prior to any procedures being 
done specifically for the study. Participants must be informed that participation is voluntary and that 
they may withdraw from the study at any time, without prejudice. A copy of the informed consent 
document will be given to the participants for their records. The informed consent process will be 
conducted and documented in the source document (including the date), and the form signed, before 
the participant undergoes any study-specific procedures. Study-specific procedures (like right heart 
catheterization) may be scheduled but not performed before consent is obtained. Many of the study 
endpoints including the six-minute walk distance, BNP, NYHA functional class, and echocardiogram are 
also part of routine clinical care. As such clinically obtained testing within the specified time window 
may be used as part of the baseline research assessment. Because these tests are not <study-specific= it 
is not considered a violation if they are obtained before consent is obtained. The rights and welfare of 
the participants will be protected by emphasizing to them that the quality of their medical care will not 
be affected if they decline to participate in this study. 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, funding agency, and 
regulatory authorities.  If the study is prematurely terminated or suspended, the Principal Investigator 


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(PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will 
provide the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
" 
Determination of unexpected, significant, or unacceptable risk to participants 
" 
Demonstration of efficacy that would warrant stopping    
" 
Insufficient compliance to protocol requirements 
" 
Data that are not sufficiently complete and/or evaluable 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
Authorized representatives of the sponsor, representatives of the Institutional Review Board (IRB), and 
the U.S. Food and Drug Administration (FDA) may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
and pharmacy records for the participants in this study. The clinical study site will permit access to such 
records. 
 
The study participant9s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at Axio Research. This will not include the participant9s contact or 
identifying information. Rather, individual participants and their research data will be identified by a 
unique study identification number. The study data entry and study management systems used by Axio 
Research staff will be secured and password protected. At the end of the study, all study databases will 
be de-identified and archived at Axio Research. 
 
Certificate of Confidentiality  
 
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued by the 
National Institutes of Health (NIH).  This certificate protects identifiable research information from 
forced disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, legislative, 


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or other proceeding, whether at the federal, state, or local level. By protecting researchers and 
institutions from being compelled to disclose information that would identify research participants, 
Certificates of Confidentiality help achieve the research objectives and promote participation in studies 
by helping assure confidentiality and privacy to participants. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at Axio Research. After the study is completed, 
the de-identified, archived data will be transmitted to and stored at the University of Washington, for 
use by other researchers including those outside of the study. Permission to transmit data to the 
National Institute of Health (NIH) data banks will be included in the informed consent.  
 
With the participant9s approval and as approved by local Institutional Review Boards (IRBs), de-
identified biological samples will be stored at the University of Washington with the same goal as the 
sharing of data with the NIH data banks. A transcript wide analysis of RNA samples may be performed. 
These samples could be used for future studies on any topic related to pulmonary vascular disease or 
right heart failure. The NIH will be provided with a code-link that will allow linking the biological 
specimens with the phenotypic data from each participant, maintaining the blinding of the identity of 
the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed and data has been submitted to the 
NIH data banks.  
 
When the study is completed, access to study data and/or samples will be provided through the 
University of Washington. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Peter Leary, MD, PhD 
University of Washington 
1959 NE Pacific St. 
Seattle, WA 98195 
(206) 685-2484 
learyp@uw.edu 
 
 
10.1.6 SAFETY OVERSIGHT 
 
Primary safety oversight will be performed by the Principal Investigator and Study Co-Investigators. 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the appropriate expertise, including a pulmonary hypertension specialist, a statistician, 
ethics specialist, cardiovascular specialist, and clinical trials specialist. Members of the DSMB should be 


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independent from the study conduct and free of conflict of interest, or measures should be in place to 
minimize perceived conflict of interest.  The DSMB will meet at least semiannually to assess safety and 
efficacy data on each arm of the study. The DMSB will operate under the rules of an approved charter 
that will be written and reviewed at the organizational meeting of the DSMB. At this time, each data 
element that the DSMB needs to assess will be clearly defined. The DSMB will provide its input to 
National Institutes of Health staff. All changes to the protocol or consent will be submitted to the NHLBI 
and DSMB for review prior to submission to the IRB or execution in the study. 
 
10.1.7 CLINICAL MONITORING 
 
Not applicable. 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
The sole clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.   
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site for clarification/resolution. 
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of auditing and inspection by local and regulatory authorities. 
 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into the International Business Machines (IBM) Clinical 
Development database system provided by Axio Research. The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the source 
documents. 


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10.1.9.2 STUDY RECORDS RETENTION  
 
Study documents should be retained for a minimum of 6 years after study closure.  
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol or International Conference on 
Harmonization Good Clinical Practice (ICH GCP). The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
" 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
" 
5.1 Quality Assurance and Quality Control, section 5.1.1  
" 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations.  All deviations must be addressed in study source documents and entered into the IBM 
Clinical Development system.  Protocol deviations must be sent to the reviewing Institutional Review 
Board (IRB) per their policies. The site investigator is responsible for knowing and adhering to the 
reviewing IRB requirements.  
 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested from other researchers after the completion 
of the primary endpoint by contacting the University of Washington.  
 
In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-
funded research that generates large-scale human or non-human genomic data, as well as the use of these 
data for subsequent research. Large-scale data include transcriptomic, RNA sequencing data. 
 
 
 


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10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with the National Heart, Lung, and Blood Institute (NHLBI) has established 
policies and procedures for all study group members to disclose all conflicts of interest and will establish 
a mechanism for the management of all reported dualities of interest. 
 
 
 


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53. McLaughlin VV, et al. ACCF/AHA 2009 Expert consensus document on pulmonary hypertension. J Am 
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12 APPENDIX 1: EMPHASIS-10 QUESTIONNAIRE 
 
 
 


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13 APPENDIX 2: FUNCTIONAL CLASS DECISION AID 
 
Functional Class Decision Aid 
Does the patient have symptoms most likely related to pulmonary hypertension: 
 1. At rest? 
yes        
no        
n/a        
FC IV 
 2. When getting up or dressing? 
yes        
no        
n/a        
 3. When washing, brushing teeth or having a shower? 
yes        
no        
n/a        
 4. When walking around in the house? 
yes        
no        
n/a        
 5. When walking on level ground at slow speed? 
yes        
no        
n/a        
 
 6. When climbing up to 2 flights of stairs  
at reduced (slow) speed? 
yes        
no        
n/a        
FC III 
 7. When walking on level ground  
at normal (pedestrian) speed? 
yes        
no        
n/a        
 
 8. When climbing 2 or more flights of stairs  
at normal speed? 
yes        
no        
n/a        
FC II 
 9. When walking uphill? 
yes        
no        
n/a        
 
 10. When performing vigorous physical activity? 
yes        
no        
n/a        
FC I 
 
Investigator Determined    Functional class for this patient: WHO FC 
 
 
 

ICF_003.pdf: 
Study Title: Repurposing a histamine antagonist to benefit patients with 
pulmonary hypertension (REHAB-PH) 
 
National Clinical Trial (NCT) Identified Number: NCT03554291 
 
PI Name: Peter Leary, MD PhD 
 
IRB Approval Dates: 
Initial approval: 8/9/2018 
Current version of the protocol reviewed/approved: 1/20/2023 
Current version of the consent reviewed/approved: 1/20/2023 
Most recent continuing review approval: 4/25/2024 – 4/24/2025  


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UNIVERSITY OF WASHINGTON
CONSENT FORM
Repurposing a Histamine Antagonist to Benefit Patients with Pulmonary Hypertension
(REHAB-PH)
Researchers: 
Peter J. Leary, MD, PhD, Associate Professor, Division of Pulmonary, Critical Care, and Sleep, 
 (206) 685-2484 
Laurie Hogl, Research Coordinator, Division of Pulmonary, Critical Care, and Sleep, 
 (206) 543-8334 
24-hour emergency telephone number: (206) 598-6190 
The above number will reach University of Washington Medical Center; ask the operator to page Dr. 
Peter Leary. 
Researchers’ statement
We are asking you to be in a research study.  The purpose of this consent form is to give you the 
information you will need to help you decide whether to be in the study or not.  Please read the 
form carefully.  You may ask questions about the purpose of the research, what we would ask 
you to do, the possible risks and benefits, your rights as a volunteer, and anything else about the 
research or this form that is not clear.  When we have answered all your questions, you can 
decide if you want to be in the study or not.  This process is called “informed consent.”  We will 
give you a copy of this form for your records.
PURPOSE OF THE STUDY
We would like to better understand right heart failure in patients with pulmonary arterial 
hypertension (PAH). This clinical trial is testing to see if an over-the-counter drug, famotidine, 
will improve ability to exercise and right heart function in participants with PAH.  Famotidine is 
an FDA-approved drug used to treat symptoms of heartburn. In this study we are testing 
famotidine for an unapproved use in participants with right heart failure. We are enrolling up to 
80 participants at the University of Washington. We are asking you to be in this trial because you 
are currently being treated for PAH at the University of Washington. 
STUDY PROCEDURES
If you agree to be in this study, you will be randomized into one of two groups. Randomization 
means that you are placed into a group by chance and will have an equal chance of being placed 
in either the group receiving famotidine or the group receiving placebo. A placebo is a “sugar 
tablet” made to look like the investigational drug. This study is considered a ‘double blind’ 
study. This means that neither you nor the study doctor will be aware of which group you are 
assigned to. 
     Approved 
     1/20/2023
     UW IRB


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This study will last 24 weeks from the time of enrollment and consists of two or three in-person 
visits and one phone call. A phone call will be made at Week 4 and in-person visits will be at 
Baseline and Week 24. The Week 12 visit may be done in person of via phone. Each in person 
visit will be at the University of Washington Medical Center Pulmonary Vascular Disease Clinic 
and will add about an additional 20-30 minutes to your normal clinic visit.
Baseline Visit
At the baseline visit, you will be consented and eligibility will be assessed. You will undergo a 
standardized clinical assessment, which includes vital signs, weight, a physical examination, a 
review of your medical history, demographics, medications, and an assessment of your 
symptoms. Blood will be collected for routine tests. If you are of child-bearing potential, we will 
also do a pregnancy test by blood serum or urineIf positive, you will be ineligible for the study. 
You must also agree to the use of effective contraception. 
You will be asked to complete a 6-minute walk distance (6MWD). You will be asked to walk for 
6 minutes while someone times you and watches to evaluate the distance you can travel within 
the 6 minutes. You can let them know you want to stop at any time. You will also be asked to 
complete a short questionnaire designed to determine how pulmonary hypertension affects your 
life. In addition, an echocardiogram will be scheduled and will take about 60 minutes. An 
echocardiogram is a sonogram of the heart.  
Sub-studies will be described in a later section and include right heart catheterizations and/or 
cardiopulmonary exercise tests (CPET) at Baseline and Week 24.  Each test will take about 2 
hours. Participants may elect to do either, both, or neither sub-study. For individuals who want to 
participate in both sub-studies, these can be performed on the same or different days as long as 
they are within 14 days of the baseline visit and within 7 days of the Week 24 visit. If you 
choose to do both sub-studies on the same day, the CPET will be performed prior to the right 
heart catheterization. 
For most participants in the main study, all study assessments will occur during one study visit; 
however, sub-study participants and occasional main study participants may have study 
assessments on two or more different days. If this occurs then randomization will occur 
following the last baseline study assessment. You may go through baseline procedures and not 
qualify for the study. 
Study drug will be dispensed on the day of the last study assessment and will be started the day 
following the last baseline assessment. All baseline assessments must be completed over the 14 
days before study drug is started. A study physician will also provide Tums and Omeprazole as 
needed for short and long term heartburn control. We hope that you will use only these 
medications for heartburn, but will also give you a list of medications to avoid if buying over-
the-counter heartburn medication since some of these may be the study drug (famotidine) or 
similar drugs. Use of these medications could invalidate the trial.  
Week 4 Phone Call
A phone call will be made on day 28 ± 7 to assess study drug compliance and adverse events.
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Week 12 Visit
At Week 12, day 84 ± 7, you will undergo a standard clinical assessment, which includes vital 
signs, weight, a physical examination, a review of your medications, and an assessment of your 
symptoms. You will be asked to complete a 6MWD and a questionnaire designed to determine 
how pulmonary hypertension affects your life. Study drug will be dispensed at this visit and you 
will be instructed to take one tablet daily (20 mg of famotidine or placebo). Due to the COVID-
19 pandemic, this visit may be done in person or as a phone call based on the prevalence of 
COVID-19 in the community or preference. We encourage you to come to this visit in person, if 
possible. If done via phone this visit will include a symptom assessment, a review of your 
medications and a questionnaire. The Investigational Drug Service at UWMC will ship the next 
supply of study medication to your home via FedEx overnight prior to this visit.
Week 24 Visit
Similar to the Baseline visit, Week 24, day 168 ± 7, you will undergo a standard clinical 
assessment, which includes vital signs, weight, a physical examination, a review of your 
medications, and an assessment of your symptoms. You will be asked to complete a 6MWD, a 
questionnaire, and an echocardiogram. Blood will be collected for routine tests and a pregnancy 
test either by blood serum or urine if you are of child bearing potential. Individuals who 
participate in the exercise sub-study, right heart catheterization sub-study, or both sub-studies 
will repeat the exercise and/or heart catheterization within 7 days of the final visit. The Week 24 
visit must be done while taking study drug and thus, study drug will be returned after all Week 
24 assessments, including the sub-studies, have been completed.
OPTIONAL OPT-OUT STUDY PROCEDURE
Additional blood, up to 32 ml (2.2 tablespoons), will be collected and stored at your Baseline and 
Week 24 visit. This blood is in addition to the non-optional blood draw described above and does 
not involve a separate needle “poke”. This additional blood will be stored and may be used over 
time to help understand potential markers important to patients with pulmonary hypertension 
and/or right heart failure. Such markers may include tests for proteins, RNA and other 
components of blood. RNA is a genetic material that has a major role in making proteins. This 
evaluation is not required to take part in the study. You retain the right to contact the study team 
at any time in the future and withdraw your consent. 
OPTIONAL OPT-IN RIGHT HEART CATHETERIZATION EVALUATION
This evaluation is not required in order to take part in the study. If you choose to take part in this 
evaluation, this test will be performed at the Baseline Visit and at the last visit, Week 24. The 
right heart catheterization will be scheduled within 14 days of your Baseline Visit AND within 7 
days of your Week 24 Visit. The baseline visit must be done while not taking study drug and the 
week 24 visit must be done while taking study drug. This is a procedure which is performed 
frequently for patients with PAH and everyone considered for the study will have had a least one 
right heart catheterization to diagnose their disease. The purpose of this optional evaluation is to 
track changes in the measurements of your heart and lungs that might be related to study 
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treatment with famotidine. You should allow 3-4 hours to complete the right heart 
catheterization. On the day of your right heart catheterization you will check into the cardiac 
catheterization laboratory at the University of Washington Medical Center. A nurse will check 
you vital signs and basic bloodwork to make sure that the procedure is safe to perform. Once this 
is done, you will go into the cardiac catheterization laboratory where Dr. Leary will numb the 
area for the procedure with lidocaine. This will typically be the right side of your neck. After 
numbing the area, Dr. Leary will place a catheter into a vein, the right atria, right ventricle, and 
pulmonary artery. He will measure pressures at each position and check to see how much blood 
your heart is pumping. The process of inserting the catheter and taking measurements normally 
takes approximately 20-30 minutes. After these measurements, the catheter will removed, a 
nurse will hold pressure on the area to ensure that there is no bleeding, and then you will be free 
to go.
OPTIONAL OPT-IN CARDIOPULMONARY EXERCISE TEST EVALUATION
This evaluation is not required in order to take part in the study. If you choose to take part in 
this evaluation, this test will be performed at the Baseline Visit and at the last visit, Week 24. 
The cardiopulmonary exercise test (CPET) will be scheduled within 14 days of your Baseline 
Visit and within 7 days of the Week 24 Visit. The baseline visit must be done while not taking 
study drug and the week 24 visit must be done while taking study drug. If you choose to take 
part in the CPET, this will be done via bicycle ergometry and will be performed in the Exercise 
Testing Laboratory of the UW Lung Function Testing Center. This is a routine clinical test 
used by pulmonologists and cardiologists, but unlike the right heart catheterization, is not 
routinely done for all individuals with PAH. In this test we measure how well your body 
tolerates physical activity. Due to the COVID-19 Pandemic, the Lung Function Testing 
department at UWMC is requiring novel coronavirus testing prior to any procedures done in 
the lab. As long as this requirement is in place, you will be given a phone number to call to 
arrange testing at a drive through testing site within 72 hours of your appointment. At the drive 
through site, you will stay in your car and a nurse will use a nasal swab (like a long Q-tip) 
inserted into your nose and back of throat to collect cells which will be sent to the lab. You will 
be notified in the event of a positive test result.
On the day of the test, you will check into the Lung Function Testing Center at the University of 
Washington Medical Center. You should wear clothing suitable for exercise. A respiratory 
therapist will check your vital signs and conduct breathing tests. After this they will hook up an 
EKG, monitor your oxygen via a probe on your finger, and place a neoprene mask over your 
nose and mouth. These will measure a number of important exercise characteristics. You will 
then ride a stationary bicycle in the exercise lab. The test is variable in length and designed to 
push you to exercise as hard as you can tolerate in a highly supervised setting. Most participants 
exercise for 5-15 minutes with increasing resistance on the stationary bicycle. This is followed 
by a “cool-down” period on the bicycle. When you are done, a respiratory therapist will continue 
to monitor you for 5-10 minutes at rest. After this time, you will be free to go.   
Some information may be abstracted from your medical record if you have already had tests 
done for clinical care (such as six-minute walk distance, safety labs, and one echocardiogram).
A table summarizing most of the study procedures and schedule can be found below. 
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Study drug will be dispensed on the day of the last study assessment and will be started the day 
following the last baseline assessment. Study drug compliance will be assessed at the Week 4 
phone call, Week 12 visit, and the Week 24 visit.
Baseline
Visit
Week 4 
Phone Call
Week 12
Visit
Week 24
Visit
Visit #
1
Phone Call
2
3
Informed Consent
History and Physical Exam
X
X
X 
X
Blood draw
Pregnancy test if premenopausal 
6 minute-walk distance 
Echocardiogram
Questionnaire
X 
X 
X 
X
X
X  
X
X 
X 
X 
X
X
OPTIONAL Testing
Right heart catheterization
Cardiopulmonary Exercise Test
Covid testing for exercise testing (as required 
per lab requirement)
X
X
X
X
X
X
Although the baseline visit can be completed in a single visit in most cases, all testing in the 
baseline visit must be completed within 14 days. Similarly, all testing in the week 12 and week 
24 visits must be completed within 7 days of the assigned date (if Week 12 is remote, there will 
be no 6MWD or physical exam)
RISKS, STRESS, OR DISCOMFORT
While we use every effort to protect your personal information, absolute confidentiality cannot 
be guaranteed and is always a potential risk of participation in research.
You may be uncomfortable with some of the questions and/or uncertainty of whether you are 
taking the study drug or placebo. Please remember that if you decide to participate, you can skip 
any question for any reason.
If you were taking a medication like famotidine for heartburn symptoms and are assigned to 
placebo for this study, you may have worsening of your heartburn symptoms. The investigators 
can provide medicines to treat your symptoms such as calcium carbonate and omeprazole. 
Famotidine is very well tolerated and available over-the-counter where it is commonly marketed 
as Pepcid. Headaches and gastrointestinal upset have been reported and very rare instances of 
allergic reactions to the medication (e.g. hives or difficulty breathing).
The blood draws may cause some temporary discomfort and may include pain at the needle 
insertion site, slight bruising, or development of a small hematoma. There is a small risk of 
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infection at the needle insertion site. Some people become anxious with blood draws and are 
prone to fainting.
There are few risks associated with a six-minute walk test since you decide how fast to walk 
depending on your ability. Changes in blood pressure, heart rate, and fainting can happen.
During the echocardiography, discomfort during the acquisition of images is possible.
Right heart catheterization risks include temporary discomfort and may include pain at the 
needle insertion site, chest pain, nausea, vomiting, dizziness, fainting, temporary high or low 
blood pressure, slight bruising, or development of a small hematoma/bleeding. The topical 
lidocaine injection can cause redness, irritation or allergic reactions in rare instances (e.g. hives 
or difficulty breathing). Fewer than one in five hundred procedures may be complicated by 
infection requiring antibiotics, surgery to correct if there is damage to the blood vessel or heart 
valves, surgery to remove air if there is lung collapse, or blood thinners if a blood clot develops 
in the vein. It is also possible to develop an abnormal or potentially dangerous heart rhythm 
requiring drugs or electrical shocks during the procedure. Death has been reported in very rare 
cases. 
Dr. Leary performs 6-12 right heart catheterizations every week and has done more than 2,000 
right heart catheterizations over the course of his career. He has had one complication while 
supervising a trainee requiring overnight hospitalization (lung collapse) to correct and will do all 
of the heart catheterizations for this study personally without trainees. If Dr. Leary is physically 
unable to do the right heart catheterization within the study mandated time window, Dr. 
Steinberg, an interventional cardiology attending, will do the procedure.
Cardiopulmonary exercise testing (CPET) risks include changes in blood pressure and heart rate, 
discomfort, increased risk for fainting and the potential for you to develop an abnormal heart 
rhythm during the test. In rare circumstances, there can be serious complications such 
musculoskeletal injury, heart attack, or stroke. Death has been reported in very rare cases.
The Covid testing may cause some discomfort from having a swab inserted in your nose and 
throat. It may cause coughing and a gagging feeling or cause a burning sensation and eye 
watering. Occasionally people feel some irritation in their nose or throat for several hours after 
the test.
Pulmonary arterial hypertension is a serious disease.  Some problems are more common for 
patients with this disease regardless of whether or not they participate in a study. These problems 
include dizziness, fainting, leg swelling, abdominal swelling, chest pain, shortness of breath, low 
oxygen, coughing up blood, nausea, vomiting, diarrhea, jaw pain, flushing, joint pain, muscle 
pain, infection, abnormal heart rhythm, heart failure, pericardial effusion (fluid around the heart), 
abnormalities in blood counts, abnormalities in kidney function and electrolytes, cirrhosis 
(damage to the liver), blood clots, stroke, cardiac arrest, and death.
For women of childbearing potential, pregnancy and the post-partum period is a highly 
dangerous and volatile time for women with pulmonary arterial hypertension and as a result, if 
you are currently pregnant, lactating, or have evidence of dynamic disease with pulmonary 
vasodilator adjustment within 30 days of randomization, you will not be able to participate in the 
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study. If you are able to become pregnant, you will be given a serum pregnancy test before entry 
into the study. You are asked to use a dual-method of contraception while participating in the 
study. You should not become pregnant while in the study. If you do become pregnant, you must 
inform the study coordinator. 
There may be risks related to the study procedures that are not yet known to the researchers. This 
includes unanticipated side effects from the use of the drug. As this is an investigational drug, 
you will be updated with any learned information during the study that may affect your 
willingness to participate.
There is a possibility that you may be withdrawn from the study. This may occur if Dr. Leary 
and/or your other pulmonary hypertension physician(s) feel that your continuation in the study 
would be detrimental to your well-being, a serious adverse event occurs due to the trial 
medication, any relevant deterioration in your health occurs, the protocol is violated, or you are 
unable to stay on the study drug or off other H2 blockers. If you are female and of childbearing 
potential, you will be withdrawn if you become pregnant.
 
ALTERNATIVES TO TAKING PART IN THIS STUDY
You are free not to participate in this clinical study and will continue to receive the same high 
quality care that you have always received with no impact on your current treatment. Please take 
your time to make your decision about taking part in this study. You may discuss your decision 
with your friends and family. You can also discuss it with your healthcare team. If you have any 
questions or concerns, you can ask the study doctor for more explanation. 
BENEFITS OF THE STUDY
We hope that the results of this study will help patients with pulmonary hypertension in the 
future. It is possible that if you receive famotidine, you will experience an improved functional 
capacity and improved metrics of right heart failure relative to those who receive placebo. Some 
participants will not receive any direct benefit, though some people might find satisfaction in 
contributing to scientific knowledge about their disease. 
COSTS
If you choose to participate in the study, you do not have to pay for study drug and Omeprazole 
and Tums, study visits, and tests that have to be done for the study. You or your insurance 
company will have to pay for routine care, such as clinic visits and some echocardiograms, walk 
tests, and blood work that you would receive whether or not you are in the study. Researchers 
will access your medical record to obtain these results. You may talk to the study staff and your 
insurance company about what is covered. 
SOURCE OF FUNDING
The study team and the University of Washington are receiving financial support for this study 
from the National Institute of Health/National Heart, Lung, and Blood Institute. 
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CONFIDENTIALITY OF RESEARCH INFORMATION
Data collected about you for this study will be kept in the research record. Identifiable 
information will be coded and linked to study information. This information and all study data 
will be kept on a password secured computer database.
Any publications regarding the results of this study will not include any information that would 
identify you. De-identified data may be used for future studies. Participating in this study is 
completely voluntary. Even if you decide to participate now, you may change your mind and 
stop at any time.
Government or university staff sometimes review studies such as this one to make sure they are 
being done safely and legally.  If a review of this study takes place, your records may be 
examined.  The reviewers will protect your privacy.  The study records will not be used to put 
you at legal risk of harm.
The U.S. Food and Drug Administration (FDA) reserves the right to review study data that may 
contain identifying information. 
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time (Clinical 
trials identifier: NCT03554291) 
Your participation in this study will be noted in your UW medical record.
We have a Certificate of Confidentiality from the federal National Institutes of Health.  This 
helps us protect your privacy.  The Certificate means that we do not have to give out identifying 
information about you even if we are asked to by a court of law.  We will use the Certificate to 
resist any demands for identifying information.  
We can’t use the Certificate to withhold your research information from you if you give your 
written consent to give it to an insurer, employer, or other person.  Also, you or a member of 
your family can share information about yourself or your part in this research if you wish.    
There are some limits to this protection.  We will voluntarily provide the information to:

a member of the federal government who needs it in order to audit or evaluate the 
research;

individuals at the University of Washington, the funding agency, and other groups 
involved in the research, if they need the information to make sure the research is being 
done correctly;

the federal Food and Drug Administration (FDA), if required by the FDA;

authorities, if we learn of child abuse, elder abuse, or the intent to harm yourself or 
others. 
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USE OF INFORMATION AND SPECIMENS
Genetic Testing
If you participate in the optional opt-out study of RNA, we will also perform a genetic analysis 
of your blood sample focused on a specific kind of genetic code known as RNA. Usually 
researchers study just a few areas of your genetic code that are linked to a disease or condition, 
but for this study, all or most of your genes will be analyzed and used by researchers to study 
links to many diseases and conditions.
Using Your Data in Future Research
The information and/or specimens that we obtain from you for this study might be used for 
future studies. We may remove anything that might identify you from the information and 
specimens. If we do so, that information and specimens may then be used for future research 
studies or given to another investigator without getting additional permission from you. It is also 
possible that in the future we may want to use or share study information that might identify you. 
If we do, a review board will decide whether or not we need to get additional permission from 
you. 
GENOMIC DATA SHARING
The National Institutes of Health (NIH) has developed data (information) banks that collect 
study data.  The NIH will store your de-identified information in these data banks for other 
researchers to use in future studies on any topic. The researchers could be from government, 
academic, or commercial institutions. 
If you participate in the optional opt-out genetic study of RNA, the information from this study 
may be stored in a public unrestricted data bank that anyone can use. This public information 
will not include your name or other information that could identify you. It is possible that your 
genomic information could be used to identify you when combined with information from other 
public sources, but we believe this is unlikely to happen. You will not receive any results from 
allowing your data to be placed in the NIH data banks. You will not be able to withdraw your 
information after it has been submitted to the NIH data banks.
If you participate in the optional opt-out genetic study of RNA, there is a risk that others will be 
able to trace this information back to you or close biological relatives. The current risk of this 
happening is very small, but may grow in the future as new technologies are developed.  If this 
should happen, someone might use this information to learn something about your health or 
genetic heritage. If linked to a medical condition and inappropriately shared with someone, it 
could affect your ability to get or keep some kinds of insurance. There is a possibility that this 
information could affect family members because certain conditions and traits run in families 
and are inherited through genes. This could hurt family or other relationships. There is a risk that 
your information could become known to the public, employers, or law enforcement agencies. 
The information may be used to enforce negative stereotypes. 
There may also be other risks that are not yet known.
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OTHER INFORMATION
You may refuse to participate and you are free to withdraw from this study at any time. If you 
choose to do so then you will still continue to receive the same high quality care that you 
received before participating and during the study.
You will be compensated $100 for each in-person visit to the University of Washington, which 
will cover parking, travel costs, and other incidentals. You will receive $25 for the Week 12 visit 
if done remotely.
Blood collected as part of this study will be stored in a locked research laboratory in the Division 
of Pulmonary, Critical Care, and Sleep Medicine. Blood will be identified only by your 
identification code and the link between this code and your personally identifying information 
will be maintained in a password secured computer database. 
Results from standard clinical tests will be returned to you and the results may affect the need to 
add additional PAH therapy, adjust diuretics, and consider advanced treatments like lung 
transplant.
RESEARCH-RELATED INJURY
If you think you have been harmed from being in this research or have a medical problem or 
illness related to this research, contact the study staff listed at the beginning of the consent form 
right away. The study staff will treat you or refer you for treatment. 
It is important that you promptly tell the researchers if you believe that you have been injured 
because of taking part in this study. You can tell the researcher in person or call him/her at the 
number(s) listed at the top of this form. This number is monitored 24 hours a day.
If you are injured as a result of being in this study, necessary medical treatment will be offered at 
a UW Medicine facility.
The costs of the treatment may be billed to you or your health insurance just like other medical 
costs, or it may be covered by the UW’s discretionary Human Subjects Assistance Program 
(HSAP), depending on a number of factors.  The researcher may request HSAP coverage by 
following established procedures. If you wish to request HSAP coverage yourself, contact the 
researcher or the UW Human Subjects Division at hsdinfo@uw.edu or 206-543-0098. You may 
also call collect to the UW Human Subjects Division at 206-221-5940 if you do not otherwise 
have access to a telephone. Ask the researcher if you would like information about the limits and 
conditions of the HSAP. The UW does not normally provide any other form of compensation for 
injury. However, the law may allow you to seek payment for injury-related expenses if they are 
caused by malpractice or the fault of the researchers. You do not waive any right to seek 
payment by signing this consent form. We will bill your health insurance for treating problems 
that result from your pulmonary arterial hypertension or from standard clinical care. If you have 
no health insurance or your insurance refuses to pay, we will bill you.
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If you have questions about the research, please contact one of the researchers listed on this 
form. If you have questions about your rights as a research subject, please contact the University 
of Washington Human Subjects Division at (206) 543-0098.
 Please do not include me in the RNA 
isolation and stored blood as described in the 
optional section of this consent form.
_________ Initials
I would like to participate in the right heart 
catherization sub-study. 
 Yes    No      _________ Initials
I would like to participate in the 
cardiopulmonary exercise test sub-study.
 Yes    No      _________ Initials
You may contact me in the future about other 
studies.
 Yes    No      _________Initials
Printed name of study staff obtaining consent*
Signature*
                         Date*
Subject’s statement
This study has been explained to me.  I volunteer to take part in this research.  I have had a 
chance to ask questions.  If I have questions later about the research, or if I have been harmed by 
participating in this study, I can contact one of the researchers listed on the first page of this 
consent form.  If I have questions about my rights as a research subject, I can call the Human 
Subjects Division at (206) 543-0098 or call collect at (206) 221-5940.  I give permission to the 
researchers to use my medical records as described in this consent form. I will receive a copy of 
this consent form.
Printed name of subject
Signature of subject
Date
___________________________________________________________
E-mail address if you consent to the use of e-mail in order to contact you
Copies to:
Subject
Investigator’s file
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