A Phase 2, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Rodatristat Ethyl in Patients With Pulmonary Arterial Hypertension
Phase: PHASE2
Conditions: Pulmonary Arterial Hypertension
Sponsor: Altavant Sciences GmbH

Clinical Study Protocol
Protocol RVT-1201-2002
Altavant Sciences GmbH
Effective: 19JAN2022
1
Confidential
e
CLINICAL STUDY PROTOCOL
Protocol Title
A Phase 2b, Dose-Ranging, Randomized, Double-Blind, 
Placebo-Controlled, Multicenter Study of Rodatristat Ethyl in 
Patients with Pulmonary Arterial Hypertension
Protocol Name/Number
ELEVATE 2 / RVT-1201-2002, Version 4.0 (Amendment 3)
Approval Date
19JAN2022
Compound Name/Number
Rodatristat ethyl / RVT-1201 
Indication
Treatment of Pulmonary Arterial Hypertension
Study Phase
Phase 2b
Sponsor Name
Altavant Sciences GmbH
Legal Registered Address
Sponsor:
Altavant Sciences GmbH
Viaduktstrasse 8
CH-4051 Basel
Switzerland
U.S. Agent:
Altavant Sciences, Inc.
6501 Weston Parkway
Suite 330
Cary, North Carolina 27513
United States of America
Study Region(s)
United States, Canada, Poland, United Kingdom, France, Spain, 
Germany, Italy, Belgium, Bulgaria, Ukraine, Latvia, Austria, 
Republic of Moldova, Bosnia and Herzegovina, Serbia, and Czech 
Republic
Regulatory Agency 
Identifier Number(s)
IND: 126945
File Number: HC6-24-c223565
EudraCT: 2020-004971-42
1:  All sites outside the United States are subject to the requirements of 21 CFR 312.120 and not under the IND 126945
CONFIDENTIALITY STATEMENT
The confidential information in this document is provided to you as an investigator, potential 
investigator, or consultant for review by you, your staff, and applicable Independent Ethics 
Committee/Institutional Review Board. It is understood that the information shall not be 
disclosed to others without written authorization from Altavant Sciences GmbH except to the 
extent necessary to obtain informed consent from those persons to whom the investigational 
product may be administered.
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Clinical Study Protocol
Protocol RVT-1201-2002
Altavant Sciences GmbH
Effective: 19JAN2022
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Confidential
Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY
Document
Date
Amendment 3, Version 4.0
19JAN2022
Amendment 2, Version 3.0
21DEC2021
Amendment 1.9, Version 2.9 (Serbia Specific 
Amendment)
21DEC2021
Amendment 1.8, Version 2.8 (Germany Specific 
Amendment)
07SEP2021
Amendment 1.7, Version 2.7 (Poland Specific 
Amendment)
23AUG2021
Amendment 1.6, Version 2.6 (France Specific 
Amendment)
20JUL2021
Amendment 1.5, Version 2.5 (Czech Republic
Specific Amendment)
14JUL2021
Amendment 1.4, Version 2.4 (Poland Specific 
Amendment)
14JUL2021
Amendment 1.3, Version 2.3 (France Specific 
Amendment)
22JUN2021
Amendment 1.2, Version 2.2 (Italy and Germany 
Specific Amendment)
17JUN2021
Amendment 1.1, Version 2.1 (UK and Bulgaria 
Specific Amendment)
28MAY2021
Amendment 1, Version 2.0
19NOV2020
Original Protocol
18SEP2020
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Protocol RVT-1201-2002
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Effective: 19JAN2022
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Amendment 3 (19JAN2022)
Section# and Name
Description of Change
Brief Rationale
1.3 Schedule of 
Assessments (Main 
Study)
1.4 Schedule of 
Assessments (First 
24 Weeks of OLE)
Week 8 of the Main Study and OLE have been changed 
from a telephone/telemed visit to a clinic visit.  Weight, 
vital signs, ECG and collection of safety laboratories are 
being added to Week 8 of both the Main Study and the 
OLE.
Assessments are 
being added to 
Week 8 as an 
additional safety 
measure so there 
is not 8 weeks 
between visits.
1.3 Schedule of 
Assessments (Main 
Study)
1.4 Schedule of 
Assessments (First 
24 Weeks of OLE)
Additional unscheduled safety assessments may be 
conducted at any time during the study if the Investigator 
or Sponsor deems it necessary for the safety of the 
patient.
Additional 
wording added 
to clarify 
unscheduled 
visits.
3.0 Objectives and 
Endpoints
Deletion of the following from additional objectives:
R
Peptide (NT-proBNP)
This is a 
discrepancy –
this objective is 
under Secondary 
endpoints 
already and so 
deleted here.
9.2.5.5 Other Tests
Additional wording added to end of section:
Additional unscheduled laboratory assessments may be 
conducted at any time during the study if the Investigator 
or Sponsor deems it necessary for the safety of the 
patient.
Additional 
wording added 
to clarify 
unscheduled 
visits.
Amendment 2 (21DEC2021)
Section# and Name
Description of Change
Brief Rationale
1.1 Synopsis
4.2 Number of 
Patients
Addition of Serbia, Republic of Moldova, Austria,
Bosnia
Addition of new sites from the original 45-50 sites,
approximately 68 sites.
Additional 
countries and 
sites added for 
enrollment
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Altavant Sciences GmbH
Effective: 19JAN2022
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Ex-US clinical sites are subject to 21 CFR 312.120 
(acceptance of foreign data) and are non-IND sites
Clarify ex-US 
sites are not 
under the US 
IND
1.1 Synopsis
3.0 Objectives and 
Endpoints
Objectives and Endpoints subheadings were added 
(safety, additional and PK/PD).  No changes to actual 
Objectives or Endpoints were done.
Clarification of 
type of 
objectives and 
endpoints.
Included in 
Amendment 1.9 
(Serbia, RA 
request)
1.1 Synopsis
In synopsis only: title change from Primary and 
Secondary Endpoints to Primary and Secondary 
Objectives and update to Exploratory Objectives 
Change to reflect 
the synopsis 
wording is all 
Objectives rather 
than Endpoints.  
Both Main Study 
Objectives and 
End Points are 
found in Section 
3 of the Protocol.
1.1 Synopsis
5.1 Inclusion Criteria
Change to #7 Inclusion criteria
From (changes in italics):
a. Forced expiratory volume in one second (FEV1)
 60% of predicted normal, and
b. )(9)RUFHG9LWDO&DSDFLW\)9&UDWLR 0.70, and 
c. Total lung capacity (TLC)  70% of predicted normal 
(high-resolution computed tomography [HRCT] required 
for 7/& 60% and < 70%)
To (changes in bold):
a.
Forced expiratory volume in one second 
(FEV1 60% of predicted normal, and
b. 7RWDOOXQJFDSDFLW\7/&RISUHGLFWHG
normal RU)9&SUHGLFWHGLI7/&LV
not available; For subjects with CTD 
DVVRFLDWHG3$+LI7/&LVRI
Change in 
wording to clear 
up ambiguity. 
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Clinical Study Protocol
Protocol RVT-1201-2002
Altavant Sciences GmbH
Effective: 19JAN2022
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Confidential
predicted but < 70% of predicted or if 
)9&Rf predicted but < 70% of 
predicted, high resolution computed 
tomography [HRCT] obtained within 6 
months of screening may be utilized to 
demonstrate limited interstitial lung 
disease
1.1 Synopsis
5.1 Inclusion Criteria
From:
3.
Body mass index (BMI)  18 kg/m2 DQG 38 kg/m2
To:
3.
Body mass index (BMI)  18 kg/m2 DQG 40 kg/m2
Increase in BMI 
to be more 
inclusive of 
patient 
population.
1.1.Synopsis
5.1 Inclusion Criteria
From (changes in italics):
5. Confirmed diagnosis of PAH and meet ALL the
following hemodynamic criteria by means of a screening
RHC completed prior to randomization:
a. mPAP of > 20 mmHg
b. 395 400 dyne•sec/cm5
c. Pulmonary capillary wedge pressure (PCWP) or left
ventricular end diastolic pressure (LVEDP) of
 12 PP+JLI395 400 and < 500 dyne•sec/cm5, or
3&:3/9('3 15 PP+JLI395 500 dyne•sec/cm5
d. 6MWD of 100 to 550 meters at Screening
To (changes in bold):
5. Confirmed diagnosis of PAH and meet ALL the
following hemodynamic criteria by means of a screening
RHC completed prior to randomization:
a. mPAP of > 20 mmHg
b. 395 350 dyne•sec/cm5
c. Pulmonary capillary wedge pressure (PCWP) or left
ventricular end diastolic pressure (LVEDP) of
 12 PP+JLI395 350 and < 500 dyne•sec/cm5, or
3&:3/9('3 15 PP+JLI395 500 dyne•sec/cm5
Updated 
guidelines for
pulmonary 
hypertension 
(PH) is defined 
as a mean 
pulmonary 
arterial pressure 
(mPAP) greater 
than 20 mmHg,
confirmed by 
right-sided heart 
catheterization,
therefore this 
update is being 
made.
The selection of 
a minimal PVR 
of 400 
dyn.sec.cm-5
was selected for 
the ELEVATE-2
study based upon 
precedent of 
recent phase 2 
clinical trials of 
other agents, 
given the 
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Clinical Study Protocol
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Effective: 19JAN2022
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Below criteria was separated out from Inclusion #5
6. 6MWD of 100 to 550 meters at Screening
mechanism of 
action of 
rodatristat ethyl, 
there is no 
scientific 
evidence to 
suggest that 
subjects with 
lower, yet 
substantial 
pulmonary 
vascular disease 
will not 
demonstrate a 
treatment 
response, thus 
the lower limit of 
PVR is changed 
to greater than or 
equal to 350 
dyn.sec.cm-5.
6MWD is not a 
hemodynamic 
criteria and 
therefore now a 
stand alone 
inclusion 
criteria.
1.1 Synopsis
5.2 Exclusion 
Criteria
Bolded wording added:
4. Three or more of the following risk factors for left 
ventricular disease:
a.
BMI > 30 kg/m2
b. Diagnosis of essential hypertension that is actively 
treated
c.
Diabetes mellitus
Alternative 
diagnostic 
criterion if LAVi
not available.
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Clinical Study Protocol
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Effective: 19JAN2022
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d. History of significant coronary artery disease
(e.g., chronic stable angina, history of coronary 
intervention within the last 3 months, or a stenosis 
> 70% at coronary angiography)
e.
Atrial fibrillation
f.
Left atrial volume index > 41 mL/m2 [or left atrial 
diameter (LA) > 4 cm if LAVi unavailable]
1.1 Synopsis
5.2 Exclusion 
Criteria
Exclusion criteria changed from (in italics) to (in bold)
15. Patients with:
Uncontrolled arterial hypertension (Systolic Blood Pressure 
[SBP] > 180 mmHg and/or Diastolic Blood Pressure [DBP] 
> 110 mmHg), or hypotension (SBP < 90 mmHg and/or 
DBP < 50 mmHg)
15. Patients with (during Screening):
a.
Severe hypertension (SBP > 180 mmHg and/or 
Diastolic Blood Pressure [DBP] > 110 mmHg), and 
patients with severe hypotension (SBP < 90 mmHg 
and/or DBP < 50 mmHg)
b.
Hypertension or hypotension considered not controlled 
in line with clinical standards
Updated to 
clarify 
‘uncontrolled’
Included in 
Amendment 1.8 
(Germany, RA 
request)
1
Synopsis
5.2 Exclusion 
Criteria
Added wording in bold:
26. Use of any investigational drug within 30 days or 
5 half-lives (whichever is longer) prior to Screening 
or 90 days if an investigational drug for PAH, unless 
local health authority guidelines mandate a longer 
period, or in consultation with the medical monitor,
will not interfere with the safety or efficacy of the 
study
Added wording 
to allow for 
flexibility.
1.1 Synopsis
5.2 Exclusion 
Criteria
Addition of exclusion criteria #27. Any history of 
hypersensitivity to rodatristat ethyl, any of its 
components, or any components in the placebo 
preparation.
Exclusion 
criteria missed in 
original protocol
Included in 
Amendment 1.2 
(Germany, Italy 
and Czech 
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Clinical Study Protocol
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Effective: 19JAN2022
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Republic RA
request)
1.1 Synopsis
5.2 Exclusion Criteria
The following exclusion criteria has been added:
28. Patient is deprived of their liberty by a judicial or 
administrative decision, or is  
receiving psychiatric care, and is admitted to a health 
or social institution
29. Patient is subject to legal protection or is unable to 
express consent
Criteria was 
added at request 
of Regulatory 
Authority.
Included in 
Amendment 1.3 
(France RA 
request)
Schedule of 
Assessments (Main 
Study)
9. Study 
Assessments and 
Procedures
9.1.6 Pulmonary 
Function Tests 
(PFTs)
Addition of Assessment:
Pulmonary Function Tests (PFTs)
(unless completed in last 24 weeks)
Wording added in bold:
Once all screening procedures are complete and the 
Investigator determines that the patient is eligible, the 
site must upload/send the required supporting 
documentation for approval by the Sponsor. The required 
information will include the RHC report (including 
tracings), PFTs obtained (may use PFTs completed 
within the 24 week period prior to screening or 
obtained at Screening), the screening echocardiogram, 
as well as specific information about the patient’s 
medical history and disease state to further ensure the 
appropriateness of each patient being enrolled into this 
study. Approval from the Sponsor must be obtained prior 
to randomization.
9.1.6. Pulmonary Function Tests (PFTs)
PFTs (performed with or without bronchodilation) 
should be completed at Screening if there are no 
historical results from tests completed within 24 
weeks prior to Screening.
PFTs were 
already part of 
the Inclusion 
Criteria but were 
not in the 
Schedule of 
Assessments or 
described in 
Study 
Assessments and 
Procedures 
section.
1.3 Schedule of 
Assessments (Main 
Study)
Dispensing IP via IRT deleted from Week 8 and 18.
Echocardiogram assessment moved from Day 1 to 
Screening
Enough IP will 
be dispensed at 
Week 4 and 
Week 12 to 
enable dosing 
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Clinical Study Protocol
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Effective: 19JAN2022
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Plasma NT-proBNP level has been deleted from 
Screening.
New wording in bold: 
Rodatristat Ethyl and Rodatristat PK: At Day 1 and Week 4, a 
predose PK sample will be collected (patients will take study 
medication in the clinic). At Week 12, a postdose PK sample 
will be collected between 1 to 8 hours after the morning dose 
(patients will take the morning dose in the clinic and the 
time of dose will be recorded – all other assessments can be 
done pre or post dose). At Week 24, no study medication 
will be taken prior to the clinic visit (the last dose in the 
Main Study will be the evening before the Week 24 visit)
and a PK sample will be collected. If the subject enrolls in the 
OLE, this PK sample will be collected prior to the first dose of 
study treatment in the OLE. 
through to Week 
12 and Week 24.
Echocardiogram 
is needed as a 
Screening tool.  
Plasma NT-
proBNP level 
only needs to be 
performed on 
patients who are 
eligible for the 
study, not at 
Screening.
Clarification on 
when to take 
dose at Week 12 
visit and when 
the last dose for 
the Main Study 
is completed.
1.3 Schedule of 
Assessments (Main 
Study)
9.2.6
Pharmacogenetic 
Testing
Additional wording in Bold/addition to Schedule of 
Assessment table:
A separate and specific informed consent form will be 
provided to patients to allow the sponsor to obtain and 
test a patient’s blood sample taken at the Baseline/Day1 
and the Week 24 visits for pharmacogenetic markers 
that may be predictive of the natural history of the 
disease, response to therapy and tolerability of therapy. 
Addition of a 
pharmacogenetic 
blood draw at 
Week 24.
1.1 Schedule of 
Assessments 
(Main Study)
9.1.10 Registry to 
Evaluate Early and 
Long-term 
Pulmonary Arterial 
Hypertension 
Disease Management 
REVEAL Lite 2.0 has been deleted from the table.
Added wording in bold:
REVEAL Lite 2 includes 6 non-invasive variables: FC, 
vital signs (SBP and HR), 6MWD, NT-proBNP, and 
renal insufficiency (by eGFR). REVEAL Lite 2 will be 
a calculated parameter (by statistician) at Baseline 
and Week 24 of the Main Study and Week 24 of the 
OLE (this score will not be in the eCRF).
This is a 
calculation that 
will be 
performed by the 
Statistician.  This 
is not an 
assessment that 
the site performs 
and therefore 
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Lite 2 Risk 
Assessment 
Calculator
does not need to 
be in the table.
1.4 Schedule of 
Assessments – Open-
Label Extension –
(First 24 weeks of 
Open Label 
Extension)
First 24 weeks of OLE has been updated to mirror the 
Main Study (with the exception of PK, PD, and 
actigraphy)
Up to one-third 
of the patients 
will receive 
rodatristat ethyl 
for the first time 
in the OLE.  
Safety and 
efficacy 
procedures have 
been updated to 
ensure patient 
safety.
Included in 
Amendment 1.1 
(UK and 
Bulgaria RA 
request)
Included in 
Amendment 1.8 
(Germany RA 
request)
1.3 Schedule of 
Assessments – Main 
Study
1.4 Schedule of 
Assessments – First 
24 Weeks of Open-
Label Extension
1.5 Schedule of 
Assessments – Open-
Label Extension Post 
24 Weeks
5.4.1 Contraception
9.2.1 Pregnancy 
Testing
Insertion of requirement for additional pregnancy testing 
in women whose menstruation is delayed or who have 
infrequent or irregular menstrual cycles.
Wording added in bold:
Serum pregnancy tests will be obtained for all female 
patients of childbearing potential at Screening and every 
4 weeks while on IP.
Pregnancy tests will be completed in women of child-
bearing potential every 4 weeks while on study. Weeks 
8, 16 and 20 will be performed at home (with a kit 
given to the subject by the site) and the results will be 
confirmed with the subject by a phone call.
Adding 
instructions for 
sites to perform 
pregnancy 
testing per 
CTFG 
Guideline,
contraception 
and pregnancy 
testing 
recommendation.
Included in 
Amendment 1.7 
(Poland RA 
request)
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Clinical Study Protocol
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Included in 
Amendment 1.4 
(Czech Republic 
RA request)
Included in 
Amendment 1.8 
(Germany RA 
request)
2.1 Background
9.5 Pharmacokinetics
Addition to background:
Rodatristat ethyl is a prodrug for the active tryptophan 
hydroxylase 1 (TPH1) inhibitor rodatristat.  In vitro, 
nonclinical, and human pharmacokinetic (PK) studies to 
date have provided valuable information on the PK 
properties of rodatristat ethyl and its active moiety, 
rodatristat. Rodatristat ethyl has low to moderate oral 
bioavailability in nonclinical species and is rapidly 
converted to rodatristat in vivo. Both rodatristat ethyl 
and rodatristat are highly protein bound and little is 
excreted in the urine.  Biliary excretion predominates in 
rats and no further metabolism of rodatristat has been 
detected in human hepatocyte preparations. However, 
preliminary investigations have also identified a 
metabolite, M15, in the plasma of dogs and humans after 
administration of rodatristat ethyl. After single-dose 
administration, the half-life of rodatristat ethyl and 
rodatristat are approximately 5 and 12 hours, 
respectively, reaching steady-state exposure, according 
to trough concentrations, by Day 5.  The highest 
exposures achieved in healthy subjects to date were 
reached on Day 7 following 800 mg twice daily (BID) 
doses of rodatristat ethyl.
Addition of M15 metabolite in PK section.
A metabolite 
profiling study 
performed in 
dogs led to the 
identification of 
an additional 
major 
metabolite, M15, 
in plasma after 
the start of this 
study.  Blood for 
PK samples will 
analyze for M15 
in addition to 
rodatristat ethyl 
and rodatristat.
4.5 Criteria for Study 
Termination
Additional wording in Section 4.5:
The study may resume once concerns about safety, 
protocol compliance, and data quality are addressed 
and the IRBs/ECs and competent authorities are 
satisfied. The study will only resume after prior 
submission and approval of the substantial 
amendment (if required) by the competent authority.
Clarification of 
procedures
Included in 
Amendment 1.1 
(UK and 
Bulgaria RA 
request)
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4.8 End of Study 
Definition
New wording in bold:
A patient is considered to have completed the study if 
he/she completed 24 weeks of treatment including the 
Week 24 visit and the Follow-up Visit (for patients that 
complete the study through Week 24 but decide not to 
rollover to the OLE), or the last scheduled procedure 
shown in the Schedule of Assessments(SoA; 
Section 1.3). If the patient decides to continue into the 
OLE, subject must not participate in another 
interventional study until completing the final follow-
up visit (4 weeks after the last dose of study drug) 
according to the Schedule of Assessments OLE 
(Section 1.4 or 1.5).
Sentence added 
to define end of 
study for patient 
participating in 
OLE.
Included in 
Amendment 1.3 
France RA 
request
5.3 Other Eligibility 
Criteria
Wording updated to reflect change in process:
From 
To determine patient eligibility at Screening, a single 
repeat of certain tests such as laboratory values, vital 
signs, or ECGs may be allowed, with consultation of the 
Medical Monitor.
To:
To determine patient eligibility at Screening, a single 
repeat of certain tests such as laboratory values, vital 
signs, or ECGs will be allowed.
Clarification on 
updated 
procedure for 
single repeat 
Screening 
procedures.
5.4.1 Contraception
Correction of inconsistencies in the protocol.  
-Inclusion 1a has contraception beginning 4 weeks prior 
to first dose of IP and Section 5.4.1 has contraception 
starting at Screening.  Correction of Inclusion 1a to 
match Section 5.4.1., contraception should start at 
Screening.
-Inclusion 1a and 1b have contraception ending for 
women 4 weeks after the last dose of IP and for men 100 
days after the last dose of IP and Section 5.4.1 has 
contraception ending for women 4 weeks after the last 
study visit and for men 100 days after the last visit.  The 
protocol now has contraception ending for both women 
and men 4 weeks and 100 days after the last dose of IP, 
respectively.
Correction of 
inconsistency
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Clinical Study Protocol
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Effective: 19JAN2022
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5.4.1 Contraception
Addition of contraception method:
Sexual abstinence – (refraining from heterosexual 
intercourse). If study patient chooses this option, site 
staff must follow-up to reconfirm throughout the study.  
If patient becomes sexually active, one of the above 
choices must be utilized and documented.
Clarification on 
highly effective 
method of birth 
control
Included in 
Amendment 1.2 
(Germany, Italy 
and Czech 
Republic RA 
request)
Included in 
Amendment 1.4 
(Poland and 
Austria RA 
request)
Included in 
Amendment 1.6 
(France RA 
request)
5.4.1
Contraception
Deletion of contraception method:
Cervical cap or diaphragm (double barrier) plus 
spermicide
Cervical cap or 
diaphragm with 
a condom and 
spermicide is not 
a method that 
can achieve a 
failure rate of 
less than 1% per 
year
Included in 
Amendment 1.1 
(UK and 
Bulgaria RA 
request)
Included in 
Amendment 1.2 
(Germany, Italy 
and Czech 
Republic RA 
request)
Included in 
Amendment 1.4 
(Poland and 
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Austria RA 
request)
Included in 
Amendment 1.6 
(France RA 
request)
6.1 Table 3 Footnote
* The components in rodatristat ethyl are provided in 
Section 3.2.2, Table 1 of the Investigator’s Brochure.
The active and placebo are formulated with the same 
excipients
Clarifying 
statement
Included in 
Amendment 1.2 
(Germany, Italy 
and Czech 
Republic RA 
request)
6.4 Measures to 
Minimize bias: 
Randomization and 
Blinding
Added wording in bold:
This is a double-blind study. The Sponsor, Investigator,
patient, and study site personnel will be blinded to all
treatment group assignments. The Investigator will have 
the ability, in the IRT system, to unblind a patient, and 
the decision will reside solely with the Investigator.
Prior to unblinding, if safety allows, the Investigator 
should contact the Medical Monitor to discuss the 
reasons for unblinding.
At the time of Screening for entry into the OLE, all 
patients will be re-randomized to receive either 300 
mg BID or 600 mg BID rodatristat ethyl in an open-
label fashion.  Patients will not know what they 
received in the Main Study until all patients have 
completed the Main Study and the database is locked.
At the time of re-randomization in the OLE, patients 
will be assigned a new randomization number.  Once 
this number has been assigned, it cannot be 
reused/reassigned.
Additions to 
paragraph to 
reduce 
ambiguity.
Wording added 
to section to 
make clear the 
process for 
randomization 
and dose level in 
the OLE.
6.5 Investigational 
Product Compliance
Statement added:
Statement added 
to clarify what is 
considered IP 
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Full compliance with the IP regimen, per subject, will 
be considered to be >80%.
compliance in 
this study.
1.1 Synopsis
4.1 Overall Design
7.1.4 Open-Label 
Extension Design
Wording added in bold:
Patients who participate in the OLE will continue to 
receive rodatristat ethyl for 6.5 years, until the 
Investigator or patient chooses to stop the IP, any 
stopping criteria in the Main Study are met, IP becomes 
commercially available, or the Sponsor stops the study 
for lack of efficacy or a safety signal (whichever 
preceding criteria comes first). In no case will a 
patient be allowed to exceed 10 years of exposure 
unless the product is approved for a chronic 
indication.
Deletion of: 
Investigator or patient chooses to stop the IP, any 
stopping criterion in the Main Study is met, IP becomes 
commercially available, or the Sponsor stops the study 
for lack of efficacy or a safety signal.
Addition to Overall Design section:
Female patients of childbearing potential will 
undergo pregnancy testing every 4 weeks and will be 
required to use 2 reliable methods of contraception to 
reduce the risk of pregnancy, starting at Screening,
during the course of the study and for at least 4 weeks 
following the last dose of rodatristat ethyl.
If there is not a clinic visit, a urine pregnancy test will 
be sent home with the patient and results will be 
followed up with a phone call.
A stop date for 
the total time a 
subject can be on 
rodatristat ethyl 
has been 
established and 
added to the 
protocol.
Included in 
Amendment 1.2 
(Germany, Italy,
and Czech 
Republic RA 
request)
8.1. Discontinuation 
of Investigatrional 
Product
Wording added in bold:
The Investigator must also discontinue/withdraw a 
patient’s participation in the study if any of the following 
criteria apply:
Updated to 
define stopping 
criteria for IP 
non-compliance.
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x
Pregnancy
x
Significant protocol violation/lack of 
compliance with the study and/or study 
procedures - non-compliance with IP for 
discontinuation of patient is defined as < 
50%.
x
Severe constipation (e.g., obstipation with 
manual evacuation indicated) and/or severe, 
persistent, or worsening abdominal pain
x
Any significant worsening on postdose 
C-SSRS indicative of active suicidal ideation 
with intent to act (defined as C-SSRS Suicidal 
Ideation category score of 4 or 5) or behavior 
(either preparatory acts/behavior, aborted 
attempt, interrupted attempt, or actual 
attempt)
x
Severe depression or anxiety based on a 
+$'6'HSUHVVLRQRU$Q[LHW\VFRUH 15, or a 
QIDS-&7RWDO6FRUH 16.
x
Any severe psychiatric or CNS AE as
determined by the Investigator.
9.2.1 Pregnancy 
Testing
Clarification that if FSH does not confirm 
postmenopausal status, in addition to pregnancy testing, 
patients must use approved contraception
Clarification of 
pregnancy 
testing and use 
of contraception 
in patients where 
post-menopausal 
status is not 
confirmed by 
FSH.
Included in 
Amendment 1.1 
(UK and 
Bulgaria RA 
request)
9.2.8 Suicidal 
Ideation and 
Behavior Risk 
Monitoring
Wording updated to reflect the immediate 
discontinuation of investigational product in any patient 
who experiences suicidal ideation or behavior, following 
a risk assessment.
Updated wording 
to be consistent 
with Section 8.1 
and reflect the 
procedures to be 
taken if patient 
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exhibits suicidal 
ideation or 
behavior while 
on
investigational 
product.
Included in 
Amendment 1.1 
(UK and 
Bulgaria RA 
request)
9.3.2 Time Period 
and Frequency for 
Collecting Adverse 
Events, Adverse 
Events of Special 
Interest, and Serious 
Adverse Events
Wording added:
Adverse events of special interest should be reported to 
the sponsor should they meet the definition of an SAE, 
and all timelines for reporting of SAEs should be 
adhered to.
Clarification of 
reporting of 
Adverse of 
Special Interest
Included in 
Amendment 1.1 
(UK and 
Bulgaria RA 
request)
9.1.1 Right Heart 
Catheterization
All of the following wording has been deleted from this 
section:
Parameters measured during the RHC:
Ь
Heart rate (HR) - HR should be determined at the 
time of the cardiac output measure preferably by
thermodilution. HR should be measured until 
2 consecutive values do not differ by more 
than 10%; the last value will be recorded in the 
eCRF.
Ь
Cardiac Output by the Thermodilution or Fick (if 
thermodilution is not available) Method -
Thermodilution is the preferred method for the 
estimation of cardiac output. At least 
3 determinations that are within 10% variability 
of one another must be measured. Measurements 
must be repeated until this reliability is met. The 
mean cardiac output will be defined as the 
average of these 3 measurements and used for the 
calculation of PVR. The mean value will be 
recorded in the eCRF. Investigators must ensure 
There is a Right 
Hearth 
Catheterization 
Manual sites 
should be 
referring to, so 
this list of 
parameters is 
being deleted so 
there are no
discrepancies.
There will not be 
a core imaging 
laboratory for 
adjudication of 
the RHC 
endpoints.
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that the individual values and the calculation of 
the mean are recorded in the source documents.
If the mean cardiac output is auto-generated, 
investigators must ensure that the measurements 
used to calculate the mean are within the 
10% variability and are available to be recorded 
in the source documents and in the eCRF. The 
last value will be recorded in the eCRF.
Ь
Systemic arterial pressure (systolic, diastolic, and 
mean) - Systemic arterial pressures should be 
taken just prior to entry of the catheter and should 
be measured until 2 consecutive mean values do 
not differ by more than 10%. The last value will 
be recorded in the eCRF. All values should be 
available in the source documents.
Ь
PAP (systolic, diastolic, and mean) - Pulmonary 
arterial pressures should be measured at end 
expiration and should be measured until 
2 consecutive mean values do not differ by more 
than 10%. The last value will be recorded in the 
eCRF. All values should be available in the 
source documents. Mean PAP as determined by 
the site’s medical instrument (automatically 
generated) will be entered into the EDC system.
If the site’s medical instrument does not 
automatically generate the mPAP, it should then 
be calculated manually using the following 
equation: 
mPAP = ([diastolic PAP × 2] + systolic PAP) ÷ 3.
Ь
Mean right atrial pressure (RAP) - Mean RAP 
should be measured until 2 consecutive values do 
not differ by more than 10%. If mean RAP 
values are less than 10 mmHg, the 2 consecutive 
values must not differ by more than 1 mmHg.
The last value will be recorded in the eCRF. All 
values should be available in the source 
documents.
Ь
PCWP or LVEDP - The PCWP or LVEDP 
should be recorded as the mean of 3 separate 
measurements taken at end-expiration, involving 
balloon deflation and re-wedging of the balloon 
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for these separate measurements. It is strongly 
preferred that the same assessment (PCWP or 
LVEDP) be performed for both RHC 
assessments. In situations where this is not 
possible, the Investigator should provide an 
explanation in the eCRF. All values should be
available in the source documents.
Ь
SvO2 - Blood gas by pulmonary artery mixed 
venous blood sample should be measured and 
recorded in the eCRF. All values should be 
available in the source documents.
Ь
Calculated parameters:
R
PVR (dyne•sec/cm5) = [(mPAP – PCWP) 
÷ mean CO] × 80 
or [(mPAP – LVEDP) ÷ mean CO] × 80
R
Cardiac Index = CO ÷ BSA
R
Stroke Volume (SV) = CO ÷ HR
R
PAC = ratio of SV to pulmonary artery
pulse pressure
R
(Weight) kg0.425 x (Height) cm0.725 x
0.007184 = BSA in M2
9.1.9
Pulmonary 
Arterial 
Hypertension-
Symptoms and 
Impact Questionnaire
Deleted wording in italics:
Prior to departing the study site at the Day 1 Baseline 
Visit, patients will be instructed and trained on how to 
complete the questionnaire.
Added wording in bold:
Prior to departing the study site at the Screening Visit,
patients will be instructed and trained on how to 
complete the questionnaire. Patients will start the PAH-
SYMPACT questionnaire 6 days prior to the visit for 
which PAH-SYMPACT is collected, with the Day 7 
being completed on the day of the visit.
Clarity on how 
the PAH-
Sympact 
questionnaire is 
being 
administered.
1.3 Schedule of 
Assessments (Main 
Study)
Deleted wording in italics:
Coagulation testing will be done at Baseline, Week 12,
and Week 24 for all patients on the Main Study and 
every clinic visit post 24 weeks in the OLE.
Clarification of 
when 
coagulation test 
will be 
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1.4 Schedule of 
Assessent (OLE –
First 24 Weeks) 
9.2.5.2 Coagulation 
Added wording in bold:
Coagulation testing will be done at Screening, Week 12, 
and Week 24 for all patients on the Main Study and at 
Week 12 and Week 24 of the OLE in the first 
24 weeks and every clinic visit post 24 weeks in the 
OLE.   
completed under 
the new design. 
9.2.5.5 Other tests
Urine Creatinine (for calculation of 5-HIAA) at each 
5-HIAA collection time
Addition of urine 
creatinine for 
clarification.
Appendix 1. 
Concomitant and 
Prohibited 
Medications 
Marketed drugs known to prolong QT/QTc AND which 
are also clearly associated with a known risk of Torsades 
de Pointe 
source: www.CredibleMeds.org (Woosley, 2021)
An update to the 
list of marketed 
drugs known to 
prolong QT/QTc 
AND which are 
also clearly 
associated with a 
known risk of 
Torsades de 
Pointe was made 
in 2021.  
Amendment 1 of 
the protocol 
included the 
2019 version.  
This protocol has 
been updated 
with the new list.
Appendix 1 
6.6.1. Rodatristat 
Drug Interaction 
Potential 
Amodiaquine, Pimozide, and Quinidine were deleted 
from the Narrow Therapeutic Drug table as acceptable 
concomitant medications. 
Amodiaquine, 
pimozide, and 
quinidine are 
drugs that are 
known to 
prolong QTcF 
and therefore not 
allowed in this 
study. 
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Amendment 1 (19NOV2020)
Section# and Name
Description of Change
Brief Rationale
1.1 Synopsis
Words deleted in italics and 
added in bold:
Study center(s):
United States, Canada, 
Poland, United Kingdom, 
France, Spain, Germany, 
Italy, Belgium, Bulgaria, 
Russia, Ukraine, 
Netherlands, Czech 
Republic, Latvia
Final country list completed
1.1 Synopsis
Addition of Objective and 
Endpoint to evaluate the 
effect of rodatristat ethyl on 
selexipag/ACT-333679 PK
Additional PK assessments to further 
evaluate interaction between rodatristat 
ethyl and selexipag/ACT-333679 
1.1 Synopsis
5.1 Inclusion Criteria
2.
Added wording in 
bold:
3.
Male and female 
patients must be at 
least 18 years of age 
at the time of signing 
the informed consent.
Clarification of age of patient who can be 
enrolled.
1.1 Synopsis  
5.1 Inclusion Criteria
Deleted wording in italics:  
A male patient is eligible to 
participate if he does not
have a female partner who is 
pregnant or who intends to 
become pregnant during the 
study.
Wording deleted as conflicting with intent 
and contraception wording.
1.1 Synopsis
4.1 Overall Design
6.4 Methods to Reduce 
Measures to Minimize 
Bias: Randomization and 
Blinding
Additional wording in Bold
added:
Eligible patients will be 
stratified during the 
randomization process based 
on the number of background 
PAH therapies they are 
receiving (1, 2 or 3) and use 
of selexipag (yes/no). The 
The results of a drug interaction with 
rodatristat ethyl and selexipag in healthy 
volunteers is available.  The new criteria 
in stratification and capping of patients on 
selexipag are due to the results of this 
study. 
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number of patients who are 
receiving a prostanoid 
infusion will be capped at 
50% of the total number of 
patients enrolled.  The 
number of patients who are 
receiving selexipag will be 
capped at 20% of the total 
enrolled.
1.2 Study Schematic
Figure 1 updated to reflect 
accurate study visits
Figure 1 Study Schematic was not aligned 
with correct study visits
1.3 Schedule of 
Assessments – Main 
Study
Week 18 (Day 140) changed 
to Week 18 (Day 126)
The number of days for Week 18 was 
wrong in original protocol
1.3 Schedule of 
Assessments – Main 
Study
Physical exam will not be 
conducted at Follow-up Visit
Change is being made to accommodate a 
home visit, if needed.
1.3 Schedule of 
Assessments – Main 
Study and Section 9.2.7, 
Optional Sample for 
Future Research
Optional Sample for Future 
Research was added to the 
protocol
The addition of this optional future 
research sample will be used to 
increase our knowledge and 
understanding of the biology,
pathogenesis, progression and/or treatment 
outcomes, including efficacy, AEs, and the 
process of drug absorption and disposition. 
1.3 Schedule of 
Assessments – Main 
Study Footnote #5
Amendment 1 wording 
(wording in italics are 
deleted) 
Weight only (no height or 
BMI) will be performed at 
Weeks 4, 12, 18, 24, and 28
Weight does not need to be collected at 
Week 18.  This change in the footnote 
reflects what is in the table.
1.3 Schedule of 
Assessments – Main 
Study Footnote #9 and 
Morning Dose Taken in 
Clinic with Food in the 
Table
Amendment 1 wording
(additions in bold):
IP must be taken daily, 
morning and evening until 
the night before the Week 
24 visit.  Patients must be 
told not to take a dose the 
morning of the Week 24 
visit. Doses should be taken 
Updated language provides more clarity of 
process for IP and when to take the dose 
on clinic visit days
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with food.  During visits at 
the clinic or home, all 
assessments should be done 
predose, except where 
otherwise indicated.
Patients should bring their 
IP with them for each visit 
(including any empty 
bottles).
1.3 Schedule of 
Assessments – Main 
Study Footnote #12
Amendment 1 wording
(additions in bold):
Three 12 lead ECGs (at least
1 minute apart) will be 
collected on Day 1 after at 
least 5 minutes of rest.  
Single 12-lead ECGs will be 
collected at all other time 
points.
Updated language provides more guidance 
for collection of ECGs.
1.3 Schedule of 
Assessments – Main 
Study Footnote #14
9.1.1 Right Heart 
Catherization
Additional wording added at 
beginning of footnote #14:
RHC results from 4 weeks 
prior to the Screening visit 
may be used for entry 
provided the historical RHC 
includes all required 
information and provided 
that changes to the patient’s 
PAH regimen were not 
made.
New criteria allow for hemodynamics 
obtained during a recent RHC to be 
considered when determining a patient’s 
eligibility for participation in the study.
1.3 Schedule of 
Assessments – Main 
Study Footnote #17
Original protocol wording: 
At Day 1 and Weeks 4
and 24, a predose PK sample 
will be collected (patients 
will take study medication in 
the clinic).  At Week 12, a 
postdose PK sample will be 
collected between 1 to 
8 hours after the morning 
dose (patients will take the 
Clarification of collection of PK and PD
samples
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morning dose at home before 
the clinic visit).
Amendment 1 new
wording:
At Day 1 and Week 4, a 
predose PK sample will be 
collected (patients will take 
study medication in the 
clinic). At Week 12, a 
postdose PK sample will be
collected between 1 to 
8 hours after the morning 
dose (patients will take the 
morning dose at home 
before the clinic visit).   At 
Week 24, no study 
medication will be taken 
prior to the clinic visit and 
a PK sample will be 
collected. If the subject 
enrolls in the OLE, this PK 
sample will be collected 
prior to the first dose of 
study treatment in the 
OLE. 
Blood and spot urine samples 
for 5-HIAA (and urine 
samples for creatinine) will
be collected pre-dose on
Day 1 and at Weeks 4, 12, 
and 24.
1.3 Schedule of 
Assessments – PK 
Sampling and Main 
Study Footnote #18
Additional of PK sample for 
selexipag/ACT-333679 at 
Baseline and Week 4
Additional PK assessments to further 
evaluate interaction between rodatristat 
ethyl and selexipag/ACT-333679
1.4 Schedule of 
Assessments – OLE first 
24 Weeks
Addition of PK sample for 
selexipag/ACT-33679 at 
Week 4 of OLE
Additional PK assessments to further 
evaluate interaction between rodatristat 
ethyl and selexipag/ACT-333679
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1.4 Schedule of 
Assessments – OLE first 
24 Weeks
Wording in italics will be 
deleted.  
Footnote 4: Placebo subjects 
from the Main Study will be 
re-randomized to active IP.  
As necessary, a 6month 
supply of IP will be 
dispensed. IP must be taken 
daily morning and evening.
Removing wording to allow for flexibility 
of dispensing IP.
3 Objectives and 
Endpoints
Addition of Objective and 
Endpoint to evaluate the 
effect of rodatristat ethyl on 
selexipag/ACT-333679 PK
Additional PK assessments to further 
evaluate interaction between rodatristat 
ethyl and selexipag/ACT-333679 
6.1Description of IP,
Table 3
Updated wording in bold for 
the Physical Appearance of 
the IP:  
White to off-white modified 
oval shaped tablet, 
debossed with “2E8” on one 
side
Updated to reflect the new tablet 
appearance.
6.2 Dose Regimen
Additional wording added to 
section in bold:
The last dose of IP for the 
Main part of the study will 
be the last dose the night 
before the Week 24 visit (all 
Week 24 assessments will 
be collected post last dose).
Clarification of dosing and timing.
6.4 Measures to 
Minimize the Bias:
Randomization and 
Blinding
Added words in bold:
The Investigator will have 
the ability, in the IRT 
system, to unblind a patient 
unless it will cause an 
unacceptable safety delay in 
the care of the patient, the 
Investigator should contact 
and discuss with the 
Medical Monitor first.
Clarification of who can unblind a patient 
and how.
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6.6 Concomitant 
Medications
New wording in bold: 
(Note: Vaccines, including 
potential Covid-19 vaccine, 
are allowed but must be 
documented in the eCRF). 
Updated for clarity.
6.6.1 Rodatristat Drug 
Interaction Potential
Addition of data from 
rodatristat-selexipag 
interaction study and 
additional listing of narrow 
therapeutic substrates of 
CYP2C8
Provide data from rodatristat-selexipag 
interaction study and guidance to 
investigator regarding CYP2C8 substrates.
7.1.7 Exclusion Criteria 
OLE exclusion criteria #6 is 
deleted in Amendment 1
6. Elevated ALT, AST, or 
TBL > 2X ULN 
Criteria is being taken out of Amendment 
as there is already stopping criteria for 
ALT/AST that is being followed
7.1.9 Open-Label 
Extension Treatment 
Assignment
Additional wording added to 
the Amendment:
The first dose of IP in the 
OLE will be considered the 
first dose after all Week 24 
assessments in the Main 
Study are completed and all 
entry criteria are met.
Clarification of dosing and timing in the 
OLE.
9.2.2.5 Other Tests
Pharmacogenetics and 
Optional Blood Sample for 
Future Research added to 
‘Other Tests’ Table
Add lab samples to appropriate table
9.2.6 Pharmacogenetic 
Sampling
Wording is being added to 
the amendment to clarify the 
pharmacogenetic sample 
collection:
A separate and specific 
informed consent form will 
be provided to patients to 
allow the sponsor to obtain
and test a patient’s blood 
Pharmacogenetic sampling wording added 
for clarification.
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sample taken at the 
Baseline/Day1 visit for 
pharmacogenetic markers 
that may be predictive of 
the natural history of the 
disease, response to therapy 
and tolerability of therapy. 
If it is not collected at the 
Baseline/Day 1 visit, it may 
be collected at any time 
during the treatment 
period.  Providing this 
blood sample is optional 
and not required for 
participation in the study.
9.2.8 Suicidal Ideation 
and Behavior Risk 
Monitoring
Wording added in Bold:
Screening and Baseline 
assessments (within 1 
month) of suicidal 
ideation and behavior as 
well as potential treatment
emergent suicidal ideation 
and behavior will be 
monitored during the study 
using the C-SSRS.
Clarifying the timeframe for Baseline 
collection of the C-SSRS
9.5 Pharmacokinetics
Addition of selexipag/ACT-
33679 Pharmacokinetic 
Sampling
Additional PK assessments to further 
evaluate interaction between rodatristat 
ethyl and selexipag/ACT-333679
Appendix 1 –
Concomitant and 
Prohibited Medications
Renaming of Section, 
clarified wording, and 
additional listing of narrow 
therapeutic substrates of 
CYP2C8
Provide guidance to investigator regarding 
CYP2C8 substrates.
Appendix 12 REVEAL 
Lite 2.0 Risk Calculator
Added the scoring and 
formula for REVEAL Lite 
2.0 risk calculator
Added the scoring and calculator for 
REVEAL Lite 2.0 for calculations 
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SIGNATURE PAGE
Protocol RVT-1201-2002
A Phase 2b, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study 
of Rodatristat Ethyl in Patients with Pulmonary Arterial Hypertension
Sponsor’s Approval
This protocol has been approved by Altavant Sciences GmbH, as indicated by the signature 
below.
Company/Sponsor Signatory
Howard M. Lazarus, MD, FCCP
Chief Medical Officer
Altavant Sciences, Inc.
6501 Weston Parkway
Suite 330
Cary, North Carolina 27513
United States of America
Tel: +1-203-297-5374
Date
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INVESTIGATOR’S AGREEMENT
Protocol RVT-1201-2002
A Phase 2b, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study 
of Rodatristat Ethyl in Patients with Pulmonary Arterial Hypertension
I, the undersigned, have received and read the Investigator’s Brochure for Rodatristat Ethyl. I
have read the RVT1201-2002 protocol and agree to conduct the study as outlined in this protocol 
and in accordance with the ethical principles set forth in the Declaration of Helsinki, current 
Good Clinical Practice, and all applicable local laws and requirements. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol.
Printed Name of Investigator
Signature of Investigator
Date
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MEDICAL CONTACT INFORMATION
Table 1:
Contact Information
Role in Study
Name
Contact Information
Clinical Study Leader
Watiri Kamau-Kelley
Sr. Director, Clinical Operations
Altavant Sciences, Inc.
Watiri@altavant.com
+1-408-300-3316
Responsible Physician
Howard M. Lazarus, MD, FCCP
Chief Medical Officer
Altavant Sciences, Inc.
howard.lazarus@altavant.com
Phone:  +1-203-297-5374
North American Emergency 
Contact
Ed Parsley, DO
Medical Monitor
Altavant Sciences, Inc.
ed.parsley@altavant.com
Phone: +1-713-899-2450
Rest of the World Emergency 
Contact
Gwyn D'Souza
Medical Monitor
Altavant Sciences, Inc.
gwyn.dsouza@altavant.com
Phone: 011 44 7887 822276
Drug Safety Physician/
Serious Adverse Event 
Reporting
Pharmacovigilance (PVG)
On discovery, all SAEs should 
be immediately reported (latest 
within 24 hours of knowledge of 
the event) to SPONSOR or 
Sponsors’ safety vendor by 
filling out the SAE form in the 
eCRF.
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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE............................................2 
SIGNATURE PAGE .....................................................................................................................28 
INVESTIGATOR’S AGREEMENT.............................................................................................29 
MEDICAL CONTACT INFORMATION ....................................................................................30 
TABLE OF CONTENTS...............................................................................................................31 
LIST OF TABLES.........................................................................................................................36 
LIST OF FIGURES .......................................................................................................................36 
LIST OF ABBREVIATIONS........................................................................................................37 
1. 
PROTOCOL SUMMARY..........................................................................................40 
1.1. 
Synopsis......................................................................................................................40 
1.2. 
Study Schematic .........................................................................................................49 
1.3. 
Schedule of Assessments – Main Study.....................................................................50 
1.4. 
Schedule of Assessments – Open-Label Extension – (First 24 weeks of 
Open-Label Extension)...............................................................................................54 
1.5. 
Schedule of Assessments – Open-Label Extension – (Post 24 Weeks of the 
Open-Label Extension)...............................................................................................56 
2. 
INTRODUCTION......................................................................................................57 
2.1. 
Background.................................................................................................................57 
2.2. 
Study Rationale...........................................................................................................58 
2.3. 
Benefit/Risk Assessment ............................................................................................58 
3. 
OBJECTIVES AND ENDPOINTS............................................................................61 
4. 
STUDY DESIGN .......................................................................................................63 
4.1. 
Overall Design............................................................................................................63 
4.2. 
Number of Patients .....................................................................................................63 
4.3. 
Treatment Assignment................................................................................................64 
4.4. 
Dose Adjustment Criteria ...........................................................................................64 
4.4.1. 
Dose Reduction...........................................................................................................64 
4.4.1.1. 
Diarrhea ......................................................................................................................64 
4.4.1.2. 
Aminotransferase (Alanine aminotransferase or Aspartate Aminotransferase) 
Elevation.....................................................................................................................65 
4.5. 
Criteria for Study Termination ...................................................................................65 
4.6. 
Scientific Rationale for Study Design ........................................................................65 
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4.7. 
Justification for Dose..................................................................................................66 
4.8. 
End of Study Definition..............................................................................................68 
5. 
STUDY POPULATION.............................................................................................69 
5.1. 
Inclusion Criteria ........................................................................................................69 
5.2. 
Exclusion Criteria.......................................................................................................70 
5.3. 
Other Eligibility Criteria Considerations....................................................................73 
5.4. 
Lifestyle Considerations.............................................................................................73 
5.4.1. 
Contraception..............................................................................................................73 
5.4.2. 
Meals and Dietary Restrictions...................................................................................74 
5.4.2.1. 
Tryptophan-Rich Foods..............................................................................................74 
5.4.2.2. 
Food Requirements.....................................................................................................74 
5.5. 
Screen Failures............................................................................................................75 
6. 
INVESTIGATIONAL PRODUCT ............................................................................76 
6.1. 
Description of IP.........................................................................................................76 
6.2. 
Dose Regimen.............................................................................................................76 
6.3. 
Preparation/Handling/Storage/Accountability............................................................77 
6.3.1. 
Investigational Product Packaging and Labeling .......................................................77 
6.3.2. 
Investigational Product Storage..................................................................................77 
6.3.3. 
Investigational Product Administration......................................................................77 
6.3.4. 
Investigational Product Accountability ......................................................................77 
6.3.5. 
Investigational Product Handling and Disposal .........................................................78 
6.4. 
Measures to Minimize Bias: Randomization and Blinding........................................78 
6.5. 
Investigational Product Compliance...........................................................................79 
6.6. 
Concomitant Therapy .................................................................................................79 
6.6.1. 
Rodatristat-Drug Interaction Potential........................................................................80 
6.6.2. 
Pulmonary Arterial Hypertension Medications..........................................................81 
6.6.3. 
Prohibited Medications and Supplements ..................................................................82 
7. 
INTERVENTION AFTER THE END OF THE STUDY – OPEN-LABEL 
EXTENSION..............................................................................................................83 
7.1. 
Rationale for the Open-Label Extension ....................................................................83 
7.2. 
Objective.....................................................................................................................83 
7.3. 
Endpoints....................................................................................................................83 
7.3.1. 
Safety endpoints..........................................................................................................83 
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7.3.2. 
Efficacy endpoints ......................................................................................................83 
7.4. 
Open-Label Extension Design....................................................................................84 
7.5. 
Number of Patients and Inclusion/Exclusion Criteria ................................................84 
7.6. 
Inclusion Criteria ........................................................................................................84 
7.7. 
Exclusion Criteria.......................................................................................................85 
7.8. 
Open-Label Extension Procedures .............................................................................85 
7.9. 
Open-Label Extension Treatment Assignment...........................................................86 
7.10. 
Investigational Product Preparation, Handling, Storage, and Accountability............86 
7.11. 
Dose Adjustment Criteria ...........................................................................................86 
7.12. 
Criteria for Investigational Product/Study Termination.............................................86 
8. 
DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND 
PATIENT DISCONTINUATION/WITHDRAWAL.................................................87 
8.1. 
Discontinuation of Investigational Product ................................................................87 
8.1.1. 
Temporary Discontinuation........................................................................................88 
8.2. 
Patient Discontinuation/Withdrawal from the Study..................................................88 
8.2.1. 
Investigational Product Discontinuation.....................................................................88 
8.2.2. 
Study Discontinuation ................................................................................................88 
8.3. 
Lost to Follow up........................................................................................................89 
9. 
STUDY ASSESSMENTS AND PROCEDURES......................................................90 
9.1. 
Efficacy Assessments .................................................................................................90 
9.1.1. 
Right Heart Catheterization........................................................................................90 
9.1.2. 
Time to Clinical Improvement....................................................................................91 
9.1.3. 
Time to Clinical Worsening........................................................................................91 
9.1.4. 
Six-Minute Walk Test/Six-Minute Walk Distance.....................................................91 
9.1.5. 
Echocardiography.......................................................................................................91 
9.1.6. 
Pulmonary Function Tests (PFTs)..............................................................................91 
9.1.7. 
World Health Organization Functional Class.............................................................92 
9.1.8. 
N-terminal pro-Brain Natriuretic Peptide Level.........................................................92 
9.1.9. 
Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire..................92 
9.1.10. 
Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension 
Disease Management Lite 2 Risk Assessment Calculator..........................................92 
9.1.11. 
Actigraphy ..................................................................................................................92 
9.2. 
Safety Assessments.....................................................................................................93 
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9.2.1. 
Pregnancy Testing ......................................................................................................93 
9.2.2. 
Physical Examinations................................................................................................93 
9.2.3. 
Vital Signs ..................................................................................................................93 
9.2.4. 
Electrocardiograms.....................................................................................................93 
9.2.5. 
Clinical Safety Laboratory Assessments ....................................................................94 
9.2.5.1. 
Hematology.................................................................................................................94 
9.2.5.2. 
Coagulation.................................................................................................................94 
9.2.5.3. 
Clinical Chemistry......................................................................................................94 
9.2.5.4. 
Urinalysis....................................................................................................................95 
9.2.5.5. 
Other Tests..................................................................................................................95 
9.2.6. 
Pharmacogenetic Testing............................................................................................96 
9.2.7. 
Optional Blood Sample for Future Research..............................................................96 
9.2.8. 
Suicidal Ideation and Behavior Risk Monitoring.......................................................96 
9.2.8.1. 
Columbia Suicide Severity Rating Scale....................................................................97 
9.2.8.2. 
Hospital Anxiety and Depression Scale .....................................................................97 
9.2.8.3. 
Quick Inventory of Depressive Symptomatology ......................................................97 
9.3. 
Adverse Events, Adverse Events of Special Interest, and Serious Adverse 
Events .........................................................................................................................98 
9.3.1. 
Adverse Events of Special Interest.............................................................................98 
9.3.2. 
Time Period and Frequency for Collecting Adverse Event, Adverse Events 
of Special Interest, Serious Adverse Event Information ............................................98 
9.3.3. 
Method of Detecting Adverse Events, Adverse Events of Special Interest, 
and Serious Adverse Events .......................................................................................99 
9.3.4. 
Follow-up of Adverse Events, Adverse Events of Special Interest, and 
Serious Adverse Events..............................................................................................99 
9.3.5. 
Regulatory Reporting Requirements for Serious Adverse Events .............................99 
9.3.6. 
Pregnancy ...................................................................................................................99 
9.4. 
Treatment of Overdose .............................................................................................100 
9.5. 
Pharmacokinetics......................................................................................................101 
9.6. 
Pharmacodynamics...................................................................................................101 
10. 
STATISTICAL CONSIDERATIONS .....................................................................102 
10.1. 
Statistical Hypotheses...............................................................................................102 
10.2. 
Sample Size Determination ......................................................................................102 
10.3. 
Populations for Analyses..........................................................................................102 
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10.4. 
Statistical Analyses...................................................................................................103 
10.4.1. 
Efficacy Analyses.....................................................................................................103 
10.4.2. 
Safety Analyses ........................................................................................................104 
10.4.3. 
Other Analyses..........................................................................................................104 
10.5. 
Interim Analyses.......................................................................................................104 
10.5.1. 
Independent Data Monitoring Committee................................................................105 
11. 
REFERENCES .........................................................................................................106 
APPENDIX 1. CONCOMITANT AND PROHIBITED MEDICATIONS..............................108 
APPENDIX 2. DIARRHEA MANAGEMENT .......................................................................111 
APPENDIX 3. LIVER SAFETY:  SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS...............................................................................................112 
APPENDIX 4. COLLECTION OF PREGNANCY INFORMATION ....................................114 
APPENDIX 5. REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS........................................................................................116 
APPENDIX 6. SIX-MINUTE WALK TEST GUIDELINES ..................................................120 
APPENDIX 7. BORG SCALE AND INSTRUCTIONS..........................................................124 
APPENDIX 8. WORLD HEALTH ORGANIZATION FUNCTIONAL 
CLASSIFICATION OF PULMONARY HYPERTENSION ..........................126 
APPENDIX 9. PULMONARY ARTERIAL HYPERTENSION-SYMPTOMS AND 
IMPACT™ QUESTIONNAIRE ......................................................................127 
APPENDIX 10. COLUMBIA-SUICIDE SEVERITY RATING SCALE ...............................136 
APPENDIX 11. HOSPITAL ANXIETY AND DEPRESSION SCORE (HADS)...................142 
APPENDIX 12. CLINICIAN-RATED QUICK INVENTORY OF DEPRESSIVE 
SYMPTOMATOLOGY ...................................................................................143 
APPENDIX 13. REVEAL LITE 2.0 (BENZA ET AL., 2020) ................................................146 
APPENDIX 14. ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATION, FOLLOW UP, AND REPORTING ............147 
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LIST OF TABLES
Table 1: 
Contact Information....................................................................................................30 
Table 2: 
Abbreviations and Specialist Terms...........................................................................37 
Table 3: 
Investigational Products..............................................................................................76 
LIST OF FIGURES
Figure 1: 
Study Schematic .........................................................................................................49 
Figure 2: 
Percentage Change from Baseline of Urine 5-HIAA: Creatinine Ratio 
5-HIAA on Days 7 and 14 following Twice Daily Repeat Oral 
Administration of Rodatristat Ethyl in Studies KAR5585-101 and 
RVT-1201-1001..........................................................................................................67 
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LIST OF ABBREVIATIONS
The following abbreviations and specialist terms are used in this study protocol.
Table 2:
Abbreviations and Specialist Terms 
Abbreviation or Specialist 
Term
Explanation
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BID
twice daily
BMI
body mass index
BNP
brain natriuretic peptide
BP
blood pressure
CFR
Code of Federal Regulations
CHD
congenital heart defects
CI
confidence interval
CNS
central nervous system
CONSORT
Consolidated Standard of Reporting Trials
C-SSRS
Columbia Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DBP
diastolic blood pressure
DM-IV
Diagnostic and Statistical Manual of Mental Disorders – 4th Edition
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
FC
functional class
FDA
United States Food and Drug Administration
FEV1
forced expiratory volume one second
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HADS
Hospital Anxiety and Depression Scale
hCG
human chorionic gonadotropin
5-HIAA
5-hydroxyindoleacetic acid
5-HT
serotonin (5-hydroxytryptamine)
5-HTP
5-hydroxytryptophan
HIV
human immunodeficiency virus
HR
heart rate
HRCT
high-resolution computed tomography
HRT
hormone replacement therapy
ICF
informed consent form
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Abbreviation or Specialist 
Term
Explanation
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IP
investigational product
INR
international normalized ratio
IRB
Institutional Review Board
IRT
interactive response technology
ITT
intent-to-treat
IVRS
interactive voice response system
IWRS
interactive web response system
LQTS
long QT syndrome
LVEDP
left ventricular end diastolic pressure
LVEF
left ventricular ejection fraction
MAOIs
monoamine oxidase inhibitors
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCT
monocrotaline
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
m-ITT
modified intent-to-treat
mPAP
mean pulmonary artery pressure
mRAP
mean right arterial pressure
ms
millisecond
NOAEL
no observed adverse effect level
NT-proBNP
N-terminal pro-Brain Natriuretic Peptide
OLE
open-label extension
PAC
pulmonary artery compliance
PAH
pulmonary arterial hypertension
PCWP
pulmonary capillary wedge pressure
PD
pharmacodynamic
PFT
Pulmonary Function Test
P-gp
P-glycoprotein
PH
pulmonary hypertension
PK
Pharmacokinetic
PP
per protocol
PR
PR interval of the ECG
PRO
patient-reported outcome
PT
prothrombin time
PVG
pharmacovigilance
PVR
pulmonary vascular resistance
QD
once daily
QIDS-C, -SR
Quick Inventory of Depressive Symptomatology, -Clinician Rated, -Self
Reported
QRS
QRS interval of the ECG
QT
QT interval of the ECG
QTc
corrected QT interval
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Abbreviation or Specialist 
Term
Explanation
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RAP
right arterial pressure
RBC
red blood cell
REVEAL
Registry to Evaluate Early and Long-Term PAH Disease Management
RHC
right heart catheterization
RR
RR interval of the ECG or Respiratory Rate
ROW
rest of world
RV
right ventricular
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
SD
standard deviation
SDS
safety data sheet
6MWT/6MWD
six-minute walk test / six-minute walk distance
SoA
schedule of assessment
SOC
standard of care
SU5416, SUGEN
semaxanib
SUSARs
suspected unexpected serious adverse reactions
SV
stroke volume
SvO2
Mixed venous oxygen saturation
TAPSE
tricuspid annular plane systolic excursion
TBL
total bilirubin level
TEAEs
treatment-emergent adverse events
TLC
total lung capacity
TPH
tryptophan hydroxylase
TTCI
time to clinical improvement
TTCW
time to clinical worsening
ULN
upper limit of normal
WBC
white blood cell
WHO
World Health Organization
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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Name of Sponsor/Company:
Altavant Sciences GmbH
Name of Investigational Product:
Rodatristat ethyl
Name of Active Ingredient:
Rodatristat ethyl
Protocol Number/Study Name:
RVT-1201-2002 / ELEVATE 2
Title of Study:
A Phase 2b, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of 
Rodatristat Ethyl in Patients with Pulmonary Arterial Hypertension
Study region(s):
United States, Canada, Poland, United Kingdom, France, Spain, Germany, Italy, Belgium, Bulgaria,
Ukraine, Czech Republic, Latvia, Austria, Bosnia and Herzegovina, Republic of Moldova, and Serbia
Ex-US sites are non-IND sites
Studied period (years):
Estimated date first patient enrolled: March 2021
Estimated date last patient completed: October 2022
Phase of development:
2b
Rationale:
Rodatristat ethyl is an orally bioavailable prodrug that is rapidly converted to the active tryptophan 
hydroxylase (TPH) inhibitor rodatristat in the systemic circulation of multiple nonclinical species and 
humans. The clinical doses and regimens selected for this study have been selected with the goal to 
achieve optimal rodatristat exposure and serotonin (5 HT) lowering targets associated with efficacy in 
nonclinical models of pulmonary arterial hypertension (PAH) and pharmacokinetic (PK) and 
pharmacodynamic (PD) data in healthy subjects.
Objectives
Primary Objective:
x
To evaluate the effect of rodatristat ethyl on the percent change from baseline of pulmonary 
vascular resistance (PVR), as measured by right heart catheterization (RHC) in patients 
with PAH
Secondary Objectives:
x
To evaluate the effect of rodatristat ethyl on change from baseline on the following:
o
WHO FC 
o
6MWD
o
N-terminal pro-Brain Natriuretic Peptide (NT-proBNP)
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Safety Objectives:
x
To assess safety and tolerability of rodatristat ethyl in patients with PAH
Additional Objectives:
x
To evaluate the effect of rodatristat ethyl on change from baseline on the following:
o
Cardiopulmonary hemodynamics (cardiac index, mean pulmonary artery pressure 
[mPAP], mean right atrial pressure [mRAP], mean mixed venous oxygen 
saturation [SvO2], and pulmonary artery compliance [PAC])
o
Time to Clinical Worsening (TTCW) defined as the first occurrence of a composite 
end point of: 1. Death from any cause, 2. Hospitalization for worsening PAH (any 
hospitalization for worsening PAH, lung or heart and lung transplantation, atrial 
septostomy, or initiation of parenteral prostanoid therapy, 3. Disease progression 
defined as a decrease of more than 15% from Baseline in the 6-minute walk 
distance (6MWD) combined with World Health Organization (WHO) Functional 
Class (FC) III or IV symptoms at 2 consecutive visits separated by at least 14 days
(adjudicated)
o
Death from any cause
o
Echocardiographic measures of right atrial size & right ventricular (RV) function
(tricuspid annular plan systolic excursion [TAPSE], tricuspid annular systolic 
velocity, and RV fractional area change)
o
Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire 
(PAH-SYMPACT)
o
Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 
Lite 2 score
PK/PD Objectives:
x
To assess the PK of rodatristat ethyl and metabolites using population PK 
x
To assess the effect of rodatristat ethyl on plasma and urine 5-hydroxyindoleacetic acid 
(5-HIAA)
Exploratory Objectives:
x
Time to Clinical Improvement (TTCI)
x
Actigraphy
x
To evaluate the effect of rodatristat ethyl on the plasma concentration of selexipag and 
ACT-333679
See protocol Section 3 for Endpoints.
Open-Label Extension Objectives:
The objective of the OLE is to evaluate the long-term safety, tolerability, and efficacy of rodatristat 
ethyl in patients with PAH.
See protocol Section 7.3 for Open-Label Extension Endpoints.
Methodology/Overall Study Design:
This double-blind study will compare the efficacy, safety, and tolerability of 2 doses of rodatristat ethyl 
to placebo in patients with PAH.  Eligible patients will be stratified during the randomization process 
based on the number of background PAH therapies they are receiving (1, 2 or 3) and use of selexipag 
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(yes/no).  The number of patients who are receiving a prostanoid infusion will be capped at 50% of the 
total number of patients enrolled.  The number of patients who are receiving selexipag will be capped at 
20% of the total enrolled. Patients will be randomized 1:1:1 to placebo, 300 mg BID, or 600 mg BID of 
rodatristat ethyl.
Patients who complete the Main Study will have the option to enroll into the OLE and continue to 
receive rodatristat ethyl (those randomized to placebo will be re-randomized 1:1 to receive rodatristat 
ethyl 300 mg BID or 600 mg BID) for 6.5 years, until the Investigator or patient chooses to stop the IP, 
any stopping criteria in the Main Study are met, IP becomes commercially available, or the Sponsor 
stops the study for lack of efficacy or a safety signal (whichever preceding criteria comes first). In no 
case will a patient be allowed to exceed 10 years of exposure unless the product is approved for a 
chronic indication.
Disclosure Statement:
This is a parallel group treatment study with 3 arms that is participant, Sponsor, and Investigator 
blinded.
Number of participants (planned):
Approximately 90 patients with PAH are expected to be enrolled at approximately 68study sites in the 
U.S., Canada, and Rest of World (ROW). 
Inclusion Criteria:
Patients are eligible to be included in the study only if all the following criteria apply:
1.
Male and female patients must be at least 18 years of age at the time of signing the informed 
consent.
a.
Male patients and female partners must agree to use contraception as detailed in
Section 5.4.1 of the protocol starting at Screening, during the treatment period, and for at 
least 100 days after the last dose of IP.  Male patients must refrain from donating sperm 
during this period.
b.
Female patients of childbearing potential must agree to use contraception as detailed in 
Section 5.4.1 starting at Screening, during the treatment period, and for at least 4 weeks 
after the last dose of IP.
2.
Body mass index (BMI)  18 kg/m2 DQG 40 kg/m2
3.
Patients with symptomatic PAH belonging to one of the following 2018 Clinical Group 1 Sub-types:
a.
Idiopathic PAH
b.
Heritable PAH
c.
Drug- or toxin- induced
d.
PAH associated with:
1.
Connective tissue disease
2.
Congenital systemic to pulmonary shunt (atrial septal defect, ventricular septal 
defect, patent ductus arteriosus) repaired at least one year prior to Screening
3.
Human Immunodeficiency Virus (HIV) infection - if diagnosed with HIV, must 
have stable disease status defined as follows: 
a.
stable treatment with HIV medications for at least 8 weeks prior to 
Screening 
b.
no active opportunistic infection during the Screening Period 
c.
no hospitalizations due to HIV for at least 4 weeks prior to Screening 
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Clinical Study Protocol
Protocol RVT-1201-2002
Altavant Sciences GmbH
Effective: 19JAN2022
43
Confidential
4.
WHO FC II or III
5.
Confirmed diagnosis of PAH and meet all the following hemodynamic criteria by means of a 
screening RHC completed prior to randomization: 
a.
mPAP of > 20 mmHg
b.
395 350 dyne•sec/cm5
c.
Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure 
/9('3RI 12 PP+JLI395 350 and < 500 dyne•sec/cm5, or PCWP/LVEDP 
 15 PP+JLI395 500 dyne•sec/cm5
6. 6MWD of 100 to 550 meters at Screening
7.
Currently on a stable treatment regimen with one or more treatments approved for PAH. Stable 
therapy is defined as receiving the same medication(s) IRU 12 weeks prior to the screening RHC 
DQGDWDVWDEOHGRVHOHYHOIRUHDFKIRU 8 weeks prior to the screening RHC (see Protocol 
Section 6.6.2 for approved PAH medications). Any instances where doses of a medication have 
been missed prior to RHC must be discussed with the Medical Monitor prior to performing the 
RHC.
8.
Meet the following criteria determined by pulmonary function tests (PFTs) completed no more than 
24 weeks prior to Screening (performed with or without bronchodilation):
a.
Forced expiratory volume in one second (FEV1 60% of predicted normal
b.
Total lung capacity (TLC)  70% of predicted normal RU)9&SUHGLFWHGLI7/&
LVQRWDYDLODEOH)RUVXEMHFWVZLWK&7'DVVRFLDWHG3$+LI7/&LVRISUHGLFWHG
but  < 70% of predicteGRULI)9&Rf predicted but < 70% of predicted,  high 
resolution computed tomography [HRCT] obtained within 6 months of screening may 
be utilized to demonstrate limited interstitial lung disease
9.
If participating in an exercise program for pulmonary rehabilitation, the program must have been 
LQLWLDWHG 12 weeks prior to Screening, and patient must agree to maintain the current level of 
rehabilitation for the first 24 weeks of IP.  If not participating in an exercise training program for 
pulmonary rehabilitation, must agree not to enroll in an exercise training program for pulmonary 
rehabilitation during the Screening Period and the first 24 weeks of IP.
10. Willing and able to give written informed consent and to comply with the requirements of the study
for its duration.
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply:
1.
Women of childbearing potential who are pregnant, planning to become pregnant, or lactating or 
female/male patients unwilling to use effective contraception as defined in Section 5.4.1.
Medical Conditions
2.
WHO Pulmonary Hypertension (PH) Group 1 PAH associated with portal hypertension or 
schistosomiasis; PH due to left heart disease (WHO PH Group 2), lung diseases and/or hypoxia 
(WHO PH Group 3), chronic thromboembolic pulmonary hypertension (WHO PH Group 4), or 
PH with unclear multifactorial mechanisms (WHO PH Group 5).
3.
PH associated with significant venous or capillary involvement (PCWP > 15 mmHg), 
pulmonary capillary hemangiomatosis, portal hypertension, or unrepaired congenital heart 
defects (CHD).
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Clinical Study Protocol
Protocol RVT-1201-2002
Altavant Sciences GmbH
Effective: 19JAN2022
44
Confidential
4.
Three or more of the following risk factors for left ventricular disease:
a.
BMI > 30 kg/m2
b.
Diagnosis of essential hypertension that is actively treated
c.
Diabetes mellitus
d.
History of significant coronary artery disease (e.g., chronic stable angina, history of 
coronary intervention within the last 3 months, or a stenosis > 70% at coronary 
angiography)
e.
Atrial fibrillation 
f.
Left atrial volume index (LAVi) > 41 mL/m2 [or left atrial diameter (LA) > 4 cm if LAVi
unavailable]
5.
Known genetic hypertrophic cardiomyopathy.
6.
Known cardiac sarcoidosis or amyloidosis.
7.
The patient has a history of, or currently has, a constrictive cardiomyopathy. 
8.
Known history of any LVEF < 40% by echocardiogram within 3 years of randomization 
(Note: a transient decline in LVEF below 40% that occurred and recovered more than 6 months 
before the start of Screening and was associated with an acute intercurrent condition [e.g., atrial 
fibrillation] is allowed).
9.
Hemodynamically significant valvular heart disease as determined by the Investigator, 
including:
a.
greater than mild aortic and/or mitral stenosis and/or
b.
severe mitral and/or aortic regurgitation (> Grade 3)
10. Severe arthritis, musculoskeletal problems, or morbid obesity that, in the opinion of the 
Investigator, is the cause of the patient’s functional limitation and would affect the patient’s 
ability to perform or complete the 6MWT.
11. Planned major surgery within the next 3 months, including lung transplantation, major 
abdominal or major intestinal surgery.
12. End stage renal disease defined as receiving peritoneal dialysis, hemodialysis, or status after 
renal transplantation; or severe liver disease defined as Child-Pugh Class C, with or without 
cirrhosis
13. Known congenital long QT syndrome (LQTS) or known family history of LQTS 
14. 'HSUHVVLRQWKDWLVFXUUHQWO\UDWHGDVVHYHUHGHILQHGDVDVFRUHRI 16 on the QIDS-C and/or 
Hospital Anxiety and Depression Scale [HADS] 'HSUHVVLRQDQGRU$Q[LHW\VFRUH 15), recent 
suicidal behavior (either preparatory acts/behavior, aborted attempt, interrupted attempt, or 
actual attempt in the past 3 months per the Screening Columbia Suicide Severity Rating Scale 
[C-SSRS], or active suicidal ideation with intent to act (defined as C-SSRS category score of 
4 or 5 in the past month)
15. Patients with (during Screening):
a.
Severe hypertension (SBP > 180 mmHg and/or Diastolic Blood Pressure [DBP] 
> 110 mmHg), and patients with severe hypotension (SBP < 90 mmHg and/or DBP 
< 50 mmHg)
b.
Hypertension or hypotension considered not controlled in line with clinical standards
16. Clinically significant electrolyte abnormality (e.g., hypokalemia, hypomagnesemia, or 
hypocalcemia) in the judgement of the Investigator.
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Clinical Study Protocol
Protocol RVT-1201-2002
Altavant Sciences GmbH
Effective: 19JAN2022
45
Confidential
17. Current or prior history within the last 5 years of neoplasm (except for treated basal cell or 
squamous small cell carcinoma of the skin with no evidence of recurrence).
18. Any concurrent clinically significant medical condition/disorder which in the Investigator’s 
opinion would interfere with the patient’s ability to comply with or complete the study or 
could affect the interpretation of the efficacy and safety variables.
Prior/Concomitant Therapy
19. Use of any of the following medications or supplements within 30 days prior to Screening:
a.
Monoamine oxidase inhibitors (MAOIs; Refer to Appendix 1)
b.
5-Hydroxytryptophan (5-HTP) or L-tryptophan 
c.
Telotristat ethyl
20. Patients currently taking one or more drugs known to prolong the QT interval and which are 
clearly associated with a known risk of Torsades de Pointe (see Appendix 1).
Diagnostic Assessments
21. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 at Screening as
determined by central laboratory.
22. 12-Lead electrocardiogram (ECG) results at Screening demonstrating QTcF interval 
> 450 ms for males or > 470 ms for females.
23. Elevated alanine transaminase (ALT), aspartate transaminase (AST)), or total bilirubin 
(TBL) > 2X upper limit of normal (ULN).
24. Any ECG or clinical laboratory abnormality which precludes safe participation in the study 
in the opinion of the Investigator.
Lifestyle
25. History of active substance use disorder (including alcohol) within the past 2 years which, 
in the option of the Investigator, would limit the ability of the patient to provide adequate 
informed consent or to comply with study requirements
26. Use of any investigational drug within 30 days or 5 half-lives (whichever is longer) prior to 
Screening or 90 days if an investigational drug for PAH or anytime while on IP (including 
during OLE), unless local health authority guidelines mandate a longer period, or in 
consultation with the medical monitor, will not interfere with the safety or efficacy of the 
study.
27. Any history of hypersensitivity to rodatristat ethyl, any of its components, or any 
components in the placebo preparation (refer to Rodatristat Ethyl IB, 2021).
28. Patient is deprived of their liberty by a judicial or administrative decision, or is receiving 
psychiatric care, and is admitted to a health or social institution.
29. Patient is subject to legal protection or is unable to express consent.
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Clinical Study Protocol
Protocol RVT-1201-2002
Altavant Sciences GmbH
Effective: 19JAN2022
46
Confidential
Duration of Treatment and Length of Study:
The treatment duration will be 24 weeks.  The study will last up to 32 weeks in duration for patients 
completing the study that do not enroll into the OLE:
x
Screening period: up to 28 days
x
Fixed dose treatment period (including Baseline): 24 weeks
x
Safety Follow-Up Visit: 4 weeks after the end of dosing if the patient does not enroll into 
the OLE
OLE will continue for 6.5 years, until the Investigator or patient chooses to stop the IP, any 
stopping criteria in the Main Study are met, IP becomes commercially available, or the Sponsor 
stops the study for lack of efficacy or a safety signal (whichever preceding criteria comes first). 
In no case will a patient be allowed to exceed 10 years of exposure unless the product is 
approved for a chronic indication.
Investigational Product, Dosage, and Mode of Administration:
Patients will be enrolled into 1 of 3 treatment arms in a 1:1:1 randomization, with 30 patients per arm, 
receiving placebo or IP, taken with food for 24 weeks as follows:  
x
Rodatristat ethyl 300 mg + matching placebo BID (1 x 300 mg + 1 x placebo BID)
x
Rodatristat ethyl 600 mg BID (2 x 300 mg BID)
x
Matching placebo BID (2 x placebo BID)
In order to maintain the study blind, all patients will receive 2 tablets of either rodatristat ethyl and/or 
placebo in the morning and in the evening in one of the combinations noted above.
Temporary dosage reductions or discontinuations will be allowed to manage adverse events 
(AEs)/Adverse events of special interest (AESIs), including gastrointestinal AEs (e.g., diarrhea, nausea, 
or vomiting) and liver enzyme elevations occurring during the 24-week treatment period.  Use of 
antidiarrheal and/or anti-emetic medications will be permitted as directed by the Investigator.
Patients randomized to a rodatristat ethyl arm in the Main Study may continue at the dose level given 
during the Main Study in the OLE.  Patients randomized to placebo in the Main Study will be re-
randomized to one of the active rodatristat ethyl treatment arms (300 mg BID or 600 mg BID) during 
the OLE. Changing of treatment for all patients in the OLE, to receive either 300 mg BID or 600 mg 
BID, could depend on the timing and outcome of the 24-week analysis from the Main Study.  
Tolerability and all accumulated safety and efficacy data will be reviewed by the Independent Data 
Monitoring Committee (IDMC) at regular intervals.
Non-Investigational Therapies:
Patients will remain on their prescribed, pre-existing background PAH medications; doses of these 
medications should remain stable during the study.  All treatment modifications (changes in dose or 
regimen) will be documented.
Any changes to background PAH therapy during the study should be based on clear medical need and 
should be first discussed with the Medical Monitor whenever possible.
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Clinical Study Protocol
Protocol RVT-1201-2002
Altavant Sciences GmbH
Effective: 19JAN2022
47
Confidential
Statistical methods:
A detailed description of statistical methods will be provided in a separate Statistical Analysis Plan 
(SAP) that will be finalized prior to database lock.
Sample Size Justification:
The planned sample size is 90 patients with 30 patients to be randomized into 1 of the 3 treatment arms 
in a 1:1:1 randomization. A sample size of 30 per group will provide at least 80% power at a 
significance level of 0.05 (2-sided hypothesis) to detect a treatment difference of 0.75 times of standard 
deviation (SD) in the percentage change of PVR from baseline between an active arm and the placebo 
arm. For example, if the SD for PVR percent change from baseline is 24%, the study has 80% power to 
detect a difference of 18% between an active arm and the placebo arm.
Analysis Populations:
Intent-to-Treat (ITT): All patients randomized into the study.  For all summaries based on the ITT 
population, patients will be assigned to the treatment arm to which they were randomized.
Safety: The Safety Population will consist of all patients who are randomized and received at least one 
dose of study medication. For all summaries based on the safety population, patients will be assigned to 
the treatment arm corresponding to the dose they had received.
Modified Intent-to-Treat (m-ITT):  All Safety population patients that had an evaluable baseline and 
at least 1 post-baseline PVR measurement.
Per Protocol (PP): All m-ITT population patients who had no major protocol deviations.
Pharmacokinetic:
All Safety Population patients with rodatristat ethyl or rodatristat concentration data.
Efficacy Analysis:
Primary efficacy analyses will be performed using the m-ITT and PP populations.
Percent change from baseline in PVR will be analyzed using an analysis of covariance (ANCOVA) with 
baseline PVR as the covariate. Additional baseline characteristics may also be evaluated as 
covariates in the model. The estimated between-treatment differences, 95% confidence intervals
(CIs) and p-values will be presented. For patients who discontinue from the study early, the last 
observation carried forward method will be used to impute the PVR at Week 24.
Secondary efficacy analyses will be performed using the m-ITT and PP populations:
x
Change in cardiac index, mPAP, mRAP, SvO2 at rest and PAC from baseline 
x
Time to Clinical Worsening
x
Death from any cause
x
Change in WHO FC from baseline
x
Change in 6MWD from baseline 
x
Change in NT-proBNP from baseline
x
Changes in right atrial size & RV function: TAPSE, tricuspid annular systolic velocity, and
RV fractional area change from baseline
x
Change in PAH-SYMPACT from baseline 
x
Change in the REVEAL Lite 2 score
x
Change in 5-HIAA (plasma and spot urine concentration)
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Clinical Study Protocol
Protocol RVT-1201-2002
Altavant Sciences GmbH
Effective: 19JAN2022
48
Confidential
The change from baseline endpoints will be analyzed using an ANCOVA model with treatment as a 
fixed effect, randomization stratum and baseline assessment as covariates.  The estimated between 
treatment differences, 95% CIs and p-values will be presented.
The change in 6MWD from baseline will also be compared between groups using non-parametric 
analysis of covariance within the framework of the extended Cochran-Mantel-Haenszel Test.  For 
endpoints measured over time, a mixed effect of repeated measure model may be used as sensitivity 
analyses.  Details of statistical methods will be provided in the SAP. The time from the first dose of IP
until to the first clinical worsening event will be summarized using Kaplan-Meier estimates, and 
compared between treatment groups using the log-rank test.
Safety Analysis:
A summary of rodatristat exposure will be performed using the safety population.  The safety and 
tolerability of rodatristat ethyl will be evaluated by assessment of AE incidences and changes in clinical 
laboratory tests, vital signs measurements, ECG tracings, and the use of concomitant medication during 
the study. Adverse events (AEs) will be mapped to a Medical Dictionary for Regulatory Activities 
(MedDRA)-preferred term and system organ classification. The occurrence of treatment-emergent AEs 
(TEAEs) will be summarized by treatment group using MedDRA preferred terms, system organ 
classifications, and severity. Separate summaries of treatment-emergent serious adverse events (SAEs) 
and AEs considered to be related to IP will be generated. All AEs will be listed for individual patients
showing both verbatim and preferred terms. Descriptive summaries of vital signs, ECG parameters, and 
clinical laboratory results will be presented by study visit and treatment group.
Pharmacokinetic Analysis
Population Pharmacokinetic Analysis:
A population PK approach will be utilized to characterize the PK of rodatristat ethyl and rodatristat.  A 
detailed description of the PK and any PK/PD analysis methods used will be provided in the separate 
analysis plan.
Demographic and Baseline Characteristics: 
Demographic and baseline characteristics for the ITT population will be summarized using descriptive 
statistics.
Other Analyses:
Patient Reported Outcomes (C-SSRS, HADS and QIDS-C), PK concentration data, PD, and exploratory 
descriptive analyses will be described in the SAP finalized before database lock.
Independent Data Monitoring Committee:
The primary role of the IDMC which consists of independent physicians with experience in the care of 
patients with PAH and the conduct of randomized controlled trials, and one non-voting biostatistician, is 
to ensure the safety of the patients enrolled in the study/OLE. A detailed description of IDMC 
procedures is provided in a separate data monitoring committee charter maintained by the Sponsor.
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Clinical Study Protocol
Protocol RVT-1201-2002
Altavant Sciences GmbH
Effective: 19JAN2022
49
Confidential
1.2.
Study Schematic
Figure 1:
Study Schematic
Abbreviations:  BID = twice daily; IP = investigational product
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Clinical Study Protocol
Protocol RVT-1201-2002 
Altavant Sciences GmbH
Effective: 19JAN2022 
50
Confidential 
1.3.
Schedule of Assessments – Main Study
Screening
Baseline
Treatment
Follow-Up
Visit No.
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Study Week1
(Days)
-4 Wks2
(D-28 to D-1) 
Clinic
D1
Clinic
Wk 2 (D14)
Telemed/ 
Phone Call
Wk 4
(D28)
Clinic
Wk 8 (D56)
Clinic or 
Home
Wk 12
(D84)
Clinic
Wk 18 (D126)
Clinic or Home
Wk 24
(D168)
Clinic
Wk 28
(D196) 
FU3/ ET3,4
Clinic or Home
Screening/ Demography/ Baseline
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Demographics
X 
Height/Weight/BMI
X 
X5
X5
X5
X5
X5
X5
Medical History Including Cardiac 
and Pulmonary History/Current 
Conditions6
X 
X 
PAH Medication History7
X 
X 
Pulmonary Function Tests (PFTs)
(unless completed in last 24 weeks)
X 
FSH8
X
Urinary Screen for Drugs of Abuse
X
Register Patient in IRT
Screening/Randomization 
X 
X 
Treatment 
Concomitant Medications
X
X
X
X
X
X
X
X
X
Dispensing IP via IRT
X 
X 
X 
Administer Rodatristat Ethyl or 
Placebo9
X 
X 
X 
X 
X 
X 
Morning Dose Taken in Clinic with 
Food9
X 
X 
Investigational Product 
Compliance/ Accountability
X 
X 
X 
X 
Safety/Tolerability Assessments
Adverse Events10
ĸ X ĺ
Pregnancy Test (Serum/urine)11
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
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Clinical Study Protocol
Protocol RVT-1201-2002 
Altavant Sciences GmbH
Effective: 19JAN2022 
51
Confidential 
Screening
Baseline
Treatment
Follow-Up
Visit No.
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Study Week1
(Days)
-4 Wks2
(D-28 to D-1) 
Clinic
D1
Clinic
Wk 2 (D14)
Telemed/ 
Phone Call
Wk 4
(D28)
Clinic
Wk 8 (D56)
Clinic or 
Home
Wk 12
(D84)
Clinic
Wk 18 (D126)
Clinic or Home
Wk 24
(D168)
Clinic
Wk 28
(D196) 
FU3/ ET3,4
Clinic or Home
Vital Signs (BP, HR, RR, temp, 
oxygen saturation)
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG12
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory – Hematology, 
Coagulation13, Chemistry,
urinalysis,
X 
X 
X  
X 
X 
X 
X 
X 
Columbia-Suicide Severity Rating 
Scale (C-SSRS)
X 
X 
X 
X 
X 
X 
X 
Hospital Anxiety and Depression 
Scale (HADS)
X 
X 
X 
X 
X 
X 
X 
Quick Inventory of Depressive 
Symptoms (QIDS-C)
X 
X 
X 
X 
X 
X 
X 
Efficacy-Related Assessments
6MWT
X
X
X
X
X
Right Heart Catheterization (RHC)14
X
X
X14
Echocardiography15
X
X
X
WHO FC
X
X
X
X
X
Plasma NT-proBNP level
X 
X 
X 
X 
PAH Symptoms and Impact 
Questionnaire (PAH-SYMPACT)
X 
X 
X 
Actigraphy16
ĸ X ĺ
Pharmacokinetics
Rodatristat PK Sampling17
X
X
X
X
Selexipag PK sampling18
X
X
Pharmacodynamics
Urine 5-HIAA17
X
X
X
X
Urine Creatinine17
X
X
X
X
Plasma 5-HIAA17
X
X
X
X
Other
Optional Blood for Future Research
Sample
X 
X 
Pharmacogenetic Samples
X
X
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Clinical Study Protocol
Protocol RVT-1201-2002 
Altavant Sciences GmbH
Effective: 19JAN2022 
52
Confidential 
1 Visits at Week 2 (Telemed/Phone Call) and Week 4 (clinic visit) can occur within +/-2 days from the randomization date; Visits at Weeks 8 (Telemed/Phone call), 12 (clinic),
18 (clinic or home visit), 24 and 28/Follow Up (clinic) can occur within +/-5 days from the randomization date.
2 Screening may be broken up into more than 1 visit, if necessary.  Once all screening procedures are complete and the Investigator determines that the patient is eligible, the site 
must upload/send the required supporting documentation for approval by the Sponsor.
3 Patients who early terminate from the IP should be asked to return for visits as scheduled for ongoing assessments through the Week 28 Visit.  Patients who withdraw consent 
should be asked to complete the Week 28 Visit for safety.  Patients who have not completed the study as planned (through Week 24) cannot participate in OLE.  Patients who 
withdraw consent will continue to be followed for vital status from public records such as government vital statistics or obituaries, as allowed by local law, or periodic contact 
(about every 6 to 12months). 
4 Patients that complete the study (defined as completing all visits through Week 24) have the option to enroll into the OLE (See Section 1.4).  Patients who complete through 
Week 24 but decide not to enroll into the OLE, should complete the Week 28 Follow-Up Visit. 
5 Weight only (no height or BMI) will be performed at Day 1 and Weeks 4, 8, 12, 24, and 28. 
6 Must have a confirmed diagnosis of PAH in patients’ medical history
7 Background PAH therapy dose regimens must be stabilized for > 12 weeks prior to the screening RHC and on stable dose(s) > 8 weeks prior to the screening RHC to be eligible.
All changes and dose adjustments in background PAH therapy must be documented.
8 Pregnancy tests not required for women who are surgically sterile. FSH required for women with amenorrhea < 2 years at the Screening Visit only to confirm postmenopausal 
status.
9 IP must be taken daily, morning and evening until the night before the Week 24 visit. Patients must be told not to take a dose the morning of the Week 24 visit. Doses should be 
taken with food.  During visits at the clinic or home, all assessments should be done predose, except where otherwise indicated.  Patients should bring their IP with them for each 
visit (including any empty bottles). 
10 SAEs will be collected starting at informed consent form signing.  AEs will be collected starting at first dosing.
11 Serum pregnancy tests will be performed at Screening and urine pregnancy tests over the rest of the study. A negative urine pregnancy test must be completed before Day 1 
procedures.  If a positive result on a urine test, a serum pregnancy test should be completed to confirm. Pregnancy tests will be completed in women of child-bearing potential 
every 4 weeks while on study.  Weeks 8, 16 and 20 will be performed at home (with a kit given to the subject by the site) and the results will be confirmed with the subject by a 
phone call. Additional pregnancy tests should be completed anytime menstruation is delayed and in women with infrequent or irregular menstrual cycles.
12 Three 12-lead ECGs (at least 1 minute apart) will be collected on Day 1 after at least 5 minutes of rest.  Single 12-lead ECGs will be collected at all other time points. 
13 Coagulation testing will be done at Screening, Weeks 12 and 24.
14 RHC results from 4 weeks prior to the Screening visit may be used for entry provided the RHC includes all required information and provided that changes to the patient’s PAH 
regimen were not made. If prior approval is obtained from the Sponsor, the screening RHC may be performed on the same day as the randomization procedures, provided that all 
blood draws and other efficacy assessments are conducted prior to the RHC procedure, and the RHC is performed prior to randomization and IP dosing.  Week 24 RHC may
occur up to 7 days prior to or on the Week 24 Visit. If a patient terminates early, and at or after the Week 12 Visit, an RHC should be performed at the Early Termination Visit.
15 Echocardiography should be done in supine position after at least 5 minutes of rest.
16 Patients will wear a wrist device for the entire duration of the study, but for endpoint assessments, focus will be on the 3 following periods: Day 1 to Week 4, 
Week 12 to Week 16, and Week 20 to Week 24.  All details of collection will be provided in the study manual.
17 Rodatristat Ethyl and Rodatristat PK: At Day 1 and Week 4, a predose PK sample will be collected (patients will take study medication in the clinic).  At Week 12, a postdose 
PK sample will be collected between 1 to 8 hours after the morning dose (patients will take the morning dose in the clinic and the time of dose will be recorded – all other 
assessments can be done pre or post dose).  At Week 24, no study medication will be taken prior to the clinic visit (the last dose in the Main Study will be the evening before the 
Week 24 visit) and a PK sample will be collected.  If the subject enrolls in the OLE, this PK sample will be collected prior to the first dose of study treatment in the OLE. 
Blood and spot urine samples for 5-HIAA (and urine samples for creatinine) will be collected pre-dose on Day 1 and at Weeks 4, 12, and 24. 
18 Selexipag and ACT-333679 PK (for subjects using selexipag at baseline only): At Day 1 and Week 4, a predose PK sample will be collected (patients will take selexipag in the 
clinic at these visits, and the PK samples will be collected approximately 12 h after the prior dose) 
Additional unscheduled safety assessments may be conducted at any time during the study if the Investigator or Sponsor deems it necessary for the safety of the 
patient.
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Clinical Study Protocol
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Abbreviations:  5-HIAA = 5-hydroxyindoleacetic acid; 6MWT = 6-minute walk test; AEs = adverse events; BMI = body mass index; BP = blood pressure; 
C-SSRS = Columbia-Suicide Severity Rating Scale; D = day; ECG = electrocardiogram; ET = early termination; FSH = follicle stimulating hormone; FU = follow up; 
HADS = Hospital Anxiety and Depression Scale; HR = heart rate; IP = investigational product; IRT = interactive response technology; LFTs = liver function tests; mo = months; 
NT-proBNP = N-terminal pro-brain natriuretic peptide; OLE = Open-Label Extension; PAH = pulmonary arterial hypertension; PAH-SYMPACT = Pulmonary Arterial 
Hypertension Symptoms and Impact Questionnaire; QIDS-C = Quick Inventory of Depressive System-Clinician Rated; RHC = right heart catheterization; RR = respiratory rate; 
SAE = serious adverse event; temp = temperature; WHO FC = World Health Organization Functional Class; Wk = week
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1.4.
Schedule of Assessments – Open-Label Extension – (First 24 weeks of Open-Label Extension) 
Study Week1
(following Week 24 in Main Study)
D1
Clinic
(Week 24 
Main Study) 
Wk 2 (D14)
Telemed/ 
Phone Call
Wk 4(D28)
Clinic
Wk 8 (D56)
Clinic or 
Home 
Wk 12 (D84)
Clinic
Wk 18 
(D126)
Clinic or 
Home
Wk 24
(D168)
Clinic
ET2
Clinic or Home
Screening/ Demography/ Baseline
Informed Consent
X 
Inclusion/Exclusion Criteria
X
Weight
X3
X3
X3
X3
X3
Treatment 
Concomitant Medications
X
X
X
X
X
X
X
X
Re-Randomization in IRT
X 
Dispensing IP via IRT
X 
X 
X 
Administer Rodatristat Ethyl
X
X
X
X
X
X
X
Morning Dose Taken in Clinic 
with Food4
X 
X 
Investigational Product 
Compliance/ Accountability
X 
X 
X 
X 
X 
Safety/Tolerability Assessments
Adverse Events
ĸ X ĺ
Pregnancy Test (Serum/urine)5
X
X
X
X
X
Physical Examination
X
X
X
Vital Signs (BP, HR, RR, temp, 
oxygen saturation)
X 
X 
X 
X 
X 
X 
12-Lead ECG6
X 
X 
X 
X 
X 
X 
Laboratory – Hematology, 
Coagulation7, Chemistry,
urinalysis,
X  
X 
X 
X 
X 
X 
Columbia-Suicide Severity Rating 
Scale (C-SSRS)
X 
X 
X 
X 
X 
Hospital Anxiety and Depression 
Scale (HADS)
X 
X 
X 
X 
X 
Quick Inventory of Depressive 
Symptoms (QIDS-C)
X 
X 
X 
X 
X 
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Study Week1
(following Week 24 in Main Study)
D1
Clinic
(Week 24 
Main Study) 
Wk 2 (D14)
Telemed/ 
Phone Call
Wk 4(D28)
Clinic
Wk 8 (D56)
Clinic or 
Home 
Wk 12 (D84)
Clinic
Wk 18 
(D126)
Clinic or 
Home
Wk 24
(D168)
Clinic
ET2
Clinic or Home
Efficacy-Related Assessments
6MWT
X
X
X
Right Heart Catheterization
(RHC)8
X
X 
Echocardiography9
X
X
WHO FC
X
X
X
Plasma NT-proBNP level
X 
X 
X 
PAH Symptoms and Impact 
Questionnaire (PAH-SYMPACT)
X 
X 
Selexipag PK Sampling10
X
X
1 Visits at Week 2 (Telemed/Phone Call) and Week 4 (clinic visit) can occur within +/-2 days from the randomization date; Visits at Weeks 8 (Telemed/Phone call), 12 (clinic),
18 (clinic or home visit), 24 and 28/Follow Up (clinic) can occur within +/-5 days from the randomization date.
2 Patients who withdraw consent should be asked to complete the ET Visit for safety.  Patients who withdraw consent will continue to be followed for vital status from public 
records such as government vital statistics or obituaries, as allowed by local law, or periodic contact (about every 6 to 12months).
3 Weight only (no height or BMI) will be performed at Weeks 4, 8, 12, 24, and 28. 
4 IP must be taken daily, morning and evening.  Doses should be taken with food.  During visits at the clinic or home, all assessments should be done predose, except where 
otherwise indicated.  Patients should bring their IP with them for each visit (including any empty bottles).
5Pregnancy tests not required for women who are surgically sterile. Pregnancy tests will be completed in women of child-bearing potential every 4 weeks while on study.  Weeks 
8, 16 and 20 will be performed at home (with a kit given to the subject by the site) and the results will be confirmed with the subject by a phone call. Additional pregnancy tests 
should be completed anytime menstruation is delayed and in women with infrequent or irregular menstrual cycles.
6 Single 12-lead ECGs will be collected at all time points.
7 Coagulation testing will be done at Weeks 12 and 24. 
8 Week 24 RHC may occur up to 7 days prior to or on the Week 24 Visit. If a patient terminates early, and at or after the Week 12 Visit, an RHC should be performed at the Early 
Termination Visit.
9 Echocardiography should be done in supine position after at least 5 minutes of rest. 
10 Selexipag and ACT-333679 PK (for subjects using selexipag at baseline only): At Day 1 and Week 4, a predose PK sample will be collected (patients will take selexipag in the 
clinic at these visits, and the PK samples will be collected approximately 12 h after the prior dose)
Additional unscheduled safety assessments may be conducted at any time during the study if the Investigator or Sponsor deems it necessary for the safety of the 
patient.
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Abbreviations:  5-HIAA = 5-hydroxyindoleacetic acid; 6MWT = 6-minute walk test; AEs = adverse events; BMI = body mass index; BP = blood pressure; 
C-SSRS = Columbia-Suicide Severity Rating Scale; D = day; ECG = electrocardiogram; ET = early termination; FSH = follicle stimulating hormone; FU = follow up; 
HADS = Hospital Anxiety and Depression Scale; HR = heart rate; IP = investigational product; IRT = interactive response technology; LFTs = liver function tests; mo = months; 
NT-proBNP = N-terminal pro-brain natriuretic peptide; OLE = Open-Label Extension; PAH = pulmonary arterial hypertension; PAH-SYMPACT = Pulmonary Arterial 
Hypertension Symptoms and Impact Questionnaire; QIDS-C = Quick Inventory of Depressive System-Clinician Rated; RHC = right heart catheterization; RR = respiratory rate; 
SAE = serious adverse event; temp = temperature; WHO FC = World Health Organization Functional Class; Wk = week
1.5.
Schedule of Assessments – Open-Label Extension – (Post 24 Weeks of the Open-Label Extension)
1 As necessary, 6-month supply of IP will be dispensed.
2 Patients should be instructed to bring their used, partial, and unused IP containers with them to every Clinic Visit to assess compliance and IP accountability.
3 Pregnancy test will be required every 4 weeks, in women of childbearing potential only.  Urine pregnancy kits will be provided to the patient. Completion of the pregnancy test, 
and collection of adverse events and concomitant medications will be documented via telephone contact. Serum pregnancy test to be done to confirm a positive urine test.
Additional pregnancy tests should be completed anytime menstruation is delayed and in women with infrequent or irregular menstrual cycles.
4 If a patient discontinues IP for any reason a follow-up visit must be performed 4 weeks after the last dose of IP.
Abbreviations:  BP = blood pressure; HR = heart rate; IP = investigational product; RT = interactive response technology; LFTs = liver function tests; RR = respiratory rate; 
temp = temperature
Additional unscheduled safety assessments may be conducted at any time during the study if the Investigator or Sponsor deems it necessary for the safety of the 
patient.
Pregnancy Test 
Clinic Visits4
Follow Up4
(4 weeks after last dose of 
IP)
Week
Every 4 Weeks
(+/- 2 days)
Every 24 Weeks
(+/- 4 days)
IP Dispensing via IRT1
X
IP Compliance/ Accountability2
X
Concomitant medications
X
X
Vital Signs (BP, HR, RR, temp, oxygen saturation)
X
X
Pregnancy Test (serum/urine)3
X
X
X
Laboratory – Hematology, Coagulation, Chemistry (including LFTs)
X
X
Adverse Events
X
X
X
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2.
INTRODUCTION
2.1.
Background
Pulmonary arterial hypertension (PAH) is a severe, incurable disease characterized by 
remodeling of the pulmonary arterial bed, leading to elevations in resting mean pulmonary artery 
pressures, subsequent right ventricular hypertrophy, and eventually, right heart failure and 
(Agarwal & Gomberg-Maitland, 2011).  Current standard-of-care therapies for PAH target 
3 different pathways – namely, the endothelin-1 pathway, the nitric oxide pathway, and the 
prostacyclin pathway – and act primarily as vasodilators.  They reduce PAH symptoms and may 
slow disease progression, but they lack compelling disease-modifying properties.
Several lines of evidence implicate serotonin (5-hydroxytryptamine [5-HT]) in the 
pathophysiology of PAH where there are findings that 5-HT plasma levels are markedly elevated 
in PAH (Humbert et al., 2002); tryptophan hydroxylase (TPH) 1, the key rate-limiting enzyme in 
the biosynthesis of systemic 5-HT, is overexpressed in lung tissue of PAH patients 
(Eddahibi, 2006), and 5-HT acts on pulmonary artery smooth muscle cells to induce 
vasoconstriction and proliferation (MacLean & Dempsie, 2010).  In addition, 5-HT acts at the 
5-HT1B receptor and the 5-HT transporter to mediate constriction and proliferation of 
pulmonary artery smooth muscle cells (MacLean & Dempsie, 2010).  Finally, genetic deletion 
and pharmacological inhibition of TPH1 protects against the development of experimentally 
induced PAH (Abid et al., 2012; Izikki et al., 2007) in nonclinical pharmacology models.  In 
aggregate, these findings indicate that modulation of the 5-HT pathway by TPH1 inhibition is a 
novel approach that differentiates itself mechanistically from current therapeutic options and 
offers the potential to modify the underlying disease pathophysiology and progression of PAH
(Aiello et al., 2016; MacLean, 2018). 
A therapeutic strategy is needed to safely and effectively inhibit TPH1 activity in peripheral 
tissues, without unwanted central nervous system (CNS) effects that result from inhibition of 
TPH2, the predominant TPH isoform in the CNS. 
Rodatristat ethyl is a peripherally restricted TPH1/TPH2 inhibitor with little CNS penetration. 
Nonclinical data indicate that neither rodatristat ethyl nor rodatristat cross the blood brain barrier 
to a pharmacologically relevant level and do not lower brain levels of 5-HT in nonclinical 
pharmacodynamic studies in rats.  By limiting inhibition to TPH1 in the periphery, rodatristat 
ethyl may avoid potential untoward CNS effects that could otherwise be a consequence of 
inhibiting TPH2-mediated CNS 5-HT production (Kim et al., 2015; Shi et al., 2008). 
Rodatristat ethyl is a prodrug that is rapidly hydrolyzed to rodatristat, a potent TPH inhibitor that 
reduces peripheral 5-HT levels in the gut mucosa, lung, and serum in animal models of PAH.  In 
vitro, nonclinical, and human pharmacokinetic (PK) studies to date have provided valuable 
information on the PK properties of rodatristat ethyl and its active moiety, rodatristat. Rodatristat 
ethyl has low to moderate oral bioavailability in nonclinical species and is rapidly converted to 
rodatristat in vivo.  Both rodatristat ethyl and rodatristat are highly protein bound and little is 
excreted in the urine.  Biliary excretion predominates in rats and no further metabolism of 
rodatristat has been detected in human hepatocyte preparations. However, preliminary 
investigations have also identified a metabolite, M15, in the plasma of dogs and humans after 
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administration of rodatristat ethyl. After single-dose administration, the half-life of rodatristat 
ethyl and rodatristat are approximately 5 and 12 hours, respectively, reaching steady-state 
exposure, according to trough concentrations, by Day 5.  The highest exposures achieved in 
healthy subjects to date were reached on Day 7 following 800 mg twice daily (BID) doses of 
rodatristat ethyl.
Rodatristat ethyl was selected for development in the treatment of PAH based on a range of 
criteria, including achieving efficacy endpoints in nonclinical in vivo models of PAH, 
pharmacokinetic (PK) parameters, and biomarker endpoints related to both changes in systemic 
5-HT levels and PAH pathology. 
Reductions in biomarkers indicative of decreased 5-HT biosynthesis were observed in healthy 
subjects receiving repeat twice daily (BID) oral doses (range 100 to 800 mg BID) of rodatristat 
ethyl over 14 days.  Rodatristat ethyl doses of either 400 or 800 mg BID achieved reductions in 
5-HT by Day 14 comparable to those associated with efficacy in the rodent models of PAH. 
2.2.
Study Rationale
Rodatristat ethyl is expected to have efficacy for PAH.  Results from nonclinical pharmacology 
studies demonstrate that rodatristat ethyl is a potent and selective inhibitor of TPH1 with the 
potential to ameliorate disease by halting or reversing the pulmonary vascular remodeling 
characteristically observed.  Through inhibition of TPH1, rodatristat ethyl is expected to improve 
cardiopulmonary hemodynamics, functional capacity, PAH symptoms, and right ventricular 
(RV) function via its novel antiproliferative and anti-remodeling mechanism of action.
This study will evaluate rodatristat ethyl doses of 300 mg BID and 600 mg BID. Dose selection 
was guided by the goal of demonstrating a dose/exposure efficacy relationship and was 
supported by nonclinical pharmacology, toxicology, and animal model efficacy data. Results 
from Phase 1 human studies suggest that these dosing regimens should be safe and generally 
well tolerated with dose-proportional differences in systemic drug exposure.  Further details 
regarding the dose rationale can be found in Section 4.7.
2.3.
Benefit/Risk Assessment
Summaries of findings from both clinical and nonclinical studies conducted with rodatristat ethyl
as well as more detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of rodatristat ethyl may be found in the Investigator’s 
Brochure.  This section outlines the potential adverse events of special interest (AESI; based 
either on preclinical or clinical data generated to date, the mechanism of action of rodatristat 
ethyl, or the prescribing information for telotristat ethyl [a TPH inhibitor previously approved for 
the treatment of carcinoid syndrome-related diarrhea] and mitigation strategies for this protocol.
The potential risk for QTc prolongation (described in the Investigator’s Brochure) will be further 
evaluated in a definitive thorough QT study in the future. Until further data are available in that 
regard, cardiac arrhythmia, related to an increase in QT/QTc interval, will be treated as a 
potential AESI and has therefore also been included in the table of potential risks below. 
Although any potential benefits to patients with PAH will not be known until the study is 
completed, the development of a drug with disease-modifying potential will certainly be of value 
to patients with this diagnosis.
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Potential Risk
Mitigation Strategy
Impact on Eligibility
Monitoring and Stopping 
Criteria OR Management 
Criteria
Severe constipation
None
Severe constipation 
(e.g., obstipation with manual 
evacuation indicated) and/or 
severe, persistent, or worsening 
abdominal pain would warrant 
withdrawal from the study.
Depression/other 
mood-related 
disturbance due to 
central depletion 
x
Exclusion of patients with active 
suicidal thinking or behavior at 
Screening/Baseline based on the 
Columbia-Suicide Severity Rating Scale 
(C-SSRS)
x
Exclusion of patients with severe 
depression at Screening/Baseline based 
on the Quick Inventory of Depressive 
Symptoms Clinician-Rated (QIDS-C) or 
the Hospital Anxiety and Depression 
Scale (HADS)
Withdrawal of patients with:
x
Any significant worsening 
on postdose C-SSRS 
indicative of active suicidal 
ideation with intent to act 
or suicidal behavior
x
Severe depression or 
anxiety based on a HADS 
Depression or Anxiety 
Score  15 or a QIDS-C
Total Score  16.
x
Any severe psychiatric or 
CNS AE as determined by 
the Investigator.
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Potential Risk
Mitigation Strategy
Impact on Eligibility
Monitoring and Stopping 
Criteria OR Management 
Criteria
Hepatic enzyme 
elevations
Exclude patients with alanine 
aminotransferase (ALT) / aspartate
aminotransferase (AST) / gamma-glutamyl
transferase (GGT) results greater than 2X
upper limit of normal (ULN) and/or TBL 
> 2X ULN
Withdrawal criteria for 
abnormal liver function tests set 
at: 
x
ALT or AST > 3X ULN 
and TBL > 2X ULN (or 
international normalized 
ratio (INR) > 1.5)
x
ALT or AST > 3X ULN 
with appearance of fatigue, 
nausea, vomiting, right 
upper quadrant pain or 
tenderness, fever, rash 
and/or eosinophilia (> 5%)
x
ALT or AST > 5X ULN for 
> 2 weeks
x
ALT or AST > 8X ULN
Cardiac arrhythmia, 
related to an increase 
in QT/QTc interval
Exclude patients with:
x
QTcF > 450 ms (males) or > 470 ms 
(females)
x
Known congenital Long QT Syndrome 
(LQTS), or known family history of 
LQTS
x
Clinically significant electrolyte 
abnormality (i.e., hypokalemia, 
hypocalcemia, hypomagnesemia)
x
Concomitant use of QT-prolonging 
drugs clearly associated with a risk of 
Torsades de Pointe (see Appendix 1)
Withdrawal criteria for 
abnormal/worsening QT 
interval prolongation:
x
QTcF interval > 500 ms
x
QTcF interval > 480 ms 
AND increase from 
baseline  60 ms
x
QTcF interval > 480 ms 
associated with syncope, 
life-threatening 
arrhythmias, resuscitated 
cardiac arrest, or seizure
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3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints/Criteria for Evaluation
Primary
Primary
x
To evaluate the effect of rodatristat ethyl on 
the percent change from baseline of 
pulmonary vascular resistance (PVR), as 
measured by right heart catheterization (RHC) 
in patients with PAH
x
Percent change from baseline to 24 weeks of 
PVR between an active arm and the placebo 
arm
Secondary
To evaluate the effect of rodatristat ethyl from 
baseline to Week 24 on the following:
R
WHO FC
R
6MWD
R
N-terminal pro-Brain Natriuretic 
(NT-proBNP)
Secondary
To evaluate the effect of rodatristat ethyl from 
baseline to Week 24 on the following:
o
Change from baseline in WHO FC
o
Change from baseline in 6MWD
o
Change from baseline in NT-proBNP
To evaluate the effect of rodatristat ethyl from 
baseline to Week 24 on the following:
To evaluate the effect of rodatristat ethyl from 
baseline to Week 24 on the following:
x
Safety
R
To assess safety & tolerability of 
rodatristat ethyl in patients with PAH
x
Additional 
R
Hemodynamics (cardiac index, mean 
pulmonary artery pressure [mPAP],
mean right atrial pressure [mRAP],
mixed venous oxygen saturation 
[SvO2], and pulmonary artery 
compliance [PAC])
R
Time to Clinical Worsening (TTCW) 
defined as the first occurrence of a 
composite end point of: 1. Death from 
any cause, 2. Hospitalization for 
worsening PAH (any hospitalization 
for worsening PAH, lung or heart and 
lung transplantation, atrial 
septostomy, or initiation of parenteral 
prostanoid therapy), 3. Disease 
progression defined as a decrease of 
more than 15% from baseline in the 
6-minute walk distance (6MWD) 
combined with WHO FC III or IV 
symptoms at 2 consecutive visits 
separated by at least 14 days 
(adjudicated).
R
Death from any cause
x
Safety
R
Change in safety parameters 
including AEs, vital signs, laboratory 
values, and electrocardiogram (ECG)
assessments
x
Additional 
R
Change from baseline in cardiac 
index, mPAP, mRAP, SvO2 at rest 
and PAC
R
Change from baseline in TTCW
R
Death from any cause
R
Change from baseline in right atrial 
size & RV function (TAPSE, 
tricuspid annular systolic velocity, & 
RV fractional area change)
R
Change from baseline in 
PAH-SYMPACT 
R
Change from baseline in REVEAL 
Lite 2.0 Score
x
PK/PD
R
Population PK parameters of 
rodatristat ethyl, active metabolite 
rodatristat, M15, and other 
metabolites
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Objectives
Endpoints/Criteria for Evaluation
R
Echocardiographic measures of right 
atrial size & RV function (tricuspid 
annular plane systolic excursion 
[TAPSE], tricuspid annular systolic 
velocity, and RV fractional area 
change)
R
Pulmonary Arterial Hypertension-
Symptoms and Impact Questionnaire 
(PAH-SYMPACT)
R
Register to Evaluate Early and Long-
Term PAH Disease Management 
(REVEAL) Lite 2 score
x
PK/PD
R
To assess the PK of rodatristat ethyl 
and metabolites
R
To assess the effect of rodatristat 
ethyl on plasma and urinary 5-HIAA
R
Change from baseline in 
5-hydroxyindoleacetic acid (5-HIAA;
plasma and spot urine concentration)
Exploratory
To evaluate the effect of rodatristat ethyl from 
baseline to Week 24 on the following:
Exploratory
To evaluate the effect of rodatristat ethyl from 
baseline to Week 24 on the following:
x
Time to Clinical Improvement (TTCI)
x
Actigraphy
x
To evaluate the effect of rodatristat ethyl on 
the plasma concentration of selexipag and 
ACT-333679
x
A > 10% increase in 6MWD or 30 meters 
AND an improvement to or maintenance of 
WHO FC II symptomatology, in the absence 
of a deterioration in clinical condition or death 
during the 24 weeks of the Main Study
x
Change from baseline in actual daily activity, 
(counts/minute) as determined by actigraphy:
R
Light to vigorous activity/day
R
Moderate to vigorous activity/day
R
Total movement/day
R
Best 6-minute walk effort
x
Plasma selexipag and ACT-333679 trough 
concentration at baseline and Week 4
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4.
STUDY DESIGN
4.1.
Overall Design
This study will compare the efficacy, safety, and tolerability of 2 dosing regimens of rodatristat 
ethyl to placebo in patients with PAH over a 24-week treatment period. Investigational product 
(IP) will be administered on the background of stable PAH therapy. 
Approximately ninety (90) patients will be enrolled. Patients will be randomized 1:1:1 to 
placebo, 300 mg BID, or 600 mg BID of rodatristat ethyl. 
Eligible patients will be stratified based on the number of background PAH therapies they are 
receiving (1 vs 2 vs 3) and selexipag use (Yes/No).  The number of patients who are on a 
prostanoid infusion will be capped at 50% of the total enrolled. The number of patients who are 
receiving selexipag will be capped at 20% of the total enrolled.
The study will consist of a Screening Period (up to 28 days in duration), a Baseline Period 
(Day 1), a 24-week Treatment Period (Main Study), and for patients that early terminate or do
not enroll an Open-Label Extension (OLE), and a 4-week Follow-Up Period (approximately 
4 weeks after the last dose), for a total study duration of 32 weeks.
Patients who complete the Main Study will have the option to enroll into an OLE and continue to 
receive rodatristat ethyl (those randomized to placebo will be re-randomized 1:1 to receive 
rodatristat ethyl 300 mg BID or 600 mg BID) for 6.5 years, until the Investigator or patient 
chooses to stop the IP, any stopping criteria in the Main Study are met, IP becomes commercially 
available, or the Sponsor stops the study for lack of efficacy or a safety signal (whichever 
preceding criteria comes first). In no case will a patient be allowed to exceed 10 years of 
exposure unless the product is approved for a chronic indication.
All participating patients will be required to be on a stable background therapy for PAH with 
mono, dual or triple combination therapy (which may include currently approved prostanoid 
therapies) at the time of Screening. All patients will maintain their standard of care (SOC) 
regimen at entry for the duration of the study. Refer to Section 6.6.2 for more details.
During the 24-week Treatment Period, in addition to the Day 1/Baseline Visit and a telemedicine 
or phone call at Weeks 2 and 8, patients will return to the study center for safety, tolerability and 
efficacy-related assessments at Weeks 4, 12, and 24, and a clinic or home visit at Week 18, as
specified in the Schedule of Events Table, Section 1.3, as well as Follow-up at Week 28 (as 
applicable). Female patients of childbearing potential will undergo pregnancy testing every 
4 weeks and will be required to use 2 reliable methods of contraception to reduce the risk of 
pregnancy, at Screening, during the course of the study, and for at least 4 weeks following the 
last dose of rodatristat ethyl. Additional pregnancy testing in women whose menstruation is 
delayed or who have infrequent or irregular menstrual cycles should be completed as warranted.
Further details for the OLE are found in Section 7.
4.2.
Number of Patients
Approximately ninety (90) patients with PAH are expected to be enrolled at approximately 
68 study sites in the United States, Canada, and Rest of World (ROW).
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4.3.
Treatment Assignment
Patients will be randomized to IP according to a computer-generated allocation schedule, 
prepared prior to the start of the study.
At the Baseline Visit, eligible patients will be randomly allocated (1:1:1) to one of the following 
3 treatment groups:
Treatment Arm
Name
Treatment Description
Rodatristat ethyl 
300 mg BID
1 x 300 mg tablet + 1 x matching placebo BID
Rodatristat ethyl 
600 mg BID
2 x 300 mg tablets BID
Placebo
2 x matching placebo tablets BID
In order to maintain the study blind, patients will take 2 tablets in the morning and 2 tablets in 
the evening in one of the combinations noted above.
4.4.
Dose Adjustment Criteria
4.4.1.
Dose Reduction
All determinations of rodatristat ethyl dose reduction should be discussed with the Medical 
Monitor prior to implementing unless time does not allow for safety.
Temporary dosage reductions or discontinuations will be allowed to manage AEs/AESIs (or 
other instances to be discussed with the Medical Monitor), including gastrointestinal AEs
(e.g., diarrhea, nausea, or vomiting) or liver enzyme increase occurring during the 24 weeks of 
the study.  Judicious use of antidiarrheal and/or anti-emetic medications will be permitted. One 
level of dose reduction is available.
To reduce the IP, the patient will be instructed to take one tablet in the morning and one tablet in 
the evening from the appropriate dispensed bottles during the dose reduction period per dosing 
instructions supplied in a separate document.  If AEs continue, the patient may stop taking the IP
completely for up to 7 days before restarting.
4.4.1.1.
Diarrhea
In the event the patient experiences diarrhea, the dose may be reduced. The Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 grading will be used to grade the 
severity of all AEs and serious adverse events (SAEs) of diarrhea. Management 
recommendations for diarrhea are based on the CTCAE grades and are detailed in Appendix 2.
In general, the patient should be treated with anti-diarrheal drugs such as loperamide as clinically 
indicated. In addition to directly treating any diarrhea, possible intermittent or permanent 
interruption of IP and dose reduction will be possible, depending upon the frequency and 
severity of diarrhea.
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4.4.1.2.
Aminotransferase (Alanine aminotransferase or Aspartate Aminotransferase)
Elevation
Management recommendations for ALT or AST elevations are based on U.S. Food and Drug 
Administration (FDA) Guidance for Liver Toxicity.
In general, all baseline or treatment-emergent ALT or AST elevations > 3X ULN should be 
confirmed within 48 to 72 hours with repeat assessments of ALT and AST as well as TBL,
alkaline phosphatase (ALP), prothrombin time/INR, and complete blood count for eosinophil 
levels.  Further details for managing IP reduction, restart, and discontinuation can be found in
Appendix 3.
If at any time, the criteria as outlined in Section 8 are met, the IP must be permanently 
discontinued.
4.5.
Criteria for Study Termination
This study (including OLE) 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 the Investigators,
Institutional Review Boards (IRB)/Ethics Committees (EC), regulatory authorities. If the study 
is prematurely terminated or suspended, the Investigators will promptly inform the IRB/ECs and 
will provide the reason(s) for the termination or suspension. Circumstances that may warrant 
termination or suspension include, but are not limited to: 
x
Determination of unexpected, significant, or unacceptable risk to participants
x
Demonstration of efficacy that would warrant stopping
x
Insufficient compliance to protocol requirements
x
Data that are not sufficiently complete and/or evaluable
x
Determination of futility
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed and the IRBs/ECs and competent authorities are satisfied. The study will only resume 
after prior submission and approval of the substantial amendment (if required) by the competent 
authority.
4.6.
Scientific Rationale for Study Design
The design of this study will provide efficacy, safety, and dosing information to support proof of 
concept. Two rodatristat ethyl doses will be studied. Patients with idiopathic PAH and other 
Group 1 PAH sub-types will be included in this study.
Placebo-controlled randomized studies provide the most robust results and are thus considered 
the most appropriate design. However, approved therapies for PAH are available, making a
placebo-controlled rodatristat ethyl monotherapy study unethical. Therefore, rodatristat ethyl (or 
placebo) will be evaluated in addition to standard of care (SOC) PAH-specific treatments, 
i.e., this study will only include patients on stable, approved, and available treatments at baseline. 
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Patients on prior monotherapy and combination regimens to include up to 3 agents will be 
permitted to participate. Treatment with oral, inhaled, or parenteral prostanoids will be 
permitted.  Any changes to background PAH therapy during the study should be based on clear 
medical need. 
In prior studies of patients treated with PAH therapies, up to 24 weeks of treatment with study 
medication were considered necessary to demonstrate efficacy based on potential impact on 
pulmonary hemodynamics.  This duration of exposure will also allow for assessment of safety,
tolerability, and possible effects on exercise ability, patient reported outcomes, and biomarkers. 
The OLE will provide long term safety, tolerability, and efficacy of rodatristat ethyl in patients
with PAH. In order to minimize bias during the OLE, patients will remain blinded to original 
treatment assignment in the Main Study.  Patients receiving active rodatristat ethyl during main 
treatment period will continue at their originally randomized dose to generate additional 
long-term safety and efficacy data. Patients originally randomized to placebo will also have the 
opportunity to receive active rodatristat ethyl during the OLE, providing additional patient 
exposures for further assessment of safety and efficacy.
4.7.
Justification for Dose
The dose levels selected are based on prior pharmacodynamic (PD) observations in nonclinical 
models of PAH and PK, PD, safety, and tolerability data in healthy subjects receiving rodatristat 
ethyl for up to 14 days.
Disease-modifying effects of rodatristat ethyl were demonstrated in the semaxanib (SU5416, 
SUGEN) hypoxia and the monocrotaline (MCT) injury rat models of PAH.  In the MCT rat 
model, rodatristat ethyl decreased serum and lung 5-HT levels and reduced the extent of vascular 
remodeling. In the SU5416 hypoxia rat model, rodatristat ethyl significantly reduced RV
systolic pressure, RV hypertrophy, the biomarker brain natriuretic peptide (BNP), and pulmonary 
vessel wall thickness and occlusions as measured by histological analysis, without impacting 
systolic blood pressure (SBP). These benefits were observed at GRVHVRI 100 mg/kg, which 
results in approximately a 40% reduction in 5-HT biosynthesis (IB, 2020). Based on these data,
a target reduction in 5-HT (as determined by urinary 5-HIAA excretion rate) of at least 40% was 
the basis for the doses selected in the current study.
After 14 day BID administration to healthy subjects, rodatristat ethyl at doses of 400 to 800 mg 
BID resulted in 50 to 60% reductions in urinary 5-HIAA.  Dose-dependent increases in 
gastrointestinal treatment-emergent AEs (TEAEs; notably nausea and diarrhea) were noted with 
rodatristat ethyl, including an event of moderate diarrhea and an overall incidence rate of 
44% after administration of 800 mg BID (IB, 2020).  Therefore, the highest dose regimen 
selected for the current study is rodatristat ethyl 600 mg BID which is expected the maintain the 
majority of the 5-HT lowering effect while minimizing potential of gastrointestinal TEAEs.
The lower dose regimen of rodatristat ethyl of 300 mg BID was selected to evaluate a lower dose 
to aid in defining potential dose-response relationships and is expected to result in approximately 
40% reduction in 5-HIAA, equivalent to the reductions observed at efficacious doses in 
nonclinical models (IB, 2020). 
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Figure 2: 
Percentage Change from Baseline of Urine 5-HIAA: Creatinine Ratio 
5-HIAA on Days 7 and 14 following Twice Daily Repeat Oral Administration 
of Rodatristat Ethyl in Studies KAR5585-101 and RVT-1201-1001 
Note:  Blue boxes and green boxes represent data from Day 7 and Day 14, respectively.  Data for subjects receiving 
placebo represent totality of data across BID cohorts.
Abbreviations:  5-HIAA = 5-hydroxyindoleacetic acid; BID = twice daily
Aside from the dose-dependent gastrointestinal TEAEs observed in healthy subjects receiving 
higher doses for 14 days, which have all been considered mild with the exception of 1 event of 
moderate diarrhea, no other safety concerns were identified following single doses ranging up to 
2000 mg or following repeat dosing over 14 days of up to 800 mg administered BID to healthy 
subjects.  The majority of TEAEs for all dose regimens evaluated to date have been mild and 
have resolved without requiring intervention or discontinuation of the IP. There have been no 
SAEs reported nor any dose-limiting toxicities identified.  Mild, transient elevations in ALT 
were reported in 5 subjects who received either single or multiple doses of rodatristat ethyl (5 of 
136 subjects [3.7%]).  Further information can be found in the Investigator’s Brochure. 
With respect to nonclinical toxicology studies, rodatristat ethyl and rodatristat exposures at the 
no observed adverse effect level (NOAEL) in the 26-week rat (female only) or 39-week dog 
toxicology studies are > 4-fold higher than the expected exposure after at the higher dose 
regimen of 600 mg BID (IB, 2020).  Due to adverse decreases in mean body weight gain (20 
to -41.7% relative to controls) and food consumption at all dose levels in the 26-week study in 
male rats, the NOAEL could not be established.  Exposure at the lowest dose tested in this study 
was 4-fold higher than that anticipated at the higher dose regimen of 600 mg BID.  The major 
toxicities associated with oral rodatristat ethyl administration included mortality in rats preceded 
by clinical signs of toxicity and body weight loss occurring at exposures > 4-fold the highest 
exposure expected in the current study.  Findings in both species were indicative of 
gastrointestinal changes including decreased body weight and/or decreased rate of weight gain, 
decreased food consumption, diarrhea/fecal change, dehydration, distended abdomen (rats only), 
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intestinal dilation with mucosal thickening and macrophage vacuolation (rats only), 
histopathologic findings of intestinal dilation with vacuolated macrophages, and increased 
mucosal thickness with regeneration in the duodenum.  Observed liver enzyme elevations were 
not associated with adverse histopathology (hepatocellular necrosis) and are considered 
monitorable.
Prior studies have demonstrated coadministration of rodatristat ethyl with food can increase 
systemic exposure of rodatristat ethyl and rodatristat from 1.1- to 1.8-fold.  Thus, the prior 
Phase 1 studies in healthy subjects evaluated rodatristat ethyl administered with a standard meal
(IB, 2020).  To maintain consistency with these studies and therefore the expected PD effects, IP
will be administered BID with a standard meal.
Taken together, the nonclinical pharmacology and safety data, and prior clinical experience with 
rodatristat ethyl support the low and high BID dose regimens (300 mg and 600 mg) to be 
evaluated in patients with PAH over the 24-week treatment period.
4.8.
End of Study Definition
A patient is considered to have completed the study if he/she has completed 24 weeks of 
treatment including the Week 24 visit and the Follow-up Visit (for patients that complete the 
study through Week 24 but decide not to rollover to the OLE), or the last scheduled procedure
shown in the Schedule of Assessments(SoA; Section 1.3).   If the patient decides to continue 
into the OLE, subject must not participate in another interventional study until completing the
ET/final follow-up visit (4 weeks after the last dose of study drug) according to the Schedule of 
Assessments OLE (Section 1.4 or 1.5).
The end of the study for assessment of the primary endpoint is defined as the date of the last visit 
of the last patient in the Main Study or last scheduled procedure in the Main Study shown in the 
SoA for the last patient in the study globally, regardless of duration of participation in the OLE.
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5.
STUDY POPULATION
5.1.
Inclusion Criteria
Patients are eligible to be included in the study only if all the following criteria are met:
1. Male and female patients must be at least 18 years of age at the time of signing the 
informed consent.
a.
Male patients and female partners of childbearing potential must agree to use 
contraception as detailed in a Section 5.4.1 to the protocol starting at Screening,
during the treatment period, and for at least 100 days after the last dose of IP. Male 
patients must refrain from donating sperm during this period.
b. Female patients of childbearing potential must agree to use contraception as detailed 
in Section 5.4.1 starting at Screening, during the treatment period, and for at least 
4 weeks after the last dose of IP.
2. Body mass index (BMI)  18 kg/m2 DQG 40 kg/m2
3. Patients with symptomatic PAH belonging to one of the following 2018 Clinical Group 1
sub-types:
a.
Idiopathic PAH
b. Heritable PAH
c.
Drug- or toxin-induced
d. PAH associated with:
1. Connective tissue disease
2. Congenital systemic to pulmonary shunt (atrial septal defect, ventricular septal 
defect, patent ductus arteriosus) repaired at least one year prior to Screening
3. Human immunodeficiency virus (HIV) infection - if diagnosed with HIV, 
must have stable disease status defined as follows: 
a.
stable treatment with HIV medications for at least 8 weeks prior to 
Screening
b. no active opportunistic infection during the Screening Period 
c.
no hospitalizations due to HIV for at least 4 weeks prior to Screening
4. WHO FC II or III
5. Confirmed diagnosis of PAH and meet all the following hemodynamic criteria by means of a 
screening RHC completed prior to randomization:
a.
mPAP of >20 mmHg 
b. 395 350 dyne•sec/cm5
c.
Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic 
SUHVVXUH/9('3RI 12 PP+JLI395 350 and < 500 dyne•sec/cm5, or 
3&:3/9('3 PP+JLI395 500 dyne•sec/cm5
6. 6MWD of 100 to 550 meters at Screening
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7. Currently on a stable treatment regimen with one or more treatments approved for PAH. 
6WDEOHWKHUDS\LVGHILQHGDVUHFHLYLQJWKHVDPHPHGLFDWLRQVIRU 12 weeks prior to the 
VFUHHQLQJ5+&DQGDWDVWDEOHGRVHOHYHOIRUHDFKIRU 8 weeks prior to the screening RHC
(see Protocol Section 6.6.2 for approved PAH medications). Any instances where doses of a 
medication have been missed prior to RHC must be discussed with the Medical Monitor prior 
to performing the RHC.
8. Meet all of the following criteria determined by pulmonary function tests completed no more 
than 24 weeks prior to Screening (performed with or without bronchodilation): 
a.
Forced expiratory volume in one second (FEV1 60% of predicted normal, and
b. Total lung capacity (TLC)  70% of predicted normal RU)9&SUHGLFWHGLI
TLC is not available; For subjects with CTD asVRFLDWHG3$+LI7/&LVRI
predicted but < 70% of predicted of LI)9&RUSUHGLFWHGEXWRI
predicted, high resolution computed tomography [HRCT] obtained within 6 
months of screening may be utilized to demonstrate limited interstitial lung
disease
9. If participating in an exercise program for pulmonary rehabilitation, the program must have 
EHHQLQLWLDWHG 12 weeks prior to Screening, and patient must agree to maintain the current 
level of rehabilitation for the first 24 weeks of receiving IP.  If not participating in an 
exercise training program for pulmonary rehabilitation, patient must agree not to enroll in an 
exercise training program for pulmonary rehabilitation during the Screening Period and the 
first 24 weeks of receiving IP.
10. Willing and able to give written informed consent and to comply with the requirements of the 
study for its duration
5.2.
Exclusion Criteria
Patients are excluded from the study if any of the following criteria are met:
1. Women of childbearing potential who are pregnant, planning to become pregnant, or 
lactating or female/male patients unwilling to use effective contraception as defined in 
Section 5.4.1
Medical Conditions
2. WHO pulmonary hypertension (PH) Group 1 PAH associated with portal hypertension or 
schistosomiasis; PH due to left heart disease (WHO PH Group 2), lung diseases and/or 
hypoxia (WHO PH Group 3), chronic thromboembolic PH (WHO PH Group 4), or PH 
with unclear multifactorial mechanisms (WHO PH Group 5)
3. PH associated with significant venous or capillary involvement (PCWP > 15 mmHg), 
pulmonary capillary hemangiomatosis, portal hypertension, or unrepaired congenital 
heart defects (CHD)
4. Three or more of the following risk factors for left ventricular disease:
a.
BMI > 30 kg/m2
b. Diagnosis of essential hypertension that is actively treated
c.
Diabetes mellitus
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d. History of significant coronary artery disease (e.g., chronic stable angina, history 
of coronary intervention within the last 3 months, or a stenosis > 70% at coronary 
angiography)
e.
Atrial fibrillation
f.
Left atrial volume index > 41 mL/m2 [or left atrial diameter (LA) > 4 cm if LAVi
unavailable]
5. Known genetic hypertrophic cardiomyopathy
6. Known cardiac sarcoidosis or amyloidosis
7. The patient has a history of, or currently has, a constrictive cardiomyopathy.
8. Known history of any left ventricular ejection fraction (LVEF) < 40% by echocardiogram 
within 3 years of randomization (Note: a transient decline in LVEF below 40% that 
occurred and recovered more than 6 months before the start of Screening and was 
associated with an acute intercurrent condition [e.g., atrial fibrillation] is allowed).
9. Hemodynamically significant valvular heart disease as determined by the Investigator, 
including:
a.
greater than mild aortic and/or mitral stenosis and/or
b. severe mitral and/or aortic regurgitation (> Grade 3)
10. Severe arthritis, musculoskeletal problems, or morbid obesity that, in the opinion of the 
Investigator, is the cause of the patient’s functional limitation and would affect the 
patient’s ability to perform or complete the 6MWT.
11. Planned major surgery within the next 3 months, including lung transplantation, major 
abdominal or major intestinal surgery
12. End stage renal disease defined as receiving peritoneal dialysis, hemodialysis, or status 
after renal transplantation, or severe liver disease defined as Child-Pugh Class C, with or 
without cirrhosis
13. Known congenital LQTS or known family history of LQTS
14. 'HSUHVVLRQWKDWLVFXUUHQWO\UDWHGDVVHYHUHGHILQHGDVDVFRUHRI 16 on the QIDS-C
and/or [HADS] Depression and/or Anxiety score  15), recent suicidal behavior (either 
preparatory acts/behavior, aborted attempt, interrupted attempt, or actual attempt in the 
past 3 months per the Screening C-SSRS), or active suicidal ideation with intent to act 
(defined as C-SSRS category score of 4 or 5 in the past month)
15. Patients with (during Screening):
a.
Severe hypertension (SBP > 180 mmHg and/or Diastolic Blood Pressure [DBP] 
> 110 mmHg), and patients with severe hypotension (SBP < 90 mmHg and/or 
DBP < 50 mmHg)
b. Hypertension or hypotension considered not controlled in line with clinical 
standards
16. Clinically significant electrolyte abnormality (e.g., hypokalemia, hypomagnesemia, or 
hypocalcemia) in the judgement of the Investigator
17. Current or prior history within the last 5 years of neoplasm (except for treated basal cell 
or squamous small cell carcinoma of the skin with no evidence of recurrence) 
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18. Any concurrent clinically significant medical condition/disorder which in the 
Investigator’s opinion would interfere with the patient’s ability to comply with or 
complete the study or could affect the interpretation of the efficacy and safety variables.
Prior/Concomitant Therapy
19. Use of any of the following medications or supplements within 30 days prior to 
Screening:
x
monoamine oxidase inhibitors (MAOIs; Appendix 1)
x
5-hydroxytryptophan (5-HTP) or L-tryptophan 
x
telotristat ethyl
20. Patients currently taking one or more drugs known to prolong the QT interval and which 
are clearly associated with a known risk of Torsades de Pointe (see Appendix 1)
Diagnostic Assessments
21. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 at Screening
22. 12-Lead ECG results at Screening demonstrating QTcF interval > 450 ms for males or 
> 470 ms for females 
23. Elevated ALT, AST, or TBL > 2X ULN
24. Any ECG or clinical laboratory abnormality which precludes safe participation in the 
study in the opinion of the Investigator
Lifestyle
25. History of active substance use disorder (including alcohol) within the past 2 years 
which, in the option of the Investigator, would limit the ability of the patient to provide 
adequate informed consent or to comply with study requirements
26. Use of any investigational drug within 30 days or 5 half-lives (whichever is longer) prior 
to Screening, or 90 days if an investigational drug for PAH, unless local health authority 
guidelines mandate a longer period, or in consultation with the medical monitor, will not
interfere with the safety or efficacy of the study
27. Any history of hypersensitivity to rodatristat ethyl, any of its components, or any 
components in the placebo preparation (refer to current Rodatristat Ethyl IB).
28. Patient is deprived of their liberty by a judicial or administrative decision, or is receiving 
psychiatric care, and is admitted to a health or social institution
29. Patient is subject to legal protection or is unable to express consent
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5.3.
Other Eligibility Criteria Considerations
To determine patient eligibility at Screening, a single repeat of certain tests such as laboratory 
values, vital signs, or ECGs will be allowed.
To assess any potential impact on patient eligibility with regard to safety, the Investigator must 
refer to the rodatristat ethyl Investigator’s Brochure for detailed information regarding warnings, 
precautions, contraindications, AEs, and other significant data pertaining to the IP being used in 
this study.
5.4.
Lifestyle Considerations
5.4.1.
Contraception
Female patients of childbearing potential who have a negative serum pregnancy test at Screening 
and a negative urine pregnancy test at the randomization visit must agree to use 
protocol-specified, highly effective contraception starting at Screening and for the duration of the 
study and for at least 4 weeks following the last dose of IP as follows:
x
Use 2 methods of contraception in combination defined as a condom plus an 
approved method of effective contraception from the following list from the time of 
informed consent:

Combined (estrogen and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: oral, intravaginal, transdermal

Progestogen-only hormonal contraception: oral, injectable/implantable, 
intrauterine hormone-releasing system

Implantable intrauterine device

Bilateral tubal ligation performed less than 6 months prior to randomization

Partner with vasectomy

Sexual abstinence – (refraining from heterosexual intercourse). If study patient 
chooses this option, site staff must follow-up to reconfirm throughout the study.  
If patient becomes sexually active, one of the above choices must be utilized and 
documented.
Female patients who are considered to have no childbearing potential (surgically sterile defined 
as bilateral tubal ligation, hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) for 
at least 6 months prior to randomization may participate and are not required to use 
contraception as defined above.
Female patients who are postmenopausal and > 45 years of age with amenorrhea for at least 
2 years may participate and are not required to use contraception as defined above.
Postmenopausal women with amenorrhea for less than 2 years must have documented follicle 
stimulating hormone (FSH) levels > 35 IU/mL and negative pregnancy test at the Screening 
Visit.
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Male patients must agree to the following:
x
Not to try to impregnate his partner from the Screening Visit until at least 100 days 
after the last dose of IP
x
If his female partner is of childbearing potential, agree to use 2 methods of 
contraception in combination defined as a condom plus an approved method of 
effective contraception from the following list from the time of informed consent 
until at least 100 days after the last dose of IP:

Combined (estrogen and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: oral, intravaginal, transdermal

Progestogen-only hormonal contraception: oral, injectable/implantable, 
intrauterine hormone-releasing system

Implantable intrauterine device

Bilateral tubal ligation performed less than 6 months prior to randomization

Vasectomy

Sexual abstinence – (refraining from heterosexual intercourse). If study patient 
chooses this option, site staff must follow-up to reconfirm throughout the study.  
If patient becomes sexually active, one of the above choices must be utilized and 
documented.
x
Use condoms with partners that are pregnant until at least 100 days after the last dose 
of IP to ensure that the fetus is not exposed to the IP
x
Not donate sperm for the duration of the study until at least 100 days after the last 
dose of IP
5.4.2.
Meals and Dietary Restrictions
5.4.2.1.
Tryptophan-Rich Foods
As tryptophan-rich foods may increase 5-HT levels and interfere with biomarker assessments, 
patients will be asked to abstain from the following foods for 48 hours before study visits on
Day 1 and at Weeks 4, 12, and 24:
x
Avocado
x
Bananas
x
Eggplant
x
Kiwi fruit
x
Tree nuts, tree nut butters and tree nut products (e.g., hickory nuts, pecans, walnuts)
x
Pineapple
x
Plums
x
Tomato and tomato products
5.4.2.2.
Food Requirements
IP should be taken with food (at least a snack) at the morning and evening meals.
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5.5.
Screen Failures
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomized into the study. After obtaining informed consent, study site personnel 
will enter the patient into the Interactive Response Technology (IRT), and the patient will be 
assigned a unique patient number. The IRT should be updated promptly for patients who do not 
meet the criteria for participation in the study (screen failure) and reason.
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure patients to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing
requirements and to respond to queries from regulatory authorities. Minimal information is to be 
entered into the Electronic Data Capture (EDC), including demography, screen failure details, 
eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened on a case-by-case basis. Approval from the Sponsor must be obtained prior to 
rescreening.
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6.
INVESTIGATIONAL PRODUCT
IP is defined as any investigational medicinal product (IMP) or placebo, intended to be
administered to a study patient according to the study protocol.
6.1.
Description of IP
The IPs to be administered as part of this study are described in Table 3.
Table 3:
Investigational Products
Arm Name
300 mg BID*
600 mg BID*
Placebo*
Dose Formulation
Tablet
Tablet
Tablet
Unit Dose Strength(s)
300 mg 
300 mg
N/A
Dosage Level(s)
1 x 300 mg tablet + 1 x 
placebo tablet BID
2 x 300 mg tablets BID
2 x placebo tablets BID
Route of Administration
Oral
Oral
Oral
IP 
Rodatristat ethyl
Rodatristat ethyl
Placebo
Physical Description
White to off-white modified oval shaped tablet, debossed with “2E8” on one side
Manufacturer
Patheon Pharmaceuticals
2100 Syntex Court
Mississauga, Ontario L5N 7K9
Canada
Packaging and Labeling
IP will be provided in bottles.  Each bottle will be labeled as required per country 
requirement.
*The components in rodatristat ethyl are provided in Section 3.2.2, Table 1 of the Investigator’s Brochure. The 
active and placebo are formulated with the same excipients.
Abbreviations:  BID = twice daily; IP = investigational product; N/A = not applicable
6.2.
Dose Regimen
IP will be taken BID with food, approximately 12 hours apart.
Each patient will receive at least 4 bottles (1 kit) of IP at each clinic visit or by mail.  There is 
enough IP in each kit for 4 weeks of dosing, including overage.  The bottles of IP given at each 
clinic visit or by mail should be returned at the subsequent clinic visit for reconciliation and 
accountability.
The last dose of IP for the Main part of the study will be the last dose the night before the Week 
24 visit (all Week 24 assessments will be collected post last dose).
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6.3.
Preparation/Handling/Storage/Accountability
The Investigator or designee must maintain accurate records of receipt and the condition of the 
IP supplied for this study including dates of receipt.  They must confirm appropriate temperature 
conditions have been maintained during transit for all IP received and any discrepancies are 
reported and resolved before use of the IP.
2. Only patients enrolled in the study may receive IP. Accurate records must be kept of 
when and how much IP is dispensed and administered to each patient in the study.  Any 
reason for departure from the instructions provided in the protocol for dispensing of IP 
must also be recorded.  IP may be supplied at the site, from the site to the patient via a 
Sponsor-approved courier company, or from the depot directly to the patient where 
allowed by local regulations and approved by the patient.
3. All IP at a study site must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage conditions 
with access limited to the Investigator and authorized site staff.
4. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IP accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).
5. Further guidance and information for the final disposition of unused IP are provided in 
the Study Reference Manual.
6. A Safety Data Sheet (SDS) describing occupational hazards and recommended handling 
precautions will be supplied to the Investigator.
6.3.1.
Investigational Product Packaging and Labeling
IP will be packaged in an appropriately sized bottle and labeled per local regulations.
6.3.2.
Investigational Product Storage
IP is to be stored at 15°C to 25°C (59°F to 77°F) in a dry place and protected from light.
6.3.3.
Investigational Product Administration
Once a patient is confirmed as eligible for study participation, the patient will be randomized via 
the IRT and assigned a kit(s) of IP. For each scheduled visit, the patient will be assigned new IP
kit(s).
6.3.4.
Investigational Product Accountability
Accountability for the IP is the responsibility of the Investigator.  The study site must maintain 
accurate records including what kits were received and date, to whom the IP was dispensed, and 
all accounts of IP that is lost/missing or discarded.  Additional details will be provided in a 
pharmacy or study reference manual.
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6.3.5.
Investigational Product Handling and Disposal
Patients should return all IP (including empty, partial, and full bottles) at their regularly 
scheduled clinic visits.  Reconciliation of all IP that was dispensed, returned, or lost must be 
accounted for with documentation for any IP that was lost or missing.
Returned IP may be re-issued if the patient is continuing in the study, returned to the drug depot,
or destroyed at the site as long as the site has procedures in place for IP destruction where
allowed by local regulations. Otherwise, all returned IP will be returned to the depot at 
increments throughout the study after all IP has been accounted for and verified by the monitor.
Additional instructions for IP return and destruction will be found in the pharmacy or study 
reference manual.
6.4.
Measures to Minimize Bias: Randomization and Blinding
This is a double-blind study. The Sponsor, Investigator, patient, and study site personnel will be 
blinded to all treatment group assignments. The Investigator will have the ability, in the IRT 
system, to unblind a patient, and the decision will reside solely with the Investigator. Prior to 
unblinding, if safety allows, the Investigator should contact the Medical Monitor to discuss the 
reasons for unblinding.
Eligible patients will be stratified during the randomization process based on the number of 
background PAH therapies they are receiving (1, 2 or 3) and selexipag use. The number of 
patients who are receiving a prostanoid infusion will be capped at 50% of the total number of 
patients enrolled. The number of patients who are receiving selexipag will be capped at 20% of 
the total number of patients enrolled. Patients will be randomized 1:1:1 to placebo, 300 mg BID, 
or 600 mg BID of rodatristat ethyl using an interactive randomization system.
At the time of Screening for entry into the OLE, all patients will be re-randomized to receive 
either 300 mg BID or 600 mg BID rodatristat ethyl in an open-label fashion.  Patients will not 
know what they received in the Main Study until all patients have completed the Main Study and 
the database is locked.
At the time of randomization, in the Main Study, patients will be assigned a randomization 
number.  Once this number has been assigned, it cannot be reused/reassigned.
At the time of re-randomization in the OLE, patients will be assigned a new randomization 
number.  Once this number has been assigned, it cannot be reused/reassigned.
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Blind Break 
(IVRS/IWRS)
The Interactive Voice Response System (IVRS)/Interactive Web Response System (IWRS)
will be programmed with blind-breaking instructions.  Only in case of an emergency, when 
knowledge of the IP is essential for the clinical management or welfare of a specific patient, 
may the Investigator unblind a patient’s treatment assignment in IVRS/IWRS.  The 
Investigator has the sole responsibility for determining if unblinding of a patient’s treatment 
assignment is warranted.  Patient safety must always be the first consideration in making 
such a determination.  If the Investigator decides that unblinding is warranted, the 
Investigator should make every effort to contact the Sponsor prior to unblinding a patient’s 
treatment assignment unless this could delay emergency treatment of the patient.  If a 
patient’s treatment assignment is unblinded, the Sponsor must be notified within 24 hours 
after breaking the blind without revealing the patient’s study treatment assignment (unless 
important to the safety of patients in the study) and that the Investigator was unable to 
contact the Sponsor prior to unblinding.  The date and reason that the blind was broken must 
be recorded in the source documentation and electronic case report form (eCRF), as 
applicable.
6.5.
Investigational Product Compliance
Patient compliance with IP will be assessed at each visit by the site/study staff. Compliance will 
be assessed by direct questioning of the patient and counting returned tablets at each study visit 
to the study site.  Patients will be reminded of the importance of taking their IP as directed at 
each visit including the Weeks 2 and 8 Phone Calls. Patients will be required to bring their IP
supplies with them to each study visit to the study site so that a member of the study staff can 
check that the doses of IP were taken as directed.
Full compliance with the IP regimen, per subject, will be considered to be >80%.
Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF.
6.6.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins,
and/or herbal supplements) that the patient received in the 8 weeks prior to enrollment, is 
receiving at the time of enrollment, or receives during the study must be recorded along with:
x
Reason for use
x
Dates of administration including start and end dates
x
Dosage information including dose and frequency
New and existing concomitant therapy(ies) may be considered on a case-by-case basis by the 
Investigator for treatment of a medical need. Any concomitant medication should be recorded in 
the study records, including doses administered, the dates and times of administration and the 
reason for administration.
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. (Note: Vaccines, including potential Covid-19 vaccines, are allowed but must be 
documented in the eCRF). 
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6.6.1.
Rodatristat-Drug Interaction Potential
In vitro experiments and in silico modeling to evaluate the drug-drug interaction potential of 
rodatristat ethyl and rodatristat have not identified any moderate or high risks for potential 
drug-drug interactions (IB, 2020).  There is the potential for weak interactions with substrates of 
the drug metabolizing enzymes cytochrome P450 (CYP)2C8 and CYP3A, and drug transporters 
P-glycoprotein (P-gp) or organic anion-transporting polypeptide (OATP). 
Selexipag, and active metabolite ACT-333679, are substrates of CYP2C8 and preliminary data 
from a selexipag-rodatristat clinical interaction study in healthy subjects are available.  In that 
study, steady-state rodatristat ethyl 600 mg BID coadministered with single-dose selexipag 
400 μg increased selexipag AUC 1.18-fold and reduced ACT-333679 AUC by 40.5%.  These 
data suggest induction of CYP2C8 by rodatristat ethyl/rodatristat. The magnitude of this 
interaction in PAH patients, and the clinical relevance of these changes in exposure are 
unknown.  PK samples for assessment of selexipag and ACT-333679 trough concentration at 
baseline and Week 4, in addition to safety and efficacy data, will be collected in this study to
further investigate this finding.  In the same study, a single-dose of selexipag 400 μg had no 
relevant impact on the exposure of rodatristat ethyl or rodatristat.  
Preliminary safety data from the study show a total of 33 TEAEs in 8 subjects during the study.  
There were no SAEs or deaths. Gastrointestinal (GI) TEAEs were the most frequently reported 
TEAEs over all three periods with 25 GI TEAEs occurring in 6 subjects. All TEAEs were mild 
to moderate with the exception of one TEAE in one subject of serious diarrhea on Day 6. This 
same subject was the only subject discontinued from the study.  This subject was discontinued by 
the Investigator due to prolonged GI TEAEs (nausea, vomiting, stomachache, diarrhea) during 
the rodatristat ethyl alone dosing period (Days 5-9).   Nausea was the only TEAE reported in 2 or 
more subjects when selexipag was given alone. Diarrhea, headache, nausea and stomachache 
ZHUHUHSRUWHGLQVXEMHFWVDt approximately the same frequency during both rodatristat ethyl 
alone period and the selexipag and rodatristat ethyl coadministration period.  There were no 
changes in laboratory parameters, vital signs, or ECGs of clinical significance.
No concomitant medications based on these in vitro and clinical findings are prohibited.   
The following information is provided as guidance for the Investigator:
x
Patients using systemic narrow therapeutic range substrates of CYP2C8, CYP3A and 
P-gp should be monitored during coadministration with IP.  See Appendix 1 for a list 
of relevant substrates, for example:
o
Narrow therapeutic range CYP2C8 substrates (induction of CYP2C8 is 
possible): selexipag, trepostinil, pioglitazone, and torasemide.
o
Narrow therapeutic range CYP3A substrates (weak induction or inhibition of 
CYP3A is possible): cyclosporine, everolimus, fentanyl, sirolimus, and 
tacrolimus;
o
Narrow therapeutic range P-gp substrates:  digoxin, monitor serum levels 
approximately 2 weeks after initiation of IP or if patient reports any signs of 
toxicity; 
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x
Rodatristat was also identified as a substrate of liver uptake transporters 
OATP1B1/1B3.  Strong inhibitors of OATP1B1/1B3 may increase circulating 
concentrations of rodatristat and may increase adverse effects. Putative strong 
inhibitors of OATP1B1/1B3 are systemic atanazavir/ritonavir, clarithromycin, 
cyclosporine, erythromycin, faldaprevir, gemfibrozil, glecaprevir/pibrebtasvir, 
lopinavir/ritonavir, rifampin, sofosbuvir/velpatasvir/voxilaprevir, and telaprevir. 
Note: Hydroxymethylglutaryl-CoA reductase inhibitors or ‘statins’ also transported 
by OATP are not considered strong inhibitors of OATP.
6.6.2.
Pulmonary Arterial Hypertension Medications
The target population of patients with PAH will be receiving SOC treatment which can consist of 
monotherapy, dual, or triple combination therapy that have been taken for at least 12 weeks prior 
to the Screening RHC.  These medications should be prescribed at doses considered 
therapeutically appropriate (e.g., maximum tolerated) and stable (i.e., no changes in dose or 
schedule) for at least 8 weeks prior to this RHC. Any instances where doses have been missed 
for > 2 consecutive days on more than one occasion or other regular lapses in compliance during 
this 8-week period prior to RHC must be discussed with the Medical Monitor prior to performing 
the RHC.  Changes to these PAH medications must not be anticipated for the duration of the 
study.
No increases in background oral PAH doses or addition of a new PAH medication(s) will be 
allowed. Decreases in background oral PAH therapy dosing should only be considered in the 
event of suspected IP-related adverse effects. The Medical Monitor should be notified of any 
change to background PAH therapy.
Permissible oral, inhaled, and injectable PAH medications include:
x
Tadalafil
x
Sildenafil
x
Ambrisentan
x
Macitentan
x
Bosentan
x
Riociguat
x
Prostanoids
x
Prostacyclin receptor agonists (e.g., selexipag)
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6.6.3.
Prohibited Medications and Supplements
The following drugs are prohibited: 
x
Drugs which are known to prolong QT and which are also clearly associated with a 
known risk for Torsades de Pointe (per www.CredibleMeds.org (Woosley, 2019), 
Refer to Appendix 1).
x
MAOIs
x
Telotristat ethyl 
x
5-HTP or L-tryptophan supplements   
x
Investigational drugs (other than rodatristat ethyl) 
Refer to Appendix 1 for a complete list of concomitant medications that are prohibited in this 
study. 
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7.
INTERVENTION AFTER THE END OF THE STUDY –
OPEN-LABEL EXTENSION
7.1.
Rationale for the Open-Label Extension
The purpose of the OLE is to provide continuous, uninterrupted access to rodatristat ethyl for
patients who participated in the main part of this study if the patient appears to benefit from the 
therapy (as determined by Investigator and patient).  The OLE will also provide active IP to 
patients who received placebo in the Main Study. 
7.2.
Objective
x
To evaluate the long-term safety, tolerability, and efficacy of rodatristat ethyl in 
patients with PAH
7.3.
Endpoints
7.3.1.
Safety endpoints
x
The proportion of patients who discontinue rodatristat ethyl due to an AE
x
The proportion of patients with SAEs
x
The proportion of patients with AEs
x
The proportion of patients with treatment-emergent Grade 3 or 4 AEs
x
The proportion of patients with treatment-emergent Grade 3 or 4 laboratory 
abnormalities
7.3.2.
Efficacy endpoints
x
Change in PVR
x
Change in cardiac index, mPAP, mRAP, SvO2 at rest and PAC from baseline 
x
Time to Clinical Worsening
x
Death from any cause
x
Change in WHO FC from baseline
x
Change in 6MWD from baseline 
x
Change in NT-proBNP from baseline
x
Changes in right atrial size and RV function: TAPSE, tricuspid annular systolic 
velocity, and RV fractional area change from baseline
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7.4.
Open-Label Extension Design
Patients in the Main Study that do not discontinue prematurely and complete up to and including 
the Week 24 Visit, have the option to rollover into the OLE. Patients who continue into the OLE 
will be blinded to the treatment they received in the Main Study.  Patients who received active IP 
in the Main Study will remain on their regimen. Patients randomized to placebo in the Main
Study will be re-randomized to one of the 2 active rodatristat ethyl treatment arms (300 mg BID
or 600 mg BID) in the OLE.
Patients who participate in the OLE will continue to receive rodatristat ethyl for 6.5 years, until 
the Investigator or patient chooses to stop the IP, any stopping criteria in the Main Study are met, 
IP becomes commercially available, or the Sponsor stops the study for lack of efficacy or a 
safety signal (whichever preceding criteria comes first). In no case will a patient be allowed to 
exceed 10 years of exposure unless the product is approved for a chronic indication.
During the OLE patients will be followed by the Investigator according to clinical practice, with 
formal (per protocol) safety assessments. These safety assessments will include AEs, clinical 
laboratory tests, vital signs, and concomitant medications. Female patients of childbearing 
potential will be required to use 2 reliable methods of contraception to reduce the risk of 
pregnancy during the course of the study and for at least 30 days following the last dose of 
rodatristat ethyl.
During the first 24 weeks of the OLE patients, will also undergo efficacy assessments.  These 
efficacy assessments will include 6MWT, RHC, echocardiogram, WHO FC, and plasma 
NT-proBNP level. Urine pregnancy tests will be performed every 4 weeks in women of child-
bearing potential only, while the patient is on IP and once at 4 weeks post dose.  If there is not a 
clinic visit, a urine pregnancy test will be sent home with the patient and results will be followed 
up with a phone call. Additional pregnancy testing in women whose menstruation is delayed or 
who have infrequent or irregular menstrual cycles should be conducted as warranted.
See SoA in Section 1.4 and Section 1.5.
7.5.
Number of Patients and Inclusion/Exclusion Criteria
The maximum number of patients enrolled into the OLE will be the number of patients who 
complete the Main Study (Week 24).
7.6.
Inclusion Criteria
1. Patient must have completed study assessments and procedures up to and including 
Week 24 in the Main Study.
2. Female patients of childbearing potential must have a negative serum or urine pregnancy 
test at the Week 24 visit and must agree to use contraception as detailed in Section 5.4.1
for at least 4 weeks after the last dose of IP. A female patient of childbearing potential is 
defined in Appendix 4.
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3. Male patients are eligible to participate if they do not have a female partner who is 
pregnant or who intends to become pregnant during the OLE. Male patients and female 
partners must agree to use contraception as detailed in Section 5.4.1 of the protocol 
starting 4 weeks prior to the first dose of IP, during the treatment period, and for at least 
100 days after the last dose of IP. Male patients must refrain from donating sperm during 
this period.
4. Patient must agree not to participate in a clinical study involving another investigational 
drug or device for PH/PAH while in the OLE (does not include registry or observational 
studies).
5. Patient must be competent to understand the information given in the IRB- or 
Independent Ethics Committee (IEC)-approved Informed Consent Form (ICF) and must 
sign the form prior to the initiation of any OLE procedures.
7.7.
Exclusion Criteria
1. Patients who have demonstrated noncompliance with study visits or IP in the Main Study.
2. Planned major surgery within the next 3 months, including lung transplantation, major 
abdominal or major intestinal surgery. 
3. New major thrombo-embolic events developed after completion of the Main Study.
4. Time period > 8 weeks between Week 24 of the Main Study and start of treatment in the 
OLE.
5. A disease or condition which in the opinion of Investigator may put the patient at risk 
because of participation or limit the patients' ability to participate.
6. Alcohol or drug abuse that in the opinion of the Investigator would interfere with 
participation.
7.8.
Open-Label Extension Procedures
All assessments in the OLE will be performed as explained in the Main Study.  SoA for the OLE
are in Section 1.4 and Section 1.5.
Patients rolling into the OLE will complete the Screening/Enrollment Visit after their final visit 
in the Main Study (Week 24). All procedures for Week 24 will be completed including the 
following for the OLE:
x
Obtain informed consent
x
Review inclusion/exclusion criteria
x
Complete re-randomization procedures for all patients
x
Dispense IP and instruct patient to return all used and unused IP containers at next 
clinic visit
x
Instruct Patient to call the clinic or return promptly should an AE occur.
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7.9.
Open-Label Extension Treatment Assignment
At the Screening/Enrollment Visit of the OLE, eligible patients who received placebo during the 
main study will be randomly allocated (1:1) to one of the following 2 treatment groups:
Treatment Arm 
Name
Treatment Description
Rodatristat ethyl
300 mg BID
1 x 300 mg tablet BID
Rodatristat ethyl
600 mg BID
2 x 300 mg tablets BID
Abbreviation:  BID = twice daily
Patients who received active IP while in the Main Study may remain on the same active dose in 
the OLE or may be provided with a new dose of IP to receive either 300 mg BID or 600 mg BID 
depending on the timing and outcome of the 24-Week analysis from the Main Study.
Tolerability and all accumulated safety and efficacy data will be reviewed by the Independent 
Data Monitoring Committee (IDMC).
IP will be supplied without placebo. The first dose of IP in the OLE will be considered the first 
dose after all Week 24 assessments in the Main Study are completed and all entry criteria met.
7.10.
Investigational Product Preparation, Handling, Storage, and 
Accountability 
All IP preparation, handling, storage, and accountability will be the same as in the Main Study as 
in Section 6.
7.11.
Dose Adjustment Criteria
Dose adjustment criteria are the same as the Main Study and can be found in Section 6.
7.12.
Criteria for Investigational Product/Study Termination
All criteria for IP and study termination are the same as in the Main Study and can be found in 
Section 8.
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8.
DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND
PATIENT DISCONTINUATION/WITHDRAWAL
Unnecessary withdrawal of patients should be avoided, and all efforts should be made to retain 
patients in the study.
8.1.
Discontinuation of Investigational Product
The Medical Monitor should be notified of any change to background PAH therapy to determine 
any need for withdrawal. See Section 8.2 for study withdrawal procedures.
Patients meeting any of the following liver chemistry criteria must be withdrawn (IP should be 
discontinued immediately) from the study by the Investigator:
x
ALT or AST > 3X ULN and TBL > 1.5X ULN or INR > 1.5
x
ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%)
x
ALT or AST > 5X ULN for more than 2 weeks
x
ALT or AST >8X ULN
If liver chemistry tests meet any of the above criteria, repeat testing should be performed within 
48 to 72 hours and the patient followed until resolution.
Patients meeting any of the following confirmed QT/QTc-related criteria must be withdrawn 
from the study by the Investigator:
x
QTcF interval > 500 ms
x
QTcF interval > 480 ms AND increase from BDVHOLQH 60 ms
x
QTcF interval > 480 ms associated with syncope, life-threatening arrhythmias, 
resuscitated cardiac arrest, or seizure
The Investigator must also discontinue/withdraw a patient’s participation in the study if any of 
the following criteria apply:
x
Pregnancy
x
Significant protocol violation/lack of compliance with the study and/or study 
procedures - non-compliance with IP for discontinuation of patient is defined as 
< 50%.
x
Severe constipation (e.g., obstipation with manual evacuation indicated) and/or 
severe, persistent, or worsening abdominal pain
x
Any significant worsening on postdose C-SSRS indicative of active suicidal ideation 
with intent to act (defined as C-SSRS Suicidal Ideation category score of 4 or 5) or 
behavior (either preparatory acts/behavior, aborted attempt, interrupted attempt, or 
actual attempt)
x
6HYHUHGHSUHVVLRQRUDQ[LHW\EDVHGRQD+$'6'HSUHVVLRQRU$Q[LHW\VFRUH 15, or 
a QIDS-&7RWDO6FRUH 16.
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x
Any severe psychiatric or CNS AE as determined by the Investigator.
The Investigator may discontinue/withdraw a study patient’s participation in the study if any of 
the following criteria apply:
x
Behavioral or administrative reason
Any clinical AE, laboratory abnormality, or other medical condition or situation occurs such that 
continued participation in the study would not be in the best interest of the patient. When
applicable, patients should be informed of circumstances under which their participation may be 
terminated by the Investigator without their consent.
8.1.1.
Temporary Discontinuation
Temporary discontinuation of IP of up to 7 days will be allowed for extenuating circumstances
or to manage AEs.
8.2.
Patient Discontinuation/Withdrawal from the Study
Patients may withdraw from the study at any time at his/her own request or may be withdrawn at 
any time at the discretion of the Investigator for safety, behavioral, compliance, or administrative 
reasons.  This is expected to be uncommon.
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent.
Replacement patients may be enrolled in consultation with the Sponsor’s Medical Monitor.
8.2.1.
Investigational Product Discontinuation
If a patient is permanently discontinued from the IP, but agrees to study visits, the patient will 
come in for the Early Termination Visit and continue attending clinic visits as scheduled through 
the 24-week visit (from first dose). A final follow-up visit will not be required.
If a patient prematurely discontinues IP prior to the Week 24 Visit, the Investigator will make 
every attempt to perform a RHC, as clinically feasible, prior to or within 7 days of IP
discontinuation (but after at least 12 weeks of IP), and prior to initiation of any new PAH 
medications.
8.2.2.
Study Discontinuation
If a patient who discontinues IP decides to end all study participation, an Early Termination Visit
should be conducted, as shown in the SoA (Section 1.3), if possible. 
Patients who withdraw should be asked if they may be contacted by the study site by telephone 
unless they explicitly withdraw their consent to be followed up.
If a patient withdraws consent, he/she may request destruction of any samples taken and not 
tested, and the investigator must document this in the site study records.
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8.3.
Lost to Follow up
A patient will be considered lost to follow up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit:
x
The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in 
the study.
x
Before a patient is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and,
if necessary, a certified letter to the patient’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the patient’s 
medical record.
x
Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
x
Patients who withdraw consent will continue to be followed for vital status from 
public records such as government vital statistics or obituaries, as allowed by local 
law, or periodic contact (about every 6 to 12 months).
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 5.
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9.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA in Section 1.3 for the Main Study
and in Section 1.4 and Section 1.5 for the OLE.
Safety concerns should be discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the patient should continue or discontinue IP.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential patients
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as applicable.
Once all screening procedures are complete and the Investigator determines that the patient is 
eligible, the site must upload/send the required supporting documentation for approval by the
Sponsor. The required information will include the RHC report (including tracings), PFTs 
obtained (may use PFTs completed in the 24 week period prior to screening or obtained at 
Screening), the screening echocardiogram, as well as specific information about the patient’s 
medical history and disease state to further ensure the appropriateness of each patient being 
enrolled into this study. Approval from the Sponsor must be obtained prior to randomization.
All assessments should be completed predose unless otherwise stated.
If assessments are scheduled for the same nominal time, then the assessments should occur in the 
following order whenever possible: ECGs, vital signs, safety blood draws, PK blood draws.
Note: The timing of the assessments should allow the blood draw to occur as close as possible 
to the nominal time but before dosing.
Repeat or unscheduled samples may be taken for safety reasons or due to technical issues with 
the initial samples.
9.1.
Efficacy Assessments
The efficacy-related assessments, as outlined below, will be obtained at time points indicated in 
the SoA in Section 1.3 and Section 1.4.
9.1.1.
Right Heart Catheterization
The RHC is a common procedure used to diagnose PAH.
Cardiopulmonary hemodynamics will be assessed by RHC. All required RHC parameters must 
be collected using the same methods at Screening/Randomization and Week 24. The 
Screening/Randomization RHC will be required to confirm the diagnosis of PAH, and data from 
this RHC will serve as the baseline value for the primary and secondary analyses of 
cardiopulmonary hemodynamic parameters. Since the study is enrolling treatment-experienced 
patients, results from a historical RHC conducted prior to the Screening Visit are not expected to 
reflect the patient’s current disease status unless it was performed within 4 weeks of the 
Screening visit, includes all required information, and provided that changes to the patient’s 
PAH regimen were not made subsequent to that catheterization.
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If prior approval is obtained from the Sponsor, the screening RHC may be performed on the 
same day as the randomization procedures, provided that all blood draws and efficacy 
assessments are conducted prior to the RHC procedure, and the RHC is performed prior to 
randomization and IP dosing. The hemodynamic assessment will be conducted in the supine 
position under resting conditions. The original RHC tracings will be maintained at the site. The 
RHC tracings will have all personal health information removed and will be labeled with the 
following: patient number, patient initials, protocol number, and date recorded. 
Full details available in RHC manual.
9.1.2.
Time to Clinical Improvement
TTCI will be evaluated by a multicomponent improvement score including WHO FC and 
6MWT measurements: a > 10% increase in 6MWD or 30 meters AND an improvement to or 
maintenance of WHO FC II symptomatology, in the absence of a deterioration in clinical 
condition or death during the 24 weeks of the Main Study.
9.1.3.
Time to Clinical Worsening
TTCW is defined as the first occurrence of a composite end point of: 1. Death from any cause, 
2. Hospitalization for worsening PAH (any hospitalization for worsening PAH, lung or heart and 
lung transplantation, atrial septostomy, or initiation of parenteral prostanoid therapy), 3. Disease 
progression defined as a decrease of more than 15% from baseline in the 6MWD combined with 
WHO FC III or IV symptoms at 2 consecutive visits separated by at least 14 days (adjudicated).
9.1.4.
Six-Minute Walk Test/Six-Minute Walk Distance
The 6MWT is a simple, commonly used, standardized measure of functional exercise capacity 
and endurance. It is a commonly used measure of efficacy in PAH clinical studies. The change 
from baseline in 6MWD following intervention indicates symptomatic improvement over that 
time-period. Improvement in 6MWD has been correlated with improvements in quality of life.
Refer to Appendix 6.
9.1.5.
Echocardiography
Patients will undergo resting cardiac echocardiography at specified visits. Echocardiographic 
endpoints will include right atrial size and measures of RV function (TAPSE, tricuspid annular 
systolic velocity, and RV fractional area change). There will be a core imaging laboratory for 
centralized blinded adjudication of the echocardiographic endpoints.
Full details available in echocardiograph manual.
9.1.6.
Pulmonary Function Tests (PFTs)
PFTs (performed with or without bronchodilation) should be completed at Screening if there are 
no historical results from tests completed within 24 weeks prior to Screening.
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9.1.7.
World Health Organization Functional Class
PAH functional disease severity is classified according to WHO FC.  Patients are classified into 
1 of 4 functional classes on the basis of their degree of physical limitation and associated 
symptoms. Refer to Appendix 7 for full description of each Functional Class.
9.1.8.
N-terminal pro-Brain Natriuretic Peptide Level
NT-proBNP is a strong predictor of disease progression and mortality in PAH patients. Current 
PAH treatment guidelines recommend measurement of NT-proBNP levels for both risk 
assessment and longitudinal follow up. NT-proBNP levels are also a good marker of response to 
treatment.
9.1.9.
Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire
The PAH SYMPACT Questionnaire is the first instrument for quantifying PAH symptoms and 
impacts. It is a brief, disease-specific patient-reported outcome (PRO) instrument possessing 
good psychometric properties.
The questionnaire consists of two parts:
x
Day 1 to Day 6: The Questionnaire asks 13 questions regarding the patient’s PAH 
symptoms for the past 24 hours. The patient is required to complete these questions 
each day for Days 1 to 6.
x
Day 7: The Questionnaire asks 12 questions regarding the patient’s PAH symptoms 
for the past 24 hours and an additional 11 questions about the “Impacts” that best 
describes how the patient’s life was affected by PAH.
Prior to departing the study site at the Screening Visit, patients will be instructed and trained on 
how to complete the questionnaire. Patients will start the PAH-SYMPACT questionnaire 6 days 
prior to the visit for which PAH-SYMPACT is collected, with the Day 7 being completed on the 
day of the visit.
An example of the PAH SYMPACT Questionnaire can be found in Appendix 9.
9.1.10.
Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension
Disease Management Lite 2 Risk Assessment Calculator
REVEAL Lite 2 includes 6 non-invasive variables: FC, vital signs (SBP and HR), 6MWD, 
NT-proBNP, and renal insufficiency (by eGFR). REVEAL Lite 2 will be a calculated parameter
(by statistician) at Baseline and Week 24 of the Main Study and Week 24 of the OLE (this 
calculation will not be in the eCRF).
9.1.11.
Actigraphy
Data on physical activity will be collected using a small wrist-worn physical activity tracker
(monitor designed for documenting physical movement) that will transmit all activity through the 
24 weeks of the Main Study.
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9.2.
Safety Assessments
9.2.1.
Pregnancy Testing
Serum pregnancy tests will be obtained for all female patients of childbearing potential at 
Screening and every 4 weeks while on IP. Urine pregnancy tests will be obtained at all 
subsequent visits and must be confirmed negative at the Baseline Visit before randomization and 
IP dispensation. Additional pregnancy tests should be completed anytime menstruation is 
delayed and in women with infrequent or irregular menstrual cycles. A positive urine test will be 
confirmed by a serum test.
Serum pregnancy test and FSH levels will be obtained at the Screening Visit for any 
postmenopausal women with amenorrhea for < 2 years to confirm FSH level (must be
> 35 IU/mL). If FSH value is confirmed as postmenopausal at Screening, no further pregnancy 
tests are required.  If level does not confirm postmenopausal status, urine pregnancy tests will be 
required at all scheduled visits and patients must agree to use an approved method of highly 
effective contraception (refer to Section 5.4.1).
Planned time points for all safety assessments are provided in the SoA (Section 1.3, Section 1.4,
and Section 1.5).
9.2.2.
Physical Examinations
A complete physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal and neurological systems. Height (only at Screening) and weight 
will also be measured and recorded.
Investigators should pay special attention to clinical signs related to previous serious illnesses.
9.2.3.
Vital Signs
Vital signs will be measured after 5 minutes rest and will include temperature, systolic and 
diastolic blood pressure, respiration rate and oxygen saturation.
9.2.4.
Electrocardiograms
Three 12-lead ECGs, one minute apart, will be obtained after at least 5 minutes of rest at
Baseline. Single 12-lead ECGs will be performed at all other time points.
Each ECG performed during the study will be obtained using an ECG machine that 
automatically calculates the HR and measures PR, QRS, QT and QTcF intervals.
The corrected QT interval (QTc) using Fridericia’s formula (QTcF) will be used for each 
individual patient to determine study eligibility and for all on-study ECGs. The QTcF interval 
will be based on the ECG machine’s algorithm.
Clinically significant ECG findings that are present prior to initiation of IP, if not exclusionary, 
must be documented in the Medical History section of the eCRF. Any clinically significant
abnormality that represents a change from baseline will be reported as an AE and followed until 
resolution.
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9.2.5.
Clinical Safety Laboratory Assessments
A central laboratory will be used for clinical safety laboratory assessments. The details for 
sample collection, preparation, and shipping to the central laboratory will be provided in a 
separate lab manual. Reference ranges for all safety parameters will be provided to the site by 
the central laboratory responsible for the assessments.
See the SoA (Section 1.3, Section 1.4, and Section 1.5) for timing and frequency.
Hematology, clinical chemistry, coagulation, urinalysis, and additional parameters to be tested 
are listed below:
9.2.5.1.
Hematology
Hematology Panel
Platelet Count
Red Blood Cell (RBC) Indices:
Automated WBC 
Differential:
RBC Count
Mean Corpuscular Volume 
(MCV)
Neutrophils
White Blood Cell (WBC)
Count (Absolute)
Mean Corpuscular Hemoglobin 
(MCH)
Lymphocytes
Reticulocyte Count
Mean Corpuscular Hemoglobin 
Concentration (MCHC)
Monocytes
Hemoglobin
Eosinophils
Basophils
Hematocrit
9.2.5.2.
Coagulation 
Coagulation Panel
Prothrombin Time (PT)  
INR
Activated Partial Thromboplastin Time (aPTT)
Coagulation testing will be done at Screening, Week 12, and Week 24 for all patients on the 
Main Study and at Weeks 12 and 24 during the OLE in the first 24 weeks and every clinic visit 
post 24 weeks in the OLE. In addition, coagulation will be done at an unscheduled visit if there 
is an ALT result  3X ULN at any study visits. Refer to Appendix 3 .
9.2.5.3.
Clinical Chemistry
Clinical Chemistry Panel
Blood Urea
Nitrogen
Potassium
ALT 
Albumin
Creatinine
Chloride
Gamma-Glutamyl Transferase 
(GGT)
Total Protein
Glucose
Calcium
Alkaline Phosphatase
Urea
Sodium
Bilirubin (Total)
Bilirubin (Direct) (only if Total is 
elevated)
AST 
Bicarbonate
Magnesium
Lipase (reflex if Amylase is 
> 2X ULN)
Amylase
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9.2.5.4.
Urinalysis
Urinalysis
Bilirubin, Glucose, Protein, Blood and Ketones, Leukocytes, Nitrites, pH, Specific Gravity and 
Urobilinogen by dipstick
Microscopic examination (if blood or protein is abnormal)
Microbiology (at discretion of Investigator based on urinalysis results)
9.2.5.5.
Other Tests
Other Tests
NT-proBNP
Urine Creatinine (for calculation of 5-HIAA) at each 5-HIAA collection time
Estimated Glomerular Filtration Rate (eGFR)
FSH (as needed at Screening for confirmation of postmenopausal status)
Serum beta-hCG (pregnancy test; only at Screening)
Human Chorionic Gonadotropin (hCG) by urine dipstick
Pharmacogenetic sample
Sample for Future Research sample
Drugs of abuse: amphetamines, barbiturates, benzodiazepines, cocaine metabolites, 
methadone, opiates, phencyclidine, propoxyphene (only at Screening)
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the patient's condition.
All laboratory tests with abnormal values considered clinically significant during participation in 
the study or within 4 weeks after the last dose of IP should be repeated until the values return to 
normal or baseline or are no longer considered clinically significant by the Investigator or 
Medical Monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified, and the sponsor notified.
All protocol-required laboratory assessments must be conducted in accordance with the 
laboratory manual and the SoA (Section 1.3, Section 1.4, and Section 1.5).
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in patient management or are considered clinically 
significant by the Investigator (e.g., SAE or AE or dose modification), then the results must be 
recorded in the eCRF.
Additional unscheduled laboratory assessments may be conducted at any time during the study if 
the Investigator or Sponsor deems it necessary for the safety of the patient.
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9.2.6.
Pharmacogenetic Testing
A separate and specific informed consent form will be provided to patients to allow the sponsor 
to obtain and test a patient’s blood sample taken at the Baseline/Day1 and the Week 24 visits for 
pharmacogenetic markers that may be predictive of the natural history of the disease, response to 
therapy and tolerability of therapy. If it is not collected at the Baseline/Day 1 visit, it may be 
collected at any time during the treatment period.  Providing these blood samples is optional and 
not required for participation in the study.
9.2.7.
Optional Blood Sample for Future Research
In addition to the study-specific informed consent to be signed by each patient participating in 
the study, a separate, specific signature will be required to document a patient’s agreement to 
provide additional samples or to allow the use of the remainder of their already collected 
biomarker specimens for optional non-genetic future research, once approved by local authorities 
as applicable according to specific local regulations.  The specimens collected for optional future 
research will be used to increase our knowledge and understanding of the biology pathogenesis, 
progression and/or treatment outcomes, including efficacy, AEs, and the process of drug 
absorption and disposition.  
A plasma sample will be obtained from all patients at the Day 1/Baseline visit and at the end of 
the treatment or ET (as applicable) visit of the Main Study for future research use.  Samples will 
be collected and archived by the sponsor for up to 10 years.
9.2.8.
Suicidal Ideation and Behavior Risk Monitoring
Rodatristat ethyl acts to decrease peripheral 5-HT levels and it was designed to not cross the 
blood-brain barrier; therefore, CNS 5-HT levels are not expected to be significantly impacted.
However, patients being treated with IP should be monitored appropriately and observed closely 
for suicidal ideation and behavior or any other unusual changes in behavior, especially at the 
beginning and end of the course of treatment, or at the time of dose changes, either increases or 
decreases. IP in patients who experience signs of suicidal ideation or behavior following a risk 
assessment (see Section 8.1) must be stopped.
Screening and Baseline assessments (within 1 month) of suicidal ideation and behavior as well as 
potential treatment-emergent suicidal ideation and behavior will be monitored during the study 
using the C-SSRS.
Suicidal ideation and behavior as well as mood and anxiety assessments, as detailed below, will 
be obtained at time points indicated in the SoA in (Section 1.3).
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9.2.8.1.
Columbia Suicide Severity Rating Scale
The C-SSRS is a valid, reliable, evidenced-based suicidal ideation and behavior rating scale,
which was developed by multiple institutions, including Columbia University with National 
Institute of Mental Health support, to evaluate suicide risk (CLP, 2016).  The
rater-/clinician-administered versions of the C-SSRS for research assess severity and intensity of 
suicidal ideation, types of suicidal behaviors, and lethality of suicide attempts at time points and 
over time periods that are typical for randomized control studies. The C-SSRS has been 
identified by the FDA (FDA, 2012) as acceptable for use in clinical research and has been used 
extensively in clinical studies throughout the U.S. and around the world. 
Training should be completed by any study staff delegated to perform this assessment.  Online 
training is available, and a certificate of completion is issued once the training is completed and 
must be filed at the site.  Training must be current within the previous 2 years. The sign-up and 
training portal can be found at the following link:   
https://cssrs.columbia.edu/training/training-research-setting/ 
An example of the C-SSRS can be found in Appendix 10.
9.2.8.2.
Hospital Anxiety and Depression Scale
The HADS is a 14-item, self-rated measure designed to be used as a brief screen for depression 
(7 items) and anxiety (7 items) disorders among nonpsychiatric, medically ill, outpatient 
populations (Zigmond & Snaith, 1983).  As a screening instrument, the HADS does not provide 
a definitive diagnosis, but is the first step in a multistage process of selecting individuals at 
elevated risk for disorder to be evaluated through clinical interview.
An example of the HADS can be found in Appendix 11.
9.2.8.3.
Quick Inventory of Depressive Symptomatology 
The 16-item QIDS (Rush et al., 2003) is designed to assess the severity of depressive symptoms. 
The QIDS is available in the clinician-rated (QIDS-C) and self-reported versions (QIDS-SR). 
Both versions assess all the criterion symptom domains designated by the American Psychiatry 
Association Diagnostic and Statistical Manual of Mental Disorders - 4th edition (DSM-IV)
(APA, 1994) and the 5th edition adds reference to diagnose a major depressive episode. The 
QIDS-C version will be used in this study.  The QIDS-C is sensitive to change with medications, 
psychotherapy, or somatic treatments, making it useful for both research and clinical purposes.  
The psychometric properties of the QIDS-C have been established in various study samples.
An example of the QIDS-C can be found in Appendix 12.
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9.3.
Adverse Events, Adverse Events of Special Interest, and Serious 
Adverse Events
The definitions of an AE or SAE can be found in Appendix 14.
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient’s legally authorized representative).
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for follow up
of AEs that are serious, considered related to the IP or study procedures, or that caused the 
patient to discontinue the study (see Appendix 14).
9.3.1.
Adverse Events of Special Interest
AESIs include:
Ь
Severe constipation (and/or severe, persistent, or worsening abdominal pain)
Ь
Depression/other significant mood-related disturbance (active suicidal ideation or 
behavior, severe depressive and/or anxious symptoms, other severe psychiatric TEAE)
Ь
Elevations in hepatic enzymes (see Appendix 3)
Ь
Diarrhea (see Appendix 2)
9.3.2.
Time Period and Frequency for Collecting Adverse Event, Adverse Events of 
Special Interest, Serious Adverse Event Information
All SAEs will be collected from the signing of the ICF until the Follow-Up Visit at the time
points specified in the SoA (Section 1.3). All AEs will be collected from the first dose of IP.
Medical occurrences that begin before the start of IP but after obtaining informed consent will be 
recorded on the Medical History/Current Medical Conditions section of the eCRF not the AE 
section.
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 14. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available.
Adverse events of special interest must be reported to the Sponsor should they meet the 
definition of an SAE, and all timelines for reporting of SAEs should be adhered to.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of study 
participation. However, if the Investigator learns of any SAE, including a death, at any time 
after a patient has been discharged from the study, and he/she considers the event to be 
reasonably related to the IP or study participation, the Investigator must promptly notify the 
Sponsor.
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9.3.3.
Method of Detecting Adverse Events, Adverse Events of Special Interest, and 
Serious Adverse Events
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 14.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about AE
occurrences.
9.3.4.
Follow-up of Adverse Events, Adverse Events of Special Interest, and Serious 
Adverse Events
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs, and non-serious AESIs (as defined in Section 9.3.1), will 
be followed until resolution, stabilization, the event is otherwise explained, or the patient is lost 
to follow up (as defined in Section 8.3). Further information on follow-up procedures is given in
Appendix 14.
9.3.5.
Regulatory Reporting Requirements for Serious Adverse Events
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of an IP
under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of an IP under clinical investigation. The Sponsor will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRBs/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions
(SUSARs) according to local regulatory requirements and Sponsor policy and forwarded to 
investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then file 
it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate, according 
to local requirements.
9.3.6.
Pregnancy
Patients will be instructed that if they/their partner become pregnant during the study, this should 
be reported to the Investigator. The Investigator should also be notified of any pregnancy that 
occurs during the study but not confirmed until after completion of the study for at least 
5 terminal half-lives (4 weeks) after the last dose. In the event that a patient/patient’s partner is 
subsequently found to be pregnant after being included in the study, then consent will be sought 
from the partner and, if granted, any pregnancy will be followed, and the status of the mother 
and/or child will be reported to the Sponsor after delivery.
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Any patient reporting a pregnancy during the study will be discontinued from the IP. The patient
will also be followed to determine the outcome of the pregnancy. Information on the status of 
the mother and child will be forwarded to the Sponsor. Generally, follow up will be no longer 
than 6 to 8 weeks following the estimated delivery date. Any premature termination of the 
pregnancy will be reported. Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal 
death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs.
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
9.4.
Treatment of Overdose
Prior to this study, there has been no experience with rodatristat ethyl in patients with PAH. In 
healthy subjects, no safety concerns were identified following single doses ranging from 100 mg 
to 2000 mg or following repeat dosing over 14 days of up to 800 mg administered BID or up to 
800 mg administered once daily (QD).
An overdose in this study is defined as a dose > 1200 mg on any single dosing occasion, or 
> 2400 mg in any 24-hour period.
Altavant Sciences GmbH does not recommend specific treatment for an overdose.
In the event of an overdose, the Investigator should:
1. Contact the Medical Monitor immediately
2. Closely monitor the patient for any AE/SAE and laboratory abnormalities as applicable
3. Obtain an unscheduled plasma sample for PK analysis if requested by the Medical 
Monitor (determined on a case-by-case basis)
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the patient.
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9.5.
Pharmacokinetics
Blood samples for PK analysis of plasma rodatristat ethyl, rodatristat, M15 metabolite, selexipag, 
and ACT-333679 will be collected by indwelling cannula or venipuncture at the time points 
indicated in the SoA (Section 1.3). Note, selexipag/ACT-333679 PK samples will only be
collected in subjects using selexipag at baseline. The actual date and time of each blood sample 
collection will be recorded.
The date and time of the dose of IP taken prior to the collection of each PK sample will be 
recorded and if the meal the dose was taken with was high in fat, should also be recorded.
Sample analysis will be performed under the control of the Sponsor. Plasma concentrations of 
rodatristat ethyl, rodatristat, M15, selexipag, and ACT-333679 will be determined using 
validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. Raw data 
will be archived at the bioanalytical site(s). Once the sample(s) has been analyzed for rodatristat 
ethyl, rodatristat, M15, selexipag, and ACT-333679, any remaining sample may be analyzed for 
other rodatristat-related metabolites and the results may be reported separately.
Samples will be collected into appropriate tubes as specified by the bioanalytical laboratory. 
Details of blood collection, processing, storage, and shipment will be provided in the laboratory
manual.
Rodatristat ethyl and rodatristat concentration information that would unblind the study will not 
be reported to investigative sites or blinded personnel (including the Sponsor) until the study has 
been unblinded.
9.6.
Pharmacodynamics
Blood samples for determination of plasma 5-HIAA will be collected by indwelling cannula or 
venipuncture at the time points indicated in the SoA in Section 1.3. The actual date and time of 
each blood sample collection will be recorded.
Urine samples will be collected for determination of 5-HIAA (bioanalytical lab) and urine 
creatinine (central laboratory; for determination of creatine corrected 5-HIAA concentration) at 
the time points indicated in the SoA in Section 1.3 and Section 1.4.
Sample analysis will be performed under the control of the Sponsor. Plasma and urine 
concentrations of 5-HIAA will be determined using a validated LC-MS/MS method. Raw data 
will be archived at the bioanalytical site.
Details of sample containers and processing will be contained in the laboratory manual.
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10.
STATISTICAL CONSIDERATIONS
A detailed description of statistical methods will be provided in a separate Statistical Analysis 
Plan (SAP) and the SAP will be finalized prior to database lock.
10.1.
Statistical Hypotheses
No formal hypotheses are planned for the study.
10.2.
Sample Size Determination
The sample size for this study was not based on a formal hypothesis testing. It is expected that 
30 patients per arm will provide sufficient data to assess the safety and efficacy. Power 
calculations were conducted to examine the probability of detecting a difference among 
treatment groups for the percentage change of PVR from baseline.
A sample size of 90 patients with 30 patients to be randomized into 1 of the 3 treatment arms in a 
1:1:1 randomization is planned. A sample size of 30 patients per arm will provide at least 
80% power at a significance level of 0.05 (2-sided hypothesis) to detect a treatment difference of 
0.75 times of standard deviation (SD) in the percentage change from baseline of PVR from 
baseline between an active arm and the placebo arm. If the SD for PVR percent change is 24%, 
the study has 80% power to detect a difference of 18% between an active arm and the placebo 
arm.
10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All patients who sign the ICF
Intent-to-Treat (ITT) 
All patients randomized into the study. For all summaries based 
on the ITT population, patients will be assigned to the treatment 
arm to which they were randomized.
Modified Intent-to-Treat 
(m-ITT):
All safety population patients that had an evaluable baseline
and completed at least 1 post-baseline efficacy assessment.
Patients will be analyzed according to the treatment they
actually received.
Per Protocol (PP)
All m-ITT population patients who had no major protocol 
deviations and completed the Week 24 visit.
Safety
All patients randomly assigned to IP and who take at least 1 dose 
of IP. Patients will be analyzed according to the treatment they 
actually received.
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10.4.
Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the patient
populations to be included in the analyses and procedures for accounting for missing, unused, 
and spurious data. This section is a summary of the planned statistical analyses of the primary 
and secondary endpoints.
10.4.1.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
Primary efficacy analyses will be performed using the m-ITT and PP 
populations.
Percent change from baseline in PVR will be analyzed using an analysis of 
covariance (ANCOVA) with Baseline PVR as the covariate. Additional 
baseline characteristics may also be evaluated as covariates in the model.
The estimated between-treatment differences, 95% confidence intervals
(CIs), and p-values will be presented. For patients who discontinue from the 
study early, the last-observation-carried-forward method will be used to impute 
the PVR at Week 24.
Secondary
Secondary efficacy analyses will be performed using the m-ITT and PP 
populations:
Change in cardiac index, mPAP, mRAP, SvO2 at rest, and PAC from baseline to 
Week 24
x
TTCW
x
Change in WHO FC
x
Change in 6MWD from baseline
x
Change in NT-proBNP
x
Change in right atrial size & RV function: TAPSE, tricuspid annular 
systolic velocity, and RV fractional area change from baseline
x
REVEAL Lite 2 score
x
Change in PAH-SYMPACT from Baseline to Week 24
x
Change in 5-HIAA (plasma and spot urine concentration)
The change from baseline to Week 24 endpoints will be analyzed using an 
ANCOVA model with treatment as a fixed effect, randomization stratum and 
baseline assessment as covariates. The estimated between-treatment 
differences, 95% CIs, and p-values will be presented.
The change in 6MWD from baseline to Week 24 will also be compared between 
groups using non-parametric analysis of covariance within the framework of the 
extended Cochran-Mantel-Haenszel test. For endpoints measured over time, a 
mixed effect of repeated measure model may be used as sensitivity analyses.
Details of statistical methods will be provided in the SAP. The time from the 
first dose of IP until to the first clinical worsening event will be summarized 
using Kaplan-Meier estimates and compared between treatment groups using the 
log-rank test.
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Endpoint
Statistical Analysis Methods
Exploratory
Will be described in the SAP finalized before database lock
10.4.2.
Safety Analyses
Safety and tolerability will be evaluated by assessment of AE incidence and changes in clinical 
laboratory tests, physical examinations, vital signs measurements, ECG readings, and suicidal 
ideation and behavior ratings at various time points during the study.
The following AE summaries will be generated:
x
Adverse events
x
Serious adverse events
x
Adverse events leading to discontinuation
x
Adverse events by severity
x
Adverse events by relationship to the IP
AE verbatim text will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). All AEs, both serious and nonserious, will be listed. AE summaries by treatment 
group and consisting of the number and percent of patients reporting each event at least once will 
be generated.
Clinical values will be listed for each patient and flagged high or low relative to the normal range 
where appropriate. Descriptive summary statistics will be created by treatment and visit.
Other safety data (e.g., physical examination) will be summarized descriptively by treatment and
visit.
10.4.3.
Other Analyses
Patient reported outcomes (HADS and QIDS-C), PK, PD, and exploratory descriptive analyses 
will be described in the SAP finalized before database lock.  Population PK and any PK/PD
analyses will be documented in a separate analysis plan and may be reported separately.
The planned analyses for the OLE portion of the study will be provided in the SAP.
10.5.
Interim Analyses 
An external, multidisciplinary, IDMC will review the progress of the study and perform interim 
reviews of unblinded safety data at regular intervals and provide recommendations to the 
Sponsor whether the nature, frequency, and severity of AEs and AESIs associated with IP
warrant the early termination of the study in the best interests of the patients, whether the study 
should continue as planned, or whether the study should continue with modifications. The 
IDMC may also provide recommendations as needed regarding study design. While the IDMC 
will be asked to advise the Sponsor regarding future conduct of the study, including possible 
early study termination, the Sponsor retains final decision-making authority on all aspects of the 
study.
A separate SAP will describe the planned interim analyses in greater detail.
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10.5.1.
Independent Data Monitoring Committee
The primary role of the IDMC, which consists of independent physicians with experience in the 
care of patients with PAH and the conduct of randomized, controlled studies and one non-voting 
biostatistician, is to ensure the safety of the patients enrolled in the study, including the OLE.
Details of the IDMC’s specific activities will be defined by a mutually agreed charter, which will 
define the IDMC’s membership, conduct and meeting schedule.  This charter will be maintained 
by the Sponsor or designee.
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11.
REFERENCES
Abid, S., Houssaini, A., Chevarin, C., Marcos, E., Tissot, C.-M., Gary-Bobo, G., Wan, F., 
Mouraret, N., Amsellem, V., Dubois-Randé, J.-L., Hamon, M., & Adnot, S. (2012). Inhibition 
of gut- and lung-derived serotonin attenuates pulmonary hypertension in mice. American 
Journal of Physiology-Lung Cellular and Molecular Physiology, 303(6), L500–L508. 
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Agarwal, R., & Gomberg-Maitland, M. (2011). Current therapeutics and practical management 
strategies for pulmonary arterial hypertension. American Heart Journal, 162(2), 201–213.
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Aiello, R. J., Bourassa, P.-A., Zhang, Q., Dubins, J., Goldberg, D. R., Lombaert, S. D., Humbert, 
M., Guignabert, C., Cavasin, M. A., McKinsey, T. A., & Paralkar, V. (2016). Tryptophan 
hydroxylase 1 (TPH1) Inhibition Impacts Pulmonary Vascular Remodeling in Two Rat 
Models of Pulmonary Hypertension. Journal of Pharmacology and Experimental 
Therapeutics, 360(2), jpet.116.237933. https://doi.org/10.1124/jpet.116.237933
APA. (1994). American Psychiatric Association. Diagnostic and Statistical Manual of Mental 
Disorders: DSM-IV. American Psychiatric Publishing, Inc.
ATS. (2012). ATS Statement: Guidelines for the Six-Minute Walk Test. American Journal of 
Respiratory and Critical Care Medicine, 166(1), 111–117.
https://doi.org/10.1164/ajrccm.166.1.at1102
Benza, R., Kanwar, M., Raina, A., Scott, J., Zhao, C., Selej, M., Elliott, C. and Farber, H., 2020.
Development and Validation of an Abridged Version of the REVEAL 2.0 Risk Score 
Calculator, REVEAL Lite 2, for Use in Patients with Pulmonary Arterial 
Hypertension. Chest,.
CLP. (2016). The Columbia Lighthouse Project. https://doi.org/cssrs.columbia.edu
Eddahibi, S. (2006). 055 Cross-talk between endothelial and smooth muscle cells in pulmonary 
hypertension: critical role for serotonin-induced smooth muscle hyperplasia. Revue Des 
Maladies Respiratoires, 23(5), 540. https://doi.org/10.1016/s0761-8425(06)71883-6
FDA. (2012). Guidance for industry: suicidal ideation and behavior: prospective assessment of 
occurrence in clinical trials. Center for Drug Evaluation and Research.
Humbert, M., Labrune, P., Sitbon, O., Gall, C. L., Callebert, J., Herve, P., Samuel, D., Machado, 
R., Trembath, R., Drouet, L., Launay, J.-M., & Simonneau, G. (2002). Pulmonary arterial 
hypertension and type-I glycogen-storage disease: the serotonin hypothesis. European 
Respiratory Journal, 20(1), 59–65. https://doi.org/10.1183/09031936.02.00258702
IB. (2020). Rodatristat Ethyl Investigator’s Brochure.
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Izikki, M., Hanoun, N., Marcos, E., Savale, L., Barlier-Mur, A. M., Saurini, F., Eddahibi, S., 
Hamon, M., & Adnot, S. (2007). Tryptophan hydroxylase 1 knockout and tryptophan 
hydroxylase 2 polymorphism: effects on hypoxic pulmonary hypertension in mice. American 
Journal of Physiology-Lung Cellular and Molecular Physiology, 293(4), L1045–L1052. 
https://doi.org/10.1152/ajplung.00082.2007
Kim, J. J., Wang, H., Terc, J. D., Zambrowicz, B., Yang, Q. M., & Khan, W. I. (2015). Blocking 
peripheral serotonin synthesis by telotristat etiprate (LX1032/LX1606) reduces severity of 
both chemical- and infection-induced intestinal inflammation. American Journal of 
Physiology-Gastrointestinal and Liver Physiology, 309(6), G455–G465. 
https://doi.org/10.1152/ajpgi.00299.2014
Klinger, J. R., Elliott, C. G., Levine, D. J., Bossone, E., Duvall, L., Fagan, K., Frantsve-Hawley, 
J., Kawut, S. M., Ryan, J. J., Rosenzweig, E. B., Sederstrom, N., Steen, V. D., & Badesch, D. 
B. (2019). Therapy for Pulmonary Arterial Hypertension in Adults. Chest, 155(3), 565–586.
https://doi.org/10.1016/j.chest.2018.11.030
MacLean. (2018). The serotonin hypothesis in pulmonary hypertension revisited: targets for 
novel therapies (2017 Grover Conference Series). Pulmonary Circulation, 8(2), 1–9.
https://doi.org/10.1177/2045894018759125
MacLean, M. R., & Dempsie, Y. (2010). The Serotonin Hypothesis of Pulmonary Hypertension 
Revisited. 661, 309–322. https://doi.org/10.1007/978-1-60761-500-2_20
Rush, A. J., Trivedi, M. H., Ibrahim, H. M., Carmody, T. J., Arnow, B., Klein, D. N., Markowitz, 
J. C., Ninan, P. T., Kornstein, S., Manber, R., Thase, M. E., Kocsis, J. H., & Keller, M. B.
(2003). The 16-Item quick inventory of depressive symptomatology (QIDS), clinician rating
(QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic
major depression. Biological Psychiatry, 54(5), 573–583. https://doi.org/10.1016/s0006-
3223(02)01866-8
Shi, Z.-C., Devasagayaraj, A., Gu, K., Jin, H., Marinelli, B., Samala, L., Scott, S., Stouch, T., 
Tunoori, A., Wang, Y., Zang, Y., Zhang, C., Kimball, S. D., Main, A. J., Sun, W., Yang, Q., 
Nouraldeen, A., Yu, X.-Q., Buxton, E., … Liu, Q. (2008). Modulation of Peripheral Serotonin 
Levels by Novel Tryptophan Hydroxylase Inhibitors for the Potential Treatment of Functional 
Gastrointestinal Disorders. Journal of Medicinal Chemistry, 51(13), 3684–3687.
https://doi.org/10.1021/jm800338j
Woosley. (2019). CredibleMeds. https://doi.org/crediblemeds.org
Zigmond, A. S., & Snaith, R. P. (1983). The Hospital Anxiety and Depression Scale. Acta 
Psychiatrica Scandinavica, 67(6), 361–370. https://doi.org/10.1111/j.1600-
0447.1983.tb09716.x
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APPENDIX 1.
CONCOMITANT AND PROHIBITED MEDICATIONS 
NARROW THERAPEUTIC RANGE SUBSTRATES OF CYTOCHROME P450 
(CYP)2C8, CYP3A, AND P-GLYCOPROTEIN (P-GP) Patients using the following systemic 
narrow therapeutic range substrates of CYP2C8, CYP3A and P-gp are allowed but should be 
monitored during coadministration with IP.  
CYP2C8
Trepostinil 
Selexipag
Torasemide
Trimethoprim
Gemfibrozil
Rosiglitazone 
Pioglitazone 
CYP3A
Alfentanil
Cyclosporine 
(dihydro)ergotamine
Everolimus 
Fentanyl 
Sirolimus
Tacrolimus
P-gp
Digoxin
Dabigatran
Fexofenadine 
PROHIBITED MEDICATIONS
The following medications should not be used during the study: 
Class
Drug Name
Generic Name
Monoamine Oxidase Inhibitors (MAOIs)
Isocarboxazid
Phenelzine
Selegiline
Tranylcypromine
Tryptophan Hydroxylase Inhibitor
Telotristat Ethyl
Marketed drugs known to prolong QT/QTc
AND which are also clearly associated with 
a known risk of Torsades de Pointe 
source: www.CredibleMeds.org (Woosley,
2021) 
Amiodarone (Cordarone and others) 
Anagrelide (Agrylin and others) 
Arsenic trioxide (Trisenox)
Astemizole (Hismanal
Azithromycin (Zithromax and others
Bepridil (Vascor)
Chloroquine (Aralen) 
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Class
Drug Name
Generic Name
Chlorpromazine (Thorazine and others) 
Chlorprothixene (Truxal)
Cilostazol (Pletal)  
Ciprofloxacin (Cipro and others)
Cisapride (Propulsid)
Citalopram (Celexa and others) 
Clarithromycin (Biaxin and others)
Cocaine (Cocaine)
Disopyramide (Norpace) 
Dofetilide (Tikosyn) 
Domperidone (Motilium and others)
Donepezil (Aricept) 
Dronedarone (Multaq) 
Droperidol (Inapsine and others) 
Erythromycin (E.E.S. and others)
Escitalopram (Cipralex and others) 
Flecainide (Tambocor and others)
Fluconazole (Diflucan and others)
Gatifloxacin (Tequin)
Grepafloxacin (Raxar)
Halofantrine (Halfan)
Haloperidol (Haldol and others) 
Hydroxychloroquine (Plaquenil and others)
Ibogaine
Ibutilide (Corvert) 
Levofloxacin (Levaquin and others)
Levomepromazine/methotrimeprazine (Nosinan 
and others)
Levomethadyl acetate (Orlaam)
Levosulpiride (Lesuride and others)
Mesoridazine (Serentil)
Methadone (Dolophine and others) 
Moxifloxacin (Aveloxand others) 
Ondansetron (Zofran and others)
Oxaliplatin (Eloxatin) 
Papaverine HCl Intracoronary
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Class
Drug Name
Generic Name
Pentamidine (Pentam) 
Pimozide (Orap)
Probucol (Lorelco)
Procainamide (Pronestyl and others)
Propofol (Diprivan and others)
Quinidine (Quinaglute and others)
Roxithromycin (Rulide and others)
Sertindole (Serdolect and others)
Sevoflurane (Ultane and others) 
Sotalol (Betapace and others)
Sparfloxacin (Zagam) 
Sulpiride (Dogmatil and others)
Sultopride (Barnetil and others)
Terfenadine (Seldane)
Terlipressin (Teripress and others)
Terodiline (Micturin and others)
Thioridazine (Mellaril and others)
Vandetanib (Caprelsa)
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APPENDIX 2.
DIARRHEA MANAGEMENT
CTCAE Grade
Description
IP
Symptom/Treatment
Mild = 1
(uncomplicated)
Increase of < 4 stools 
per day over Baseline
Continue same dose
Consider anti-diarrheal 
medicines e.g., 4 mg 
loperamide followed by 
2 mg after each loose stool
or every 2-4 hours to a 
maximum of 16 mg/day until 
bowel movements cease for 
12 hours
Moderate = 2
(uncomplicated)
Increase of 4–6 stools 
per day over Baseline;
IV fluids indicated 
< 24 hours;
Not interfering with 
ADL
If Grade 2 diarrhea 
SHUVLVWVIRU 48 hours, 
IP should be 
interrupted until 
recovered to Grade  1
followed by dose 
reduction.
Dose re-escalation is 
possible within 4 weeks 
after start of reduced 
dose.
Continue anti-diarrheal 
medicines, if Grade 2
persists foU 48 hours assess 
for dehydration and 
electrolyte imbalance, 
consider IV fluids and 
electrolyte replacement as 
clinically indicated.
Severe = 3
(complicated)
,QFUHDVHRI 7 stools 
per day over Baseline;
Incontinence;
,9IOXLGV 24 hours;
Hospitalization;
Interfering with ADL
IP interruption until 
recovery to Grade  1
followed by dose 
reduction.
In case of recurrence of 
Grade 3 diarrhea despite 
optimal symptomatic 
treatment and dose 
reduction, IP should be 
permanently 
discontinued.
See Grade 2. 
Consider stool cultures and 
clostridium botulinum toxins 
to exclude any infection; 
aggressive IV fluid 
UHSODFHPHQW 24 hours,
hospitalization as clinically 
indicated, consider referral 
to a GI specialist to rule out 
potential differential 
diagnoses.
Life-threatening = 
4
(complicated)
Life-threatening 
consequences 
(e.g., haemodynamic 
collapse)
See Grade 3.
See Grade 3.
Abbreviations:  ADL = activities of daily life; CTCAE = Common Terminology Criteria for Adverse Events; 
GI = gastrointestinal; IP = investigational product; IV = intravenous
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APPENDIX 3.
LIVER SAFETY:  SUGGESTED ACTIONS AND 
FOLLOW-UP ASSESSMENTS
CTCAE Grade
Description
IP
Symptom/treatment
Mild = 1
AST or ALT
> 1.5X ULN 
< 3X ULN
Continue as planned
No action taken
Moderate = 2
AST or ALT
 3X ULN and 
< 5X ULN and no 
signs of severe liver 
damage
Reduce to one pill 
BID or interrupt 
treatment (to be 
decided by 
Investigator, based 
on individual risk 
assessment.)
Re-test ALT and AST, as 
well as ALP, TBL, and 
eosinophils within 
48-72 hours, then at ~7 days, 
then at ~2 weeks, and assess 
for signs of severe liver 
damage:
x
If AST and ALT 
< 3X ULN after 
2 weeks, return to initial 
dose if reduced, restart at 
reduced dose if 
interrupted. Monitor labs 
(see above) every 
2 weeks for at least 
8 weeks.
x
If AST and ALT 
 3X ULN after 2 weeks 
or anytime thereafter, 
permanently discontinue 
study medication.
Severe = 3
AST or ALT increase 
WR 5X ULN and 
< 8X ULN and no 
signs of severe liver 
damage
Interrupt treatment
Re-test ALT and AST, as 
well as ALP, TBL, and 
eosinophils within 
48-72 hours, then at ~7 days, 
then at ~2 weeks, and assess 
for signs of severe liver 
damage:
x
If AST and ALT 
< 3X ULN after 
2 weeks, restart at 
reduced dose. Monitor 
labs (see above) every 
week for 4 weeks, then 
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CTCAE Grade
Description
IP
Symptom/treatment
every 2 weeks for at 
least 8 weeks.
x
If AST and ALT 
 3X ULN after 2 weeks 
or anytime thereafter, 
permanently discontinue 
study medication.
Life-threatening 
= 4
AST or ALT increase 
WR 8X ULN or signs 
of severe liver 
damage:
-Increase of liver
transaminases (ALT
RU$67 3X ULN)
and
Appearance of 
fatigue, nausea, 
vomiting, right upper 
abdominal quadrant 
pain or tenderness, 
fever, rash and/or 
eosinophilia (> 5%)
or
TBL > 1.5X ULN
or
INR > 1.5
Permanently 
Discontinue
Patients showing these 
laboratory abnormalities 
need to be followed up 
closely
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BID = twice daily; CTCAE = Common Terminology Criteria for Adverse Events; INR = international normalized 
ratio; IP = investigational product; ULN = upper limit of normal
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APPENDIX 4.
COLLECTION OF PREGNANCY INFORMATION
Definitions
Woman of childbearing potential
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of IP, additional evaluation should be considered.
Women in the following categories are not considered women of childbearing potential
1. Premenarchal
2. Premenopausal female with one of the following:
x
Documented hysterectomy
x
Documented bilateral salpingectomy
x
Documented bilateral oophorectomy
3. For individuals with permanent infertility due to an alternate medical cause other than the
above, (e.g., Müllerian agenesis, androgen insensitivity), Investigator discretion should
be applied to determining study entry.
4. Note: Documentation can come from the site personnel’s review of the patient’s medical
records, medical examination, or medical history interview.
5. Postmenopausal female
x
A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause.

A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than one FSH measurement 
is required.
x
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue their HRT to 
allow confirmation of postmenopausal status before study enrollment.
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Collection of Pregnancy Information
Male patients with partners who become pregnant
x
The Investigator will attempt to collect pregnancy information on any male patient’s 
female partner who becomes pregnant while the male patient is in this study. This 
applies only to male patients who receive the investigational product.
x
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
Sponsor. Generally, the follow up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure.
Female Patients who become pregnant
x
The Investigator will collect pregnancy information on any female patient who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the Sponsor within 24 hours of learning of a 
patient's pregnancy.
x
The patient will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the patient and the neonate, and the 
information will be forwarded to the Sponsor. Generally, follow up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.
x
While pregnancy itself is not considered to be an adverse event (AE) or serious 
adverse event (SAE), any pregnancy complication or elective termination of a 
pregnancy will be reported as an AE or SAE. A spontaneous abortion is always 
considered to be an SAE and will be reported as such. Any poststudy 
pregnancy-related SAE considered reasonably related to the investigational product
by the Investigator will be reported to the Sponsor as described in Section 9.3.5.
While the Investigator is not obligated to actively seek this information in former 
study patients, he or she may learn of an SAE through spontaneous reporting.
x
Any female patient who becomes pregnant while participating in the study will 
discontinue the investigational product and be withdrawn from the study.
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APPENDIX 5.
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS
Regulatory and Ethical Considerations
x
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines

Applicable International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines

Applicable laws and regulations
x
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
Investigator and reviewed and approved by the IRB/IEC before the study is initiated.
x
Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study patients.
x
The Investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC

Notifying the IRB/IEC of serious adverse events or other significant safety 
findings as required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.
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Informed Consent Process
x
The Investigator or his/her representative will explain the nature of the study to the 
patient or his/her legally authorized representative and answer all questions regarding 
the study.
x
Patients must be informed that their participation is voluntary. Patients or their 
legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act requirements, where applicable, 
and the IRB/IEC or study center.
x
The medical record must include a statement that written informed consent was 
obtained before the patient was enrolled in the study and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign 
the ICF.
x
Patients must be reconsented to the most current version of the ICF during their 
participation in the study.
x
A copy of the ICF must be provided to the patient or the patient’s legally authorized 
representative.
Patients who are rescreened are required to sign a new ICF.
Data Protection
x
Patients will be assigned a unique identifier by the Sponsor. Any patient records or 
datasets that are transferred to the Sponsor will contain the identifier only; patient
names or any information which would make the patient identifiable will not be 
transferred.
x
The patient must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the patient.
x
The patient must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
Data Quality Assurance
x
All patient data relating to the study will be recorded on printed or electronic case 
report form (CRF) unless transmitted to the Sponsor or designee electronically 
(e.g., laboratory data). The Investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF.
x
The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF.
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x
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
x
Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, or 
on-site monitoring) are provided in the Monitoring Plan.
x
The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data.
x
The Sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations).
x
Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of patients are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.
x
Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for 2 years after last marketing approval
unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of 
the Sponsor. No records may be transferred to another location or party without 
written notification to the Sponsor.
Source Documents
x
Source documents provide evidence for the existence of the patient and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s 
site.
x
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained. The Investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available.
x
Definition of what constitutes source data can be found in the Monitoring Manual.
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Study and Site Closure
The Sponsor’s designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to:
x
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines
x
Inadequate recruitment of patients by the Investigator
x
Discontinuation of further investigational product development
Publication Policy
x
The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the Investigator agrees to submit all manuscripts or abstracts to the 
Sponsor before submission. This allows the Sponsor to protect proprietary 
information and to provide comments.
x
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement.
x
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
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APPENDIX 6.
SIX-MINUTE WALK TEST GUIDELINES
The six-minute walk test (6MWT) should be performed in accordance with the American 
Thoracic Society Guidelines. Please refer to the ATS guidelines and the following general 
procedures for conducting the 6MWT:
Testing Location:
x
The 6MWT should be performed indoors, along a long, flat, straight, enclosed corridor 
with a hard surface that is seldom traveled.  The location should be quiet and free of 
distractions and drafts.
x
The walking course must be 30 meters in length (any deviations from this must be 
reviewed with and approved by the Medical Monitor/Sponsor prior to initiating the 
study). A 100-foot hallway is, therefore, required. The length of the corridor should be 
marked every 3 meters. The turnaround points should be marked with a cone (such as an 
orange traffic cone). A starting line, which marks the beginning and end of each 60 meter
lap, should be marked on the floor using brightly colored tape.
Required Equipment:
x
Countdown timer (or stopwatch)
x
Mechanical lap counter
x
Two small cones to mark the turnaround points
x
A chair that can be easily moved along the walking course
x
Worksheets (to be provided) on a clipboard
x
A source of oxygen
x
Sphygmomanometer
x
Automated electronic defibrillator
Testing:
Patient Preparation:
x
Comfortable clothing should be worn
x
Appropriate shoes for walking should be worn
x
Patients should use their usual walking aids during the test (cane, walker, etc.)
x
The patient’s usual medical regimen should be continued on testing days
x
A light meal is acceptable before early morning or early afternoon tests, at least 2 hours 
before testing
Patients should not have smoked or exercised vigorously within 2 hours of beginning the test
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Testing Conditions:
x
The patient should sit at rest in a chair, located near the starting position, for at least 
10 minutes before the test starts. During this time, check for contraindications, measure 
pulse and blood pressure and make sure that clothing and shoes are appropriate.
x
To reduce the variability of the 6MWTs, it is of utmost importance that the eligibility tests 
(Screening and Baseline) and all following 6MWTs are performed under the same 
conditions:
R
The same tester should administer the 6MWT for a given patient throughout the trial 
whenever possible
R
The same time of day for conducting the 6MWT for a given patient should be used 
whenever possible to minimize intra-day variability
R
Patients who used walking aids at the eligibility tests (Screening and Baseline,
e.g., cane or walker) need to use the same walking aids at every subsequent 6MWT
x
Site staff will need to document if a walking aid (and what type) was used at
each test, if applicable
x
If the patient normally requires supplemental oxygen when walking, then the test should be 
performed on the patient’s “usual” walking oxygen flow rate at Baseline and during all 
subsequent 6MWTs whenever possible.  If the patient usually breathes room air while 
walking, they should perform the test on room air.
R
Patients who add supplemental oxygen after the Baseline Visit should walk without 
oxygen during subsequent walk tests whenever possible so that data will be 
comparable to baseline conditions. However, if this is not possible (from a patient 
safety perspective) then the 6MWT may be conducted with the supplemental oxygen 
and this should be noted in the electronic case report form (eCRF).
R
For patients on supplemental oxygen at Baseline, if the oxygen flow rate must be
increased during the trial due to worsening gas exchange, 6MWTs should be 
conducted using the same oxygen flow rate that was used at the Baseline Visit 
whenever possible.  However, if this is not possible (from a patient safety 
perspective) then the 6MWT may be conducted at the increased flow rate and this 
should be noted in the eCRF.
R
If the patient reduces or discontinues supplemental oxygen use during the study, the 
patient should still perform the 6MWT with the same oxygen flow rate that was used 
at the Baseline Visit.
Instructions for the Patient and Test Administrator:
x
A “warm-up” period should not be performed before the test
x
Set the lap counter to zero and the timer to 6 minutes.  Assemble all necessary equipment and 
move to the starting point.
x
The Tester/Investigator should stand near the starting line during the test but should not walk 
with the patient.  Patients will be instructed to walk alone, not run, from one end of the 
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walking course to the other, at their own pace, while attempting to cover as much ground as 
possible in 6 minutes.
x
The tester should not influence the walking pace of the patient.
x
During the walk, the patients will be allowed to stop intermittently and stand or sit, or lean 
against the wall, to rest if the patient can no longer continue, but they should resume walking 
as soon as they feel able to do so (see below for instructive language that should be used in 
this instance). The clock must continue to run during the brief rests.
x
The Tester can stop the test at any time for safety-related reasons (e.g., chest pain, intolerable 
dyspnea, leg cramps, pale or ashen-looking appearance).
Patient Instructions Before the Test - The person administering the test will use the following 
dialog with the patient immediately before the test (repeat the entire set of instructions if the 
patient does not seem to understand):
R
“The object of this test is to walk as far as possible for 6 minutes. You will walk back 
and forth in this hallway. Six minutes is a long time to walk, so you will be exerting 
yourself. You will probably get out of breath or become exhausted. You are 
permitted to slow down, to stop, and to rest, as necessary. You may lean against the 
wall while resting but resume walking as soon as you are able. You will be walking
back and forth around the cones. You should pivot briskly around the cones and 
continue back the other way without hesitation. Now I’m going to show you. Please 
watch the way I turn without hesitation.” (The tester then demonstrates by walking 
one lap and pivots around a cone briskly). 
R
“Are you ready to do that? I am going to use this counter to keep track of the number 
of laps you complete. I will click it each time you turn around at this starting line. 
Remember that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don’t 
run or jog.” (The tester should position the patient at the starting line and ask the 
patient if he/she has any questions about the test and should confirm that the patient 
understands what he/she is expected to do.  Repeat the entire set of instructions if the 
patient does not seem to understand).
R
“Start now, or whenever you are ready.”
x
Patient Instructions During the Test – As soon as the patient starts to walk, start the timer. 
The person administering the test should not walk with the patient.  The Tester should not 
talk to anyone during the testing. Only standardized phrases for encouragement can be used 
during the test.  To best ensure reproducibility and consistency of the testing, standardized 
phrases should be used every minute according to the following pattern:
R
After the 1st minute, tell the patient the following (in even tones): “You are doing 
well. You have 5 minutes to go.”
R
When the timer shows 4 minutes remaining, tell the patient the following: “Keep up 
the good work. You have 4 minutes to go.”
R
When the timer shows 3 minutes remaining, tell the patient the following: “You are 
doing well. You are halfway done.”
R
When the timer shows 2 minutes remaining, tell the patient the following: “Keep up 
the good work. You have only 2 minutes left.”
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R
When the timer shows only 1 minute remaining, tell the patient: “You are doing well. 
You have only 1 minute to go.” 
R
Do not use other words of encouragement or body language to get the patient to speed 
up.
R
If the patient is slowing down, stops or expresses that he/she wants to stop, the tester 
should say: “You can lean against the wall if you would like; then continue walking 
whenever you feel able.” Do not stop the timer.
R
If the patient stops before the 6 minutes are up and refuses to continue (or the Tester 
decides that they should not continue), wheel the chair over for the patient to sit on, 
discontinue the walk, and note on the worksheet the distance, the time stopped, and 
the reason for stopping prematurely. 
R
When the timer is 15 seconds from completion, say this: “In a moment I’m going to 
tell you to stop.  When I do, just stop right where you are, and I will come to you.”  
When the timer rings (or buzzes), say this: “Stop!”  Walk over to the patient.  Mark 
the spot where they stopped. 
R
If the patient walked for less than 6 minutes (i.e., stops prior to 6 minutes and does 
not start again), record the time walked as well as the distance.
x
Post-Test Procedures:
R
The Tester will record the number of laps from the counter and the additional distance 
covered (the number of meters in the final lap).  Calculate the total distance walked, 
rounding to the nearest meter, and record it on the worksheet.
R
Following the 6MWT, the Tester will always obtain and record the post-walk Borg 
Dyspnea Score.
Reference:  (ATS, 2012)
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APPENDIX 7.
BORG SCALE AND INSTRUCTIONS
Instructions:  Use this rating scale to report how strong your perception is. It can be exertion, 
pain or something else. First look at the verbal expressions. Start with them and then the 
numbers. Of these ten (10) or ”Extremely strong”, “Maximal” is a very important intensity level. 
This is the most intense perception or feeling you have ever had.
If your experience or feeling is “Very weak”, you should say “1”, if it is “Moderate”, say “3”. 
Note that “Moderate” is “3” and thus weaker than “Medium”, “Mean” or “Middle”. If the 
experience is “Strong” or “Heavy” (it feels “Difficult”) say “5”. Note that “Strong” is about half 
of “Maximal”. If your feeling is “Very strong”, choose a number from 6 to 8. If your perception 
or feeling is stronger than ”10”, - “Extremely strong”, “Maximal” – you can use a larger number, 
e.g. 12 or still higher (that’s why “Absolute maximum” is marked with a dot.
It's very important that you report what you actually experience or feel, not what you think you 
should report. Be as spontaneous and honest as possible and try to avoid under- or 
overestimating. Look at the verbal descriptors and then choose a number.
When rating exertion give a number that corresponds to how hard and strenuous you perceive the 
work to be. The perception of exertion is mainly felt as strain and fatigue in your muscles and as 
breathlessness or any aches.
0 ”Nothing at all”, means that you don’t feel any exertion whatsoever, no muscle fatigue, no 
breathlessness or difficulties breathing.
1 “Very weak” means a very light exertion. As taking a shorter walk at your own pace.
3 “Moderate” is somewhat but not especially hard. It feels good and not difficult to go on.
5 “Strong”. The work is hard and tiring, but continuing isn't terribly difficult. The effort and 
exertion is about half as intense as “Maximal”.
7 “Very strong” is quite strenuous. You can still go on, but you really have to push yourself and 
you are very tired.
10 “Extremely strong – Maximal” is an extremely strenuous level. For most people this is the 
most strenuous exertion they have ever experienced previously in their lives.
Ɣ,V´$EVROXWHPD[LPXP´IRUH[DPSOH´´RUHYHQPRUH
Any questions?
Borg CR10 scale®
© G. Borg, 1998, 2007
English
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Borg Scale
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APPENDIX 8.
WORLD HEALTH ORGANIZATION FUNCTIONAL 
CLASSIFICATION OF PULMONARY HYPERTENSION
Reference: (Klinger et al., 2019) 
CLASS
DESCRIPTION
Class I
Patients with pulmonary hypertension (PH) but without resulting 
limitation of physical activity.  Ordinary physical activity does not cause 
undue dyspnea or fatigue, chest pain, or near syncope. 
Class II
Patients with PH resulting in slight limitation of physical activity. They 
are comfortable at rest.  Ordinary physical activity causes undue dyspnea 
or fatigue, chest pain, or near syncope. 
Class III
Patients with PH resulting in marked limitation of physical activity.  They 
are comfortable at rest.  Less than ordinary activity causes undue dyspnea 
or fatigue, chest pain, or near syncope. 
Class IV
Patients with PH with inability to carry out any physical activity without 
symptoms.  These patients manifest signs of right-heart failure.  Dyspnea 
and/or fatigue may even be present at rest. Discomfort is increased by any 
physical activity. 
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APPENDIX 9.
PULMONARY ARTERIAL HYPERTENSION-
SYMPTOMS AND IMPACT™ QUESTIONNAIRE
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APPENDIX 10.
COLUMBIA-SUICIDE SEVERITY RATING SCALE
BASELINE/SCREENING VISIT
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SINCE LAST VISIT
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APPENDIX 11.
HOSPITAL ANXIETY AND DEPRESSION SCORE 
(HADS)
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APPENDIX 12.
CLINICIAN-RATED QUICK INVENTORY OF 
DEPRESSIVE SYMPTOMATOLOGY
NAME: ______________________________________________
TODAY'S DATE: _______________
Please circle one response to each item that best describes the patient for the last seven days.
1.
Sleep Onset Insomnia:
0
Never takes longer than 30 minutes to 
fall asleep. 
1
Takes at least 30 minutes to fall 
asleep, less than half the time. 
2
Takes at least 30 minutes to fall 
asleep, more than half the time. 
3
Takes more than 60 minutes to fall 
asleep, more than half the time.
2.
Mid-Nocturnal Insomnia:
0
Does not wake up at night. 
1
Restless, light sleep with few 
awakenings.
2
Wakes up at least once a night, but 
goes back to sleep easily. 
3
Awakens more than once a night and 
stays awake for 20 minutes or more, 
more than half the time. 
3.
Early Morning Insomnia:
0
Less than half the time, awakens no 
more than 30 minutes before 
necessary.
1
More than half the time, awakens more 
than 30 minutes before need be.
2
Awakens at least one hour before 
need be, more than half the time.
3
Awakens at least two hours before 
need be, more than half the time.
4.
Hypersomnia: 
0
Sleeps no longer than 7-8 hours/night, 
without naps. 
1
Sleeps no longer than 10 hours in a 24 
hour period (include naps). 
2
Sleeps no longer than 12 hours in a 24 
hour period (include naps). 
3
Sleeps longer than 12 hours in a 24 
hour period (include naps).
Enter the highest score on any
1 of the 4 sleep items (1–4 above) _____
5.
Mood (Sad):
0
Does not feel sad.
1
Feels sad less than half the time.
2
Feels sad more than half the time.
3
Feels intensely sad virtually all the 
time.
6. Appetite (Decreased):
0
No change from usual appetite. 
1
Eats somewhat less often and/or 
lesser amounts than usual. 
2
Eats much less than usual and only 
with personal effort. 
3
Eats rarely within a 24-hour period, 
and only with extreme personal effort 
or with persuasion by others.
7. Appetite (Increased):
0
No change from usual appetite. 
1
More frequently feels a need to eat 
than usual.
2
Regularly eats more often and/or 
greater amounts than usual.
3
Feels driven to overeat at and between 
meals.
8.
Weight (Decrease) Within The Last Two 
Weeks: 
0
Has experienced no weight change.
1
Feels as if some slight weight loss 
occurred.
2
Has lost 2 pounds or more. 
3
Has lost 5 pounds or more. 
9.
Weight (Increase) Within the Last Two 
Weeks: 
0
Has experienced no weight change.
1
Feels as if some slight weight gain has 
occurred.
2
Has gained 2 pounds or more. 
3
Has gained 5 pounds or more.
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Enter the highest score on any 1 of the 4 
appetite/weight change items (6–9
above) _____
10.
Concentration/Decision Making: 
0
No change in usual capacity to 
concentrate and decide. 
1
Occasionally feels indecisive or notes 
that attention often wanders.
2
Most of the time struggles to focus 
attention or make decisions.
3
Cannot concentrate well enough to 
read or cannot make even minor 
decisions.
11. Outlook (Self):
0
Sees self as equally worthwhile and 
deserving as others. 
1
Is more self-blaming than usual. 
2
Largely believes that he/she causes 
problems for others. 
3
Ruminates over major and minor 
defects in self.
12.
Suicidal Ideation: 
0
Does not think of suicide or death.
1
Feels life is empty or is not worth 
living.
2
Thinks of suicide/death several times a 
week for several minutes.
3
Thinks of suicide/death several times a 
day in depth, or has made specific 
plans, or attempted suicide.
13.
Involvement: 
0
No change from usual level of interest 
in other people and activities.
1
Notices a reduction in former 
interests/activities.
2
Finds only one or two former interests 
remain.
3
Has virtually no interest in formerly 
pursued activities.
14. Energy/Fatiguability:
0
No change in usual level of energy.
1
Tires more easily than usual.
2
Makes significant personal effort to 
initiate or maintain usual daily 
activities.
3
Unable to carry out most of usual daily 
activities due to lack of energy.
15. Psychomotor Slowing: 
0
Normal speed of thinking, gesturing, 
and speaking.
1
Patient notes slowed thinking, and 
voice modulation is reduced.
2
Takes several seconds to respond to 
most questions; reports slowed 
thinking.
3
Is largely unresponsive to most 
questions without strong 
encouragement.
16.
Psychomotor Agitation: 
0
No increased speed or disorganization 
in thinking or gesturing.
1
Fidgets, wrings hands and shifts 
positions often.
2
Describes impulse to move about and 
displays motor restlessness. 
3
Unable to stay seated. Paces about 
with or without permission. 
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Enter the highest score on either of
the 2 psychomotor items (15 or 16 
above) ____
Scoring
Interpretation
Enter the highest score on any 1 of the 4 sleep items
(1 – 4)
_____
Normal
0 – 5
Item 5
_____
Mild
6 – 10
Enter the highest score on any 1 appetite / weight item
(6 – 9)
_____
Moderate
11 – 15
Item 10
_____
Severe
16 – 20
Item 11
_____
Very Severe
21+
Item 12
_____
Item 13
_____
Item 14
_____
Enter the highest score on either of the 2 psychomotor items
(15 and 16)
_____
Total Score (Range 0 – 27)
_____
 1986, 2000 UT Southwestern Medical Center, Dallas
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APPENDIX 13.
REVEAL LITE 2.0 (BENZA ET AL., 2020) 
REVEAL Lite 2 is based on REVEAL 2.0, but includes only six noninvasive and modifiable parameters: 
 
1.
 New York Heart Association (NYHA) or WHO functional class (FC);  
FC I = -1, FC II = 0, FC III = +1, FC IV = +2
 
2.
Systolic BP;  
SBP < 110 mm Hg = + 1,   ^WшϭϭϬсϬ
 
3.
Heartrate 
,ZхϵϲďƉŵснϭ͕,ZчϵϲсϬ
 
4.
 6-min walk distance(6MWD);  
шϰϰϬŵŝŶс-2, 
320 - 440 min = -1
165 – 319 = 0
<165 min = +1
 
5.
Brain natriuretic peptide (BNP)/N-terminal prohormone of brain natriuretic peptide (NT-proBNP);   
BNP < 50 pg/mL OR NT-proBNP < 300 pg/mL =  -2
BNP 50 – 199 pg/mL = 0
BNP 200 - 799 pg/mL = +1 
EWшϴϬϬƉŐͬŵ>KZEd-ƉƌŽEWшϭϭϬϬƉŐͬŵ>͗нϮ
 
6.
Renal insufficiency: if estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 or reported 
as “renal insufficiency,” as assessed by the principal investigator when eGFR was unavailable +1 ); If 
шϲϬƚŚĞŶƐĐŽƌĞŝƐϬ 
 
For the REVEAL Lite 2 assessment (with scores ranging from 1 to 14);
 
a score between 1 and 5 was considered low risk,
a score of 6 or 7 was considered intermediate risk, 
ĂƐĐŽƌĞŽĨϴŽƌŚŝŐŚĞƌǁĂƐĐŽŶƐŝĚĞƌĞĚŚŝŐŚƌŝƐŬ͘
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APPENDIX 14. ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES 
FOR RECORDING, EVALUATION, FOLLOW UP, AND 
REPORTING
Definition of Adverse Event
Adverse Event Definition
x
An adverse event (AE) is any untoward medical occurrence in a patient, temporally associated with 
the use of investigational product (IP), whether or not considered related to the IP.
x
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of IP.
Events Meeting the Adverse Event Definition 
x
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (e.g., electrocardiogram, radiological scans, vital signs measurements), including those 
that worsen from Baseline, considered clinically significant in the medical and scientific judgment
of the investigator (i.e., not related to progression of underlying disease).
x
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition.
x
New conditions detected or diagnosed after IP administration even though it may have been present 
before the start of the study.
x
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
x
Signs, symptoms, or the clinical sequelae of a suspected overdose of either IP or a concomitant 
medication.  Overdose per se will not be reported as an AE/serious adverse event (SAE) unless it is 
an intentional overdose taken with possible suicidal/self-harming intent.  Such overdoses should be 
reported regardless of sequelae.
x
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an 
AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, 
symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if 
they fulfil the definition of an AE or SAE.
Events NOT Meeting the Adverse Event Definition 
x
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the patient’s condition.
x
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the patient’s condition.
x
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is the AE.
x
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).
x
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen.
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Definition of Serious Adverse Event
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
A serious adverse event is defined as any untoward medical occurrence that, at any dose:
1.
Results in death
2.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the patient was at risk 
of death at the time of the event. It does not refer to an event, which hypothetically might have caused 
death, if it were more severe.
3.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the patient has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from Baseline is 
not considered an AE.
4.
Results in persistent disability/incapacity
x
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions.
x
This definition is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption.
5.
Is a congenital anomaly/birth defect
6.
Other situations:
x
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately life
threatening or result in death or hospitalization but may jeopardize the patient or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above definition.
These events should usually be considered serious.
x
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse.
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Recording and Follow Up of Adverse Events and/or Serious Adverse Events
Adverse Event and Serious Adverse Event Recording
x
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g., hospital progress notes, laboratory reports, and diagnostics reports) related to the event.
x
The Investigator will then record all relevant AE/SAE information in the case report form.
x
It is not acceptable for the Investigator to send photocopies of the patient’s medical records to 
Sponsor in lieu of completion of the AE/SAE case report form page.
x
There may be instances when copies of medical records for certain cases are requested by Sponsor.
In this case, all patient identifiers, with the exception of the patient number, will be redacted on the 
copies of the medical records before submission to Sponsor.
x
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) 
will be documented as the AE/SAE.
Assessment of Intensity
The Investigator will make an assessment of intensity for each AE and SAE reported during the study 
and assign it to 1 of the following categories: 
x
Mild: An event that is easily tolerated by the patient, causing minimal discomfort, and not 
interfering with everyday activities.
x
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.
x
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with a SAE. Severe is a category utilized for rating the intensity of an 
event; and both AEs and SAEs can be assessed as severe.
x
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in 
the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality
x
The Investigator is obligated to assess the relationship between IP and each occurrence of each 
AE/SAE.
x
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
x
The Investigator will use clinical judgment to determine the relationship.
x
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to IP administration will be considered and 
investigated.
x
The Investigator will also consult the Investigator’s Brochure and/or Product Information, for 
marketed products, in his/her assessment.
x
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality.
x
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important that the 
Investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to the Sponsor.
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Assessment of Causality
x
The Investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment.
x
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow Up of Adverse Events and Serious Adverse Events
x
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the Sponsor to elucidate the nature 
and/or causality of the AE or SAE as fully as possible. This may include additional laboratory tests 
or investigations, histopathological examinations, or consultation with other health care 
professionals.
x
If a patient dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide the Sponsor with a copy of any post-mortem findings including 
histopathology.
x
New or updated information will be recorded in the originally completed case report form.
x
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt of the 
information.
Reporting of Serious Adverse Events
Serious Adverse Event Reporting to the Sponsor via an Electronic Data Collection Tool
x
The primary mechanism for reporting an SAE to the Sponsor will be the electronic data collection 
tool.
x
If the electronic system is unavailable, then the site will use the paper SAE data collection tool (see 
next section) in order to report the event within 24 hours).
x
The site will enter the SAE data into the electronic system as soon as it becomes available.
x
After the study is completed at a given site, the electronic data collection tool will be taken off-line 
to prevent the entry of new data or changes to existing data.
x
If a site receives a report of a new SAE from a study patient or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, then the 
site can report this information on a paper SAE form (see next section) or to the Sponsor’s medical 
monitor/SAE coordinator by telephone.
x
Contacts for SAE reporting can be found on the Contact Information page.
Serious Adverse Event Reporting to the Sponsor via Paper Case Report Form
x
Email transmission of the SAE paper case report form is the preferred method to transmit this 
information to the Sponsor’s Medical Monitor or the SAE Coordinator.
x
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier service.
x
Initial notification via telephone does not replace the need for the Investigator to complete and sign 
the SAE case report form pages within the designated reporting time frames.
x
Contacts for SAE reporting can be found on the Contact Information page.
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