Clinical trial NCT05135000
Conditions: Pulmonary Arterial Hypertension
Keywords: Pulmonary Hypertension
Sponsor: Novartis Pharmaceuticals
Start date: 2022-06-30; Completion date: 2024-04-25
Enrollment: 47 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to explore the efficacy and safety of LTP001 in participants with pulmonary arterial hypertension (PAH) to determine if LTP001 had an adequate clinical profile to warrant further clinical development in this indication.

Detailed description:
This study was a non-confirmatory, randomized, participant- and investigator-blinded, placebo controlled trial evaluating the efficacy and safety of LTP001 on top of standard of care in participants with PAH.

The study included a screening period of up to 8 weeks, followed by a 24-week treatment phase with daily dosing and visits scheduled approximately every 4 weeks. One follow-up visit, which also served as the end-of-study visit, was conducted approximately 30 days after the conclusion of the treatment phase. The total duration of the study, from the beginning of the screening period to the end-of-study visit, was approximately 37 weeks.

A total of 44 participants were planned to be randomized in a 3:1 ratio to receive either LTP001 6 mg or placebo.

Arms: arm 1: Participants received LTP001, 6 mg, oral capsules, once daily in the morning for approximately 24 weeks arm 2: Participants received LTP001 placebo capsules matching LTP001 orally once daily in the morning for approximately 24 weeks
Interventions: intervention 1: LTP001 intervention 2: Placebo
Intervention descriptions: intervention 1: LTP001, 6 mg, was administered orally once daily in the morning intervention 2: Placebo to LTP001 was administered once daily in the morning

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
LTP001 
Clinical Trial Protocol CLTP001A12201 / NCT05135000
A randomized, participant- and investigator-blinded, 
placebo-controlled study to investigate efficacy, safety and 
tolerability of LTP001 in participants with pulmonary 
arterial hypertension 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2021-000670-28 
Version number: 
03 (Clean) 
Clinical Trial Phase: 
IIa 
Release date: 
01-Nov-2022
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 4.0 dated 15-Feb-2021 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
Amendment 03 (01-Nov-2022) ......................................................................................... 13 
Amendment 02 (March 2022) ........................................................................................... 15 
Amendment 01 (December 2021) ..................................................................................... 17 
Protocol summary .............................................................................................................. 19 
1 
Introduction ....................................................................................................................... 22 
1.1 
Background ............................................................................................................ 22 
1.2 
Purpose .................................................................................................................. 23 
2 
Objectives, endpoints and estimands ................................................................................. 24 
2.1 
Primary estimands ................................................................................................. 25 
2.2 
Secondary estimands ............................................................................................. 25 
3 
Study design ...................................................................................................................... 26 
3.1 
Off-site procedures ................................................................................................ 28 
3.1.1 
Responsibility of investigators .............................................................. 28 
3.1.2 
Responsibility of Off-site Healthcare Professionals ............................. 28 
3.1.3 
Telemedicine ......................................................................................... 29 
4 
Rationale ............................................................................................................................ 29 
4.1 
Rationale for study design ..................................................................................... 29 
4.1.1 
Rationale for choice of background therapy ......................................... 31 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 31 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 31 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 31 
4.5 
Risks and benefits .................................................................................................. 32 
4.5.1 
Blood sample volume ............................................................................ 34 
4.5.2 
Risks and benefits of off-site visits ....................................................... 35 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 35 
5 
Study Population ............................................................................................................... 35 
5.1 
Inclusion criteria .................................................................................................... 35 
5.2 
Exclusion criteria ................................................................................................... 36 
6 
Treatment ........................................................................................................................... 38 
6.1 
Study treatment ...................................................................................................... 38 


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6.1.1 
Investigational and control drugs .......................................................... 39 
6.1.2 
Additional study treatments .................................................................. 39 
6.1.3 
Treatment arms/group ........................................................................... 39 
6.1.4 
Post Trial Access ................................................................................... 39 
6.2 
Other treatment(s) .................................................................................................. 39 
6.2.1 
Concomitant therapy ............................................................................. 39 
6.2.2 
Prohibited medication ........................................................................... 41 
6.2.3 
Rescue medication ................................................................................ 41 
6.2.4 
Restriction for study participants .......................................................... 41 
6.3 
Preparation and dispensation ................................................................................. 42 
6.3.1 
Handling of study treatment and other treatment .................................. 42 
6.3.2 
Instruction for prescribing and taking study treatment ......................... 43 
6.4 
Participant numbering, treatment assignment, randomization .............................. 44 
6.4.1 
Participant numbering ........................................................................... 44 
6.4.2 
Treatment assignment, randomization .................................................. 44 
6.5 
Treatment blinding ................................................................................................ 45 
6.6 
Dose escalation and dose modification.................................................................. 46 
6.7 
Additional treatment guidance ............................................................................... 46 
6.7.1 
Treatment compliance ........................................................................... 46 
6.7.2 
Recommended treatment of adverse events .......................................... 46 
6.7.3 
Emergency breaking of assigned treatment code .................................. 46 
7 
Informed consent procedures ............................................................................................ 47 
8 
Visit schedule and assessments ......................................................................................... 48 
8.1 
Screening ............................................................................................................... 55 
8.1.1 
Eligibility screening .............................................................................. 55 
8.1.2 
Information to be collected on screening failures ................................. 56 
8.2 
Participant demographics/other baseline characteristics ....................................... 56 
8.3 
Efficacy .................................................................................................................. 56 
8.3.1 
Echocardiography ................................................................................. 57 
8.3.2 
Right Heart Catheterization (RHC) ....................................................... 57 
8.3.3 
Six Minute Walk Test (6MWT) ............................................................ 58 
8.3.4 
Appropriateness of efficacy assessments .............................................. 58 
8.4 
Safety ..................................................................................................................... 58 
8.4.1 
Laboratory evaluations .......................................................................... 60 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 62 
8.4.3 
Pregnancy and assessments of fertility ................................................. 62 


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8.4.4 
Appropriateness of safety measurements .............................................. 63 
8.5 
Additional assessments .......................................................................................... 63 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 63 
8.5.2 
Pharmacokinetics (PK) .......................................................................... 64 
 
 
 
 
9 
Discontinuation and completion ........................................................................................ 66 
9.1 
Discontinuation from study treatment and from study .......................................... 66 
9.1.1 
Discontinuation from study treatment ................................................... 66 
9.1.2 
Discontinuation from study ................................................................... 67 
9.1.3 
Lost to follow-up ................................................................................... 68 
9.2 
Withdrawal of informed consent/Opposition to use data/biological samples ....... 68 
9.3 
Study stopping rules .............................................................................................. 69 
9.4 
Study completion and post-study treatment .......................................................... 69 
9.5 
Early study termination by the sponsor ................................................................. 69 
10 Safety monitoring, reporting and committees ................................................................... 70 
10.1 
Definition of adverse events and reporting requirements ...................................... 70 
10.1.1 
Adverse events ...................................................................................... 70 
10.1.2 
Serious adverse events .......................................................................... 71 
10.1.3 
SAE reporting........................................................................................ 72 
10.1.4 
Pregnancy reporting .............................................................................. 73 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 74 
10.2 
Additional Safety Monitoring ................................................................................ 74 
10.2.1 
Liver safety monitoring ......................................................................... 74 
10.2.2 
Renal safety monitoring ........................................................................ 75 
10.3 
Committees ............................................................................................................ 75 
10.3.1 
Data monitoring committee ................................................................... 75 
11 Data Collection and Database management ...................................................................... 76 
11.1 
Data collection ....................................................................................................... 76 
11.1.1 
Data collection for offsite procedures ................................................... 76 
11.2 
Database management and quality control ............................................................ 77 
11.3 
Site monitoring ...................................................................................................... 77 
12 Data analysis and statistical methods ................................................................................ 78 
12.1 
Analysis sets .......................................................................................................... 78 
12.2 
Participant demographics and other baseline characteristics ................................. 78 
12.3 
Treatments ............................................................................................................. 79 
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12.4 
Analysis supporting primary objectives ................................................................ 79 
12.4.1 
Definition of primary endpoint(s) ......................................................... 79 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 79 
12.4.3 
Handling of intercurrent events of primary estimand ........................... 80 
12.4.4 
Handling of missing values not related to intercurrent event ............... 80 
12.4.5 
Sensitivity analyses ............................................................................... 80 
12.5 
Analysis supporting secondary objectives ............................................................. 80 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 80 
12.5.2 
Safety endpoints .................................................................................... 81 
12.5.3 
Pharmacokinetics .................................................................................. 82 
12.5.4 
PK/PD relationships .............................................................................. 83 
12.6 
Analysis of exploratory endpoints ......................................................................... 83 
12.7 
Interim analyses ..................................................................................................... 83 
12.8 
Sample size calculation.......................................................................................... 83 
12.8.1 
Primary endpoint(s) ............................................................................... 83 
13 Ethical considerations and administrative procedures ...................................................... 84 
13.1 
Regulatory and ethical compliance ........................................................................ 84 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 84 
13.3 
Publication of study protocol and results............................................................... 84 
13.4 
Quality Control and Quality Assurance ................................................................. 85 
13.5 
Participant Engagement ......................................................................................... 85 
14 Protocol adherence ............................................................................................................ 85 
14.1 
Protocol amendments............................................................................................. 85 
15 References ......................................................................................................................... 87 
16 Appendices ........................................................................................................................ 88 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs ......................... 88 
16.2 
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements .......................................................................................................... 89 
16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up ...... 93 
16.4 
Appendix 4: Calculation of Pulmonary Vascular Resistance (PVR) .................... 94 
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List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 24 
Table 4-1 
Rationale for study design ..................................................................... 29 
Table 6-1 
Investigational and control drug ............................................................ 39 
Table 6-2 
 41 
Table 6-3 
Blinding and unblinding plan ................................................................ 45 
Table 8-1 
Assessment Schedule ............................................................................ 50 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 74 
Table 12-1 
Historical data used for the meta-analysis to determine the 
informative prior on PVR for the placebo group .................................. 80 
Table 12-2 
Non-compartmental pharmacokinetic parameters ................................ 82 
Table 16-1 
Liver event and laboratory trigger definitions ...................................... 89 
Table 16-2 
Follow up requirements for liver laboratory triggers - ALT, AST, 
TBL ....................................................................................................... 90 
Table 16-3 
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia ............................................................................... 91 
Table 16-4 
Specific renal alert criteria and actions ................................................. 93 
List of figures 
Figure 3-1 
Study Design ......................................................................................... 26 
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List of abbreviations 
6MWD 
Six Minute Walk Distance 
6MWT 
Six Minute Walk Test 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate Aminotransferase 
ATS 
American Thoracic Society 
AUC 
Area Under the Curve 
bid 
Twice daily 
BMP 
Bone Morphogenic Protein 
BMPR2 
Bone Morphogenetic Protein Receptor type II 
BUN 
Blood Urea Nitrogen 
 
 
CK 
Creatine Kinase 
CMO&PS  
Chief Medical Office and Patient Safety 
CO 
Cardiac Output 
COA 
Clinical Outcome Assessment 
 
 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTT 
Clinical Trial Team 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCOA 
Electronic Clinical Outcome Assessment 
EDC 
Electronic Data Capture 
ERA 
Endothelin Receptor Antagonist 
ERS 
European Respiratory Society 
eSource 
Electronic Source 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume in the first second 
 
 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl transferase 
h 
Hour 
HR 
Heart Rate 
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I.V. 
intravenous 
IB 
Investigator's Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
ID-1 
Inhibitor of differentiation/DNA binding 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Test  
 
 
LLOQ 
Lower Limit of Quantification 
LVEDP 
Left Ventricular End Diastolic Pressure  
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
milligram(s) 
mL 
milliliter(s) 
mPAP 
mean Pulmonary Arterial Pressure 
NT-
proBNP 
N-terminal fragment of the prohormone B-type Natriuretic Peptide 
NYHA 
New York Heart Association 
OHP 
Off-site Healthcare Professional 
OLE 
Open Label Extension 
p.o. 
oral(ly) 
PCWP 
Pulmonary Capillary Wedge Pressure 
PD 
Pharmacodynamic(s) 
PDE5i 
Phosphodiesterase type 5 inhibitors 
PK 
Pharmacokinetic(s) 
PoC 
Proof of Concept 
PRO 
Patient Reported Outcomes 
 
 
 
 
 
 
PT 
prothrombin time 
PVR 
Pulmonary Vascular Resistance 
QD 
Once a day 
QMS  
Quality Management System 
QTcF 
QT interval corrected by Fridericia’s formula 
RA 
Right Atrium 
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RVFAC 
Right Ventricular Fractional Area Change 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
sGC 
Soluble guanylate cyclase 
SoC 
Standard of Care 
SMURF1 
SMAD-specific E3 ubiquitin protein ligase 1 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TAPSE 
Tricuspid Annular Plane Systolic Excursion 
TASV 
Tricuspid Annular Systolic Velocity 
TGF-beta 
Transforming Growth Factor beta 
TLC 
Total Lung Capacity 
TTCW 
Time to Clinical Worsening 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 


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Glossary of terms 
Additional treatment 
Medicinal products that may be used during the clinical trial as 
described in the protocol, but not as an investigational medicinal 
product (e.g. any background therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study participant  
Clinical Outcome 
Assessment (COA) 
A measure that describes or reflects how a participant feels, functions, 
or survives 
Clinical Trial Team 
A group of people responsible for the planning, execution and reporting 
of all clinical trial activities. Examples of team members include the 
Study Lead, Medical Monitor, Trial Statistician etc. 
Coded Data 
Personal Data which has been de-identified by the investigative center 
team by replacing personal identifiers with a code. 
Cohort 
A group of individuals who share a common exposure, experience or 
characteristic, or a group of individuals followed-up or traced over time 
Control drug 
A study drug (active or placebo) used as a comparator to reduce 
assessment bias, preserve blinding of investigational drug, assess 
internal study validity, and/or evaluate comparative effects of the 
investigational drug 
Discontinuation from 
study 
Point/time when the participant permanently stops receiving the study 
treatment and further protocol required assessments or follow-up, for 
any reason. No specific request is made to stop the use of their 
samples or data. 
Discontinuation from 
study treatment 
Point/time when the participant permanently stops receiving the study 
treatment for any reason (prior to the planned completion of study drug 
administration, if any). Participant agrees to the other protocol required 
assessments including follow-up. No specific request is made to stop 
the use of their samples or data. 
Dosage 
Dose of the study treatment given to the participant in a time unit (
 
) 
Electronic Data Capture 
(EDC) 
EDC is the electronic acquisition of clinical study data using data 
collection systems, such as Web-based applications, interactive voice 
response systems and clinical laboratory interfaces. EDC includes the 
use of Electronic Case Report Forms (eCRFs) which are used to 
capture data transcribed from source data/documents used at the point 
of care 
Electronic Source Direct 
Data Capture (eSource 
DDC) 
Any technology that allows the capture of clinical study source data 
electronically by the investigator or site staff at the point of care, into an 
electronic form that has been validated to capture clinical data. 
End of the clinical trial 
The end of the clinical trial is defined as the last visit of the last 
participant. 
Enrollment 
Point/time of participant entry into the study at which informed consent 
must be obtained. The action of enrolling one or more participants 
Estimand  
As defined in the ICH E9 (R1) addendum, estimand is a precise 
description of the treatment effect reflecting the clinical question posed 
by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same participants under different treatment 
conditions being compared. Attributes of an estimand include the 
population, variable (or endpoint) and treatment of interest, as well as 
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the specification of how the remaining intercurrent events are 
addressed and a population-level summary for the variable. 
Hybrid Trial Design 
A trial model incorporating both onsite (traditional site based) and 
offsite (decentralized) elements within the same study design. 
Investigational drug/ 
treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
Mis-randomized 
participants 
Participants who were not qualified for randomization and who did not 
take study treatment, but have been inadvertently randomized into the 
study or the participant allocated to an invalid stratification factor 
Off-site 
Describes trial activities that are performed at remote location by an off-
site healthcare professional, such as procedures performed at the 
participant's home. 
Off-site healthcare 
Professional (OHP) 
A qualified healthcare professional, such as include those used in the 
study e.g. Nurse, Phlebotomist, Physician, who performs certain 
protocol procedures for the participant in an off-site location such as a 
participant's home. 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study 
(i.e. concomitant or rescue therapy) 
Participant 
A trial participant (can be a healthy volunteer or a patient). "Participant" 
terminology is used in the protocol whereas term "Subject" is used in 
data collection 
Participant number 
A unique number assigned to each participant upon signing the 
informed consent. This number is the definitive, unique identifier for the 
participant and should be used to identify the participant throughout the 
study for all data collected, sample labels, etc. 
Patient-Reported 
Outcome (PRO) 
A measurement based on a report that comes directly from the patient 
about the status of a participant's health condition without amendment 
or interpretation of the patient's report by a clinician or anyone else 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-
up) which are described in the Protocol. Periods define the study 
phases and will be used in clinical trial database setup and eventually 
in analysis 
Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data 
includes participant identifier information, study information and 
biological samples. 
Randomization 
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias. 
Randomization number 
A unique identifier assigned to each randomized participant 
Re-screening 
If a participant fails the initial screening and is considered as a Screen 
Failure, he/she can be invited once for a new Screening visit after 
medical judgment and as specified by the protocol 
Remote 
Describes any trial activities performed at a location that is not the 
investigative site where the investigator will conduct the trial, but is for 
example a home or another appropriate location 
Screen Failure 
A participant who did not meet one or more criteria that were required 
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Source Data/Document 
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, 
a spreadsheet or even hard-coded data, such as paper or eSource 
Start of the clinical trial 
The start of the clinical trial is defined as the signature of the informed 
consent by the first participant. 
Study treatment 
Any drug or combination of drugs or intervention administered to the 
study participants as part of the required study procedures; includes 
investigational drug(s), control(s) or background therapy 
Tele-visit 
Procedures or communications conducted using technology such as 
telephone or video-conference, whereby the participant is not at the 
investigative site where the investigator will conduct the trial. 
Telemedicine 
Electronic information and telecommunications technologies (both 
video-based and audio-only) to facilitate the delivery of health care and 
health related education where participant and Investigator and site 
personnel are not in the same location. 
Treatment arm/group  
A treatment arm/group defines the dose and regimen or the 
combination, and may consist of 1 or more cohorts. 
Treatment of interest 
The treatment of interest and, as appropriate, the alternative treatment 
to which comparison will be made. These might be individual 
interventions, combinations of interventions administered concurrently, 
e.g. as add-on to standard of care, or might consist of an overall 
regimen involving a complex sequence of interventions. This is the 
treatment of interest used in describing the related clinical question of 
interest, which might or might not be the same as the study treatment. 
Variable (or endpoint) 
The variable (or endpoint) to be obtained for each participant that is 
required to address the clinical question. The specification of the 
variable might include whether the participant experiences an 
intercurrent event. 
Withdrawal of study 
consent (WoC) / 
Opposition to use of data 
/biological samples 
Withdrawal of consent from the study occurs when the participant 
explicitly requests to stop use of their data and biological samples 
(opposition to use data and biological samples) AND no longer wishes 
to receive study treatment, AND does not agree to further protocol 
required assessments. This request should be in writing (depending on 
local regulations) and recorded in the source documentation. 
Opposition to use data/biological samples occurs in the countries 
where collection and processing of personal data is justified by a 
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Amendment 03 (01-Nov-2022)  
Amendment rationale  
The primary purpose of this amendment is to incorporate
  
 
 
.  
Exclusion criterion 11 has been updated with information about sperm donation to reflect the 
requirements described in Section 8.4.31. 
The protocol appendix was updated with further guidance details for hepatic and renal alert 
criteria and event follow-up. 
In addition, Section 6.2 has been updated with considerations about the use of LTP001 in 
combination with allowed standard therapies1.  
This amendment also corrects for administrative inconsistencies and adds further protocol 
clarifications to ensure data quality1. 
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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
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Amendment 02 (March 2022) 
The primary purpose of this amendment is to correct errors in the assessment schedule. In 
addition, further clarifications are made in the text, as follows: 
x Updated clinical safety data  
x Added guidance text for Six Minute Walk Test (6MWT) and 
 
x Updated withdrawal of consent language to improve clarity 
Amendment rationale 
This amendment also corrects for administrative inconsistencies and adds further protocol 
clarifications to ensure data quality. 
At the time of this amendment, the study has not achieved first patient first visit. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
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The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
 


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Amendment 01 (December 2021) 
Amendment rationale 
The primary purpose of this amendment serves to address feedback received by Novartis for 
the study protocol: 
x A requirement of a negative serum pregnancy test within 7 days prior to first dose 
administration on Day 1 to rule out pregnancy where required by health authority (
 
 or local regulations. In countries where this is not required a negative 
urine pregnancy test needs to be available prior to dosing on Day 1. 
x Excluding participants who 
 
x Excluding participants who have a long QT syndrome or who take drugs that are known to 
prolong the QT interval. 
x 
 
 
x In addition, the Six-Minute Walk Test (6MWT) is to only be conducted on-site to remove 
testing variability in the assessment. The requirement for the participant to record IMP 
dosing every day in the eDiary is removed to decrease the daily burden on participants. 
Compliance for IMP administration will be done by medication reconciliation.  
Coagulation assays (PT, INR, aPTT) and 
 
 were added to the safety laboratory panel. 
This amendment also corrects for administrative inconsistencies and adds further protocol 
clarifications to ensure data quality. 
At the time of this amendment, the study has not achieved first patient first visit. 
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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
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Protocol summary 
Protocol number 
CLTP001A12201 
Full Title 
A randomized, participant- and investigator-blinded, placebo-controlled 
study to investigate efficacy, safety and tolerability of LTP001 in 
participants with pulmonary arterial hypertension 
Brief title 
Study of efficacy and safety of LTP001 in pulmonary arterial hypertension 
participants 
Sponsor and 
Clinical Phase 
Novartis 
Phase IIa 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this study is to explore the efficacy and safety of LTP001 in 
participants with pulmonary arterial hypertension to determine if LTP001 
has an adequate clinical profile to warrant further clinical development in 
this indication. 
Primary Objective(s)  The primary objective of this study is to assess the change in pulmonary 
vascular resistance (PVR) at Week 25 in participants treated with LTP001 
compared to placebo. 
Secondary 
Objectives 
x 
To evaluate the effect of LTP001 on:  
x 
Six Minute Walk Distance (6MWD) 
x 
Hemodynamic parameters other than PVR 
x 
Measurements of right ventricular function 
x 
To assess the impact of LTP001 on:  
x 
Patient Reported Outcomes (PRO). 
x 
Time to Clinical Worsening (TTCW) 
x 
The N-terminal fragment of the prohormone B-type Natriuetic 
Peptide (NT-proBNP) 
x 
To assess the safety and tolerability of LTP001 
x 
To investigate the pharmacokinetics (PK) of LTP001 
Study design 
This is a non-confirmatory, randomized, subject- and investigator-blinded, 
placebo controlled study of LTP001 in PAH participants. 44 participants will 
be randomized in a 3:1 ratio of LTP001  mg to placebo. Participants will 
be screened for up to 8 weeks followed by 24 weeks of daily dosing with 
visits approximately every 4 weeks. One follow up visit will also be the end 
of study visit and occurs approximately 30 days after the end of treatment. 
Total study duration is approximately 37 weeks from start of screening to 
end of study visit. If a participant continues into the open-label extension 
study, then the follow-up visit may be skipped. 
Study population 
The study population is comprised of male and female adults with PAH. A 
total of approximately 44 participants are planned to be enrolled and 
randomized with approximately 40 participants available for the primary 
endpoint analysis. 
Key Inclusion 
Criteria 
x 
History of PAH belonging to one of the following subgroups of the 
World Health Organization (WHO) Clinical Classification Group 1:  
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• 
Participants with idiopathic pulmonary arterial hypertension 
(IPAH)  
• 
Hereditary pulmonary arterial hypertension 
• 
Congenital heart disease (surgically repaired at least 12 months 
prior to screening) 
• 
Drug or toxin induced (for example, anorexigen, or 
methamphetamine use). 
• 
Resting mean pulmonary arterial pressure (mPAP) > 
25 mmHg; pulmonary capillary wedge pressure (PCWP) or left 
ventricular end diastolic pressure (LVEDP) < 15 mmHg, as determined 
by right heart catheterization (RHC) within 20 days of randomization. 
• 
Pulmonary Vascular Resistance (PVR) > 6 Wood units 
(480 dynes s/cm5), as determined by right heart catheterization within 
20 days of randomization. 
• 
WHO Functional Class II-III 
• 
6MWD must be between 150 and 550 m (inclusive). The qualifying test 
needs to be within 20 days of randomization. To meet the above 
criterion additional six minute walk test (6MWT) may be performed up 
to a maximum of 3 tests in total prior to dosing; the minimal time 
difference between two tests should be at least 4 h. 
• 
Standard of care therapy which is stable at least 6 weeks prior to RHC 
and qualifying 6MWT assessment within 20 days of randomization. 
Standard of care includes one or more of the following treatments:  
• 
prostacyclin analogues and receptor agonists (if I.V., dose 
adjustments must be within 20% of initial stable dose) 
• 
endothelin receptor antagonists (ERAs) 
• 
phosphodiesterase type 5 inhibitors (PDE5i) 
• 
soluble guanylate cyclase (sGC) stimulators  
Key Exclusion 
criteria 
• 
Participants with pulmonary hypertension (PH) in the WHO Clinical 
Classification Groups 2-5, and any PAH Group 1 subgroups not 
covered by Inclusion Criterion #4. 
• 
Participants with a history of left sided heart disease, chronic left sided 
heart failure, congenital or acquired valvular disease compromising left 
ventricular function and/or pulmonary venous hypertension or 
symptomatic coronary disease (non-symptomatic, re-vascularized 
coronary artery disease would be acceptable)). 
• 
Participants with obstructive lung disease defined as: FEV1 / FVC 
< 60% and FEV1 < 60% of predicted value after bronchodilator 
administration as well as participants with moderate or severe 
restrictive lung disease: Total Lung Capacity < 70% of predicted value. 
Testing must have occurred within 24months of screening. If historical 
testing is not available, then lung function testing must be conducted 
during the screening period. 
• 
Acute or chronic impairment (other than dyspnea), which would limit 
the ability to comply with study requirements, including interference 
with physical activity and execution of study procedures such as 6MWT 
(e.g., angina pectoris, claudication, musculoskeletal disorder, multiple 
sclerosis, need for walking aids). 


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Study treatment 
Active treatment: LTP001 administered as  mg once daily 
 
(as 
 containing LTP001 
mg plus 
 containing 
LTP001 
mg) 
Placebo to LTP001 administered once daily 
 (as 
 
containing the placebo to LTP001  mg and 
 containing the 
placebo to LTP001 
mg) 
Treatment of 
interest 
The randomized treatment LTP001 
mg daily or placebo on top of allowed 
standard of care treatment for PAH. The dose of the allowed concomitant 
medication should remain stable during the trial. 
Efficacy 
assessments 
x 
Right heart catheterization (assessment of PVR, CO, right ventricular 
and pulmonary artery pressures) 
x 
Echocardiography 
x 
6MWD 
x 
Clinical worsening criteria 
Pharmacodynamic 
assessments  
x 
N-terminal fragment of the prohormone B-type natriuretic peptide (NT-
proBNP) 
Pharmacokinetic 
assessments  
x 
Drug concentrations of LTP001 at defined timepoints 
Key safety 
assessments 
Adverse event monitoring, physical examinations, monitoring of laboratory 
markers in blood and urine, ECGs and vital signs. Monitoring of cardiac 
function is defined as part of the efficacy assessments (Echocardiography, 
6MWT, clinical worsening). 
Other assessments  
x 
 
x 
 
x 
 
x 
Patient Reported Outcomes (emPHasis-10 and PAH-SYMPACT) 
Data analysis 
The purpose of this study is to determine whether WHO Group 1 PAH 
participants who belong to WHO Functional Class II-III would benefit with 
LTP001 as compared to placebo, while both arms receive standard of care 
(stable on a combination or single therapeutic from the following: ERA, 
PDE5i, sGC stimulators, prostacyclin analogues and receptor agonists (if 
I.V., dose adjustments must be within 20% of initial stable dose). The 
primary endpoint of interest is PVR and the primary analysis is change 
from baseline in PVR at Week 25 based on approximately 40 participants 
(3:1 randomization). Within a Bayesian analysis framework approximately 8 
patients will be borrowed by setting up a weakly informative prior from 
historical studies on SoC for the placebo group. An interim analysis is 
planned after 20 participants complete Week 25 to assess futility. Change 
from baseline or fold change as appropriate for the PVR will be 
summarized. Other secondary endpoints relevant to efficacy, PK and 
safety will be summarized descriptively. 
Key words 
Pulmonary arterial hypertension, pulmonary vascular resistance, 6 minute 
walk distance, time to clinical worsening, SMURF1 inhibitor, 
echocardiography, patient reported outcomes 
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1 
Introduction 
1.1 
Background 
LTP001 is a highly selective and potent, orally administered, small molecule designed to inhibit 
the SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1). SMURF1 is upregulated in 
vascular cells from patients with pulmonary arterial hypertension (PAH) (Rothman et al 2016). 
Increased activity of this ligase is expected to result in impaired bone morphogenic protein 
(BMP) signaling by degradation of mediators of the pathway activity. 
Impaired BMPR2 signaling is suspected to play an important role within the dysregulation of 
TGF-beta superfamily pathways that is found in the initiation and progression of PAH 
(Hemnes and Humbert 2017,WFUHDWHVDQLPEDODQFHLQ7*)ȕ%03VLJQDOLQJIDYRULQJ7*)ȕ
and may underlie vascular remodeling in PAH patients with and without BMPR2 mutations. 
A number of therapeutic strategies have been proposed, beyond the aspiration of gene therapy 
(Wilkins et al 2018). 
SMURF1 is upregulated in vascular cells from patients with PAH (Rothman et al 2016). 
The role of SMURF1 is to target proteins in the BMP pathway for ubiquitination, thereby 
triggering degradation of the BMP pathway signal, resulting in vascular smooth muscle cell 
proliferation and remodeling (Murakami et al 2010 and Zhu et al 1999). 
PAH is an orphan disease characterized by chronic elevation in pulmonary arterial pressure, 
which eventually leads to remodeling of the pulmonary vasculature, followed by right-sided 
heart failure. 
The classes of therapy on the market for PAH (phosphodiesterase type 5 inhibitors, endothelin 
receptor antagonists, soluble guanylate cyclase stimulators and prostacyclin analogues and 
receptor agonists), are leaving a substantial unmet medical need. Despite significant advances 
in the understanding of the underlying mechanisms and development of a number of targeted 
therapies, PAH remains a challenging condition with high morbidity and mortality 
(Beshay et al 2020). 
Therapies that specifically target remodeling of the pulmonary vasculature would be expected 
to provide significant benefit as add-on to the available standard of care. 
In the First-in-Human study of LTP001, healthy participants completed dosing with single 
doses of LTP001
 
 
 
 
 
 
 
 
. 
 
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Overall, all doses were well tolerated. For further details, refer to Section 4.5 and the 
Investigator’s Brochure.  There was no dose-dependency in the frequency of AEs. AEs were 
less frequent in the treatment arm than in the placebo arm. There were no serious or severe AEs. 
There were no significant findings when ECGs, clinical laboratory assessments and vital signs 
were reviewed. 
In the multiple dose part there was no dose-dependency in the frequency of AEs.
 
 
 
 
  
 There were no other significant findings when 
ECGs, clinical laboratory assessments and vital signs were reviewed.  
For further information please refer to the Investigator`s Brochure. 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
1.2 
Purpose 
The purpose of this study is to explore the efficacy and safety of LTP001 in participants with 
WHO Group 1 pulmonary hypertension (PH), also referred to as Pulmonary Arterial 
Hypertension (PAH). 
This proof of concept study will be executed as the efficacy of SMURF1 inhibition has not yet 
been established in the PAH population. This study will provide insights to whether SMURF1 
inhibition is effective in reducing the pulmonary vascular resistance, improves patient symptom 
burden and increases the time to clinical worsening. These endpoints are considered relevant 
for the characterization of the disease progression in PAH.
 
 
 
 
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2 
Objectives, endpoints and estimands 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To assess the efficacy of LTP001 
in participants with pulmonary 
arterial hypertension (PAH). 
• 
Change from baseline right heart catheterization PVR 
at Week 25 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To evaluate the effect of LTP001 
on Six Minute Walk Distance 
(6MWD) 
• 
Change from baseline in 6MWD at Weeks 13 and 25 
• 
To evaluate the effect of LTP001 
on hemodynamic parameters 
other than PVR 
• 
Right heart catheterization assessments including 
RV pressures, pulmonary artery pressures, wedge 
pressure, and cardiac output at Week 25 
• 
To assess the effect of LTP001 on 
measurements of right ventricular 
function 
• 
Change from baseline in tricuspid annular plane 
systolic excursion (TAPSE) by echocardiography at 
Weeks 5, 13, and 25 
Change from baseline in tricuspid annular systolic 
velocity (TASV) by echocardiography at Weeks 5, 13, 
and 25 
Change from baseline of peak velocity of excursion 
(RV S') by echocardiography at Weeks 5, 13, and 25 
Change from baseline in fractional area change (FAC) 
by echocardiography at Weeks 5, 13, and 25 
• 
To assess the impact of LTP001 
on patient reported outcomes 
(PRO) 
• 
Change from baseline in EmPHasis-10 and PAH-
SYMPACT at Weeks 13 and 25 
• 
To assess the safety and 
tolerability of LTP001. 
• 
AEs, SAEs, vital signs, ECGs, safety laboratory 
measurements 
• 
To assess the impact of LTP001 
on Time to Clinical Worsening 
(TTCW). 
• 
Time to any of the following: 
• 
Death 
• 
Hospital stay (≥ 24 h) due to worsening of PAH. 
Worsening of PAH is defined by the following right 
heart failure related signs and symptoms: syncope 
or near syncope, cyanosis, increase of 
breathlessness, clinically relevant deterioration of 
exercise capacity, decrease of oxygen saturation, 
increased peripheral edema, hepatomegaly, and 
ascites  
• 
Worsening of PAH resulting in need for lung 
transplantation or balloon atrial septostomy 
• 
Initiation of parenteral prostanoid therapy, chronic 
oxygen therapy, or any other PAH-specific 
therapies or need for increase of diuretics for 
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Objective(s) 
Endpoint(s) 
x 
Disease progression (switch in modified New York 
Heart Association/WHO FC by at least one 
grade) . 
x 
Significant drop in 6MWD (15% from baseline or 
more) due to PAH-worsening 
x 
To investigate the 
pharmacokinetics (PK) of LTP001 
x 
Cmax and tmax (Day 1 and Week 25)   
x 
To assess the impact of LTP001 
on the N-terminal fragment of the 
prohormone B-type natriuetic 
peptide (NT-proBNP) 
x 
N-terminal fragment of the prohormone B-type 
natriuetic peptide 
Exploratory objective(s) 
Endpoint(s) for exploratory objective(s) 
2.1 
Primary estimands 
Not applicable. 
2.2 
Secondary estimands 
Not applicable. 
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3 
Study design 
This is a randomized, participant- and investigator-blinded, placebo-controlled, parallel group 
study of LTP001 or placebo on top of standard of care in participants with PAH. 
Standard of care includes one or more of the following treatments: prostacyclin analogues or 
receptor agonists (if I.V., dose adjustments must be within 20% of initial stable dose), 
endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and soluble guanylate 
cyclase stimulators. 
Figure 3-1 
Study Design 
A screening period of 8 weeks will be used to assess eligibility prior to randomization. 
Screening procedures can occur throughout the 8 week screening period, except for those 
procedures which are defined at specific time-points such as the right heart catheterization, 
qualifying 6MWT, PROs, and 
 
in the Assessment Schedule (Table 8-1). In particular, the screening period may be used to 
assess if a participant appears to be adequately stable on current therapy and that the criteria for 
allowed concomitant medication is adhered to for the time period defined in Section 6.2.1 and 
Section 5.1 prior to pre-dose qualifying 6MWD and the baseline right heart catheterization. 
Participants who fulfill all enrollment criteria earlier may have a shorter screening period. 
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Preference is for screening procedures to occur from least invasive to most invasive 
(echocardiography, right heart catheterization). Since laboratory measurements require central 
review, laboratory assessments should occur 15 or more business days prior to planned 
randomization. The right heart catheterization and the qualifying 6 minute walk test prior to 
first dose should occur within 20 days prior to randomization/planned first dose. Note, the 
RHC and qualifying 6MWT may be performed on the first dosing day if they are completed 
prior to randomization. During screening, participants will be given guidance on how to use the 
wearable device (if they have chosen to use it), which will be provided approximately 7 days 
prior to scheduled start of dosing. On Day 1, eligible participants will be randomized to one of 
two treatment arms. Approximately 44 participants with PAH will be randomized in a 3:1 ratio 
to either oral LTP001 or placebo daily for 24 weeks. 
During the treatment period, visits will occur approximately every 4 weeks for assessments of 
efficacy and safety as per the assessment schedule (see Table 8-1). Safety assessments will 
include physical examinations, ECGs, vital signs, standard clinical laboratory evaluations 
(hematology, blood chemistry, and urinalysis), and adverse event and serious adverse event 
monitoring. Right heart catheterization to measure PVR for the primary objective and primary 
efficacy endpoint is performed at the end of the treatment period on Day 169 (Week 25). 
Other measures of efficacy include echocardiography (Week 5, Week 13, and Week 25) and 
the 6MWT (Week 5, Week 13, and Week 25). PAH-SYMPACT and emPHasis-10 will be 
collected for 7 day intervals with the seventh day of collection occurring within the allotted visit 
window for the following visits: Day 1, Week 5, Week 9, Week 13, Week 17, Week 21, and 
Week 25. 
 
Following the end of the treatment period, participants will have one follow-up visit 
approximately 30 days after end of treatment (Week 29), which will serve as the End of Study 
(EOS) visit. All visits from Week 5 to Week 25 have a plus 5 day visit window and Week 29 
has a plus or minus 5 day visit window. If treatment is ended early for any reason, the end of 
treatment visit procedures should occur as soon as possible thereafter. 
An unblinded interim analysis (IA) is planned for when approximately 20 participants complete 
the 24-week treatment period, and may include analyses to assess sample size, efficacy, PK, 
PD, or safety. The analysis may be used for internal decision making of the further development 
of LTP001 in PAH patients. Further analyses will be prepared for review by the DMC per the 
DMC charter. 
Pending the safety and efficacy profile of LTP001 that is observed in the current study (absence 
of study treatment discontinuation criteria or study stopping rules or an emerging safety concern 
in the review of the data), participation in the open label extension study may be offered to 
participants once the extension study is approved by the competent authorities and review 
boards.  
Transition from the current study in an open label extension (OLE) study will be defined in the 
separate protocol. For participants enrolling into the OLE study, the EOS visit will be skipped 
in order to continue treatment in the OLE protocol. Replacement of such procedures done at the 
EOS will be defined in the OLE study protocol. 
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3.1 
Off-site procedures 
At the investigator's direction and based on benefit-risk considerations of the participant's 
clinical condition, qualifying participants may be offered the option to have certain clinical trial 
procedures performed at an off-site location, as defined in Table 8-1. A hybrid model is planned 
for this study incorporating both onsite and off-site visits. The off-site procedures will be 
utilized in certain countries and sites as determined by protocol needs and based on national 
and local/site regulations. Participants have the option of participating in one or more off-site 
visits, based on their preference and the investigator’s discretion. 
One or more of the following elements may be implemented to support off-site visits where 
allowed by national and local regulations: 
• Telemedicine 
• Off-site Healthcare Professionals (OHP) 
• Direct-to-patient shipment of study supplies 
• Direct-to-patient shipment of study treatment (refer to Section 6) 
• Electronic Source (eSource) Direct Data Capture (DDC) 
Procedures for off-site visits utilizing the above listed elements are further detailed in the 
Science 37 Operational Manual and Nursing Manual of Operations and Procedures.  
 
3.1.1 
Responsibility of investigators 
Procedures that are performed off-site remain under the oversight of the investigator, who 
retains accountability for the conduct of all safety and efficacy assessments delegated to an 
OHP, and will ensure the rights, safety and wellbeing of participants. This includes the 
following (including, but not limited to): 
• the identification, management and reporting of AEs and SAEs are performed in 
accordance with the protocol and applicable regulations including the review of PROs to 
identify any unreported AEs or SAEs. 
• OHPs have appropriate qualifications, training, and experience to successfully conduct 
off-site procedures 
• source data collected off-site are reviewed and evaluated in a timely manner 
• the investigator or delegate is available to be contacted by the OHP if any issues or 
concerns are noted during an off-site visit  
• where relevant, the investigator or delegate will be present via telemedicine for a portion 
of the off-site visit to support the physical examination  
3.1.2 
Responsibility of Off-site Healthcare Professionals 
OHPs must have the required qualifications, training, and experience to conduct off-site 
assessments. OHPs are responsible to conduct delegated assessments and collect relevant data 
at off-site visits in accordance with the clinical trial protocol, International Conference for 
Harmonization (ICH) Good Clinical Practice (GCP) guidelines, and national and local 
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During an off-site visit, the OHP will conduct drug accountability and send IMP back to the 
investigational site for review by the field monitor. 
The OHPs will be provided by a third-party vendor sourced by Novartis. Where a site wishes 
to use OHPs that are not provided by Novartis this must be agreed with Novartis before use. 
Any issues or safety concerns identified by the OHP will be promptly communicated to the 
investigator or delegate according to a pre-defined communication plan. 
3.1.3 
Telemedicine 
The sponsor has qualified and contracted a third-party vendor to provide a telemedicine 
platform technology for this study. The selected platform is a validated system complying with 
relevant ICH E6 GCP guidelines. Trial participants can interact with site personnel using online 
communication tools built into the platform, enabling the following capabilities: 
x Secure video conferencing which allows the patient, OHP and site personnel to be 
connected 
x Reminders to be automatically sent to participants (e.g. visit or dosing reminders) 
x eSource Direct Data Capture (DDC) (see Section 11.1.1) 
4 
Rationale 
4.1 
Rationale for study design 
Table 4-1 
Rationale for study design 
Study Design Aspect 
Rationale 
Overall (parallel design) 
Parallel group design is the most efficient in 
studies with treatment duration of 6 months 
Randomization (strata, allocation ratio) 
Weighted 3:1 randomization increasing the 
number of participants on LTP001 thus 
maximizing the clinical information on LTP001 in 
the PAH population 
Blinding 
Participant- and investigator-blinding are 
required to avoid bias on study outcomes by 
knowing the treatment arm 
Duration of 24-week treatment period 
At earlier time points, the primary endpoint 
(change from baseline in PVR) may not have 
achieved the maximal effect, as remodeling is 
considered a slow process and may take time to 
reverse. Duration of treatment provides also 
evidence that effect is sustained over 6 months. 
Interim analysis when approximately 20 
participants completed Week 25 
Allows for early decision on program or study 
continuation or discontinuation 
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Aged up to 75 years old 
 
 
 
  
 
 
 
 
 
 
 Participants up to age 75 are included 
in the study as this age range is expected to be 
representative of the patient population. 
Safety Monitoring 
Regular collection of ECGs, vital signs, clinical 
laboratory assessments, and body weight will be 
undertaken at visits approximately every 4 
weeks during treatment. Cardiac function will be 
additionally monitored by echocardiography. 
 
 
 A DMC will 
review the study data at defined time points 
specified in the DMC charter. 
Planned off-site procedures 
Off-site procedures are planned in this study to 
minimize burden on participants, and offer them 
increased flexibility to participate in the study 
from an off-site location. This has the potential to 
broaden access to clinical trials for both 
participants and investigators. The hybrid 
approach will allow participants to maintain 
contact with investigator, both in-person during 
clinic visits and through the telemedicine 
platform during off-site participation 
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4.1.1 
Rationale for choice of background therapy 
The background therapy will be the previously used therapy by the participant. PAH-directed 
maintenance therapy needs to be tolerated and kept stable for 6 weeks prior to the RHC and 
6MWT assessments preceding randomization, but diuretic therapy may be adjusted if needed 
(for details please refer to Section 6.2.1). Otherwise, the background therapy should not be 
changed during the study. If there is a deterioration of the participant's PAH condition requiring 
an escalation of concomitant PAH-specific treatment the participant should be discontinued 
from the study treatment (for detailed study discontinuation criteria see Section 9.1) and 
subsequently return for the End of Treatment assessments. 
4.2 
Rationale for dose/regimen and duration of treatment 
LTP001 will be administered once daily 
at a dose level of mg. 
In healthy volunteers, this dose has been shown to be well tolerated at single and multiple dose 
administrations. 
 
 this dose level should be adequate 
and provide full efficacy. Further details are provided in the Investigator's Brochure. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Placebo will be used as a comparator to LTP001 to provide an unbiased control for assessing 
and interpreting safety data as well as clinical efficacy data generated from participants exposed 
to LTP001. 
4.4 
Purpose and timing of interim analyses/design adaptations 
An interim analysis is planned after approximately 20 participants complete the treatment 
period (Week 25). For these participants, the primary endpoint, PVR, will be considered for 
non-binding futility and further evaluation of the totality of the data (safety, PK/PD, and other 
clinical endpoints along with PVR) will be considered for preliminary efficacy. PVR variability 
will also be evaluated during this interim for sample size re-estimation as appropriate. 
Analyses for DMC review will be conducted as defined in the DMC charter. Additional interim 
analyses may be conducted to support decision making concerning the current clinical study, 
the sponsor’s clinical development projects in general, or in case of any safety 
concerns. Blinded trial safety data will be reviewed on an ongoing basis (at least every month). 
Pathway and target engagement markers may be analyzed at additional time-points to gain early 
insights to which degree they are modulated and to allow adjustments on the selection of 
markers (e. g. dropping markers less sensitive then others; widening panel to further markers). 
Additional information is presented in the interim analysis section (see Section 12.7). 
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4.5 
Risks and benefits 
Potential risks are based on the mechanism of action, the nonclinical toxicology data and the 
safety data from the first in human study. 
LTP001 is the first SMURF1 inhibitor to be developed. Based on current understanding of 
SMURF1 biology, there are no concerns directly related to this mechanism of action; and, 
because LTP001 is first-in-class, there are no previously identified clinical safety risks (i.e., no 
known class effects). 
Preclinical data 
Clinical data 
Single doses of LTP001 
 were well 
tolerated and did not show safety signals for LTP001 in the first in human study. 
Adverse events under LTP001 in the single dose cohorts were abdominal pain, blood 
testosterone increased, diarrhea, sinus congestion and skin lesion. All AEs were mild or 
moderate and resolved without pharmacological intervention. 
Multiple doses of LTP001
 were 
well tolerated. 
 
 
 
 
 
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Apart from the mentioned events, across participants, clinical laboratory assessments, ECGs, 
and vital signs did not show significant abnormalities. 
 
 
 
 
 
  
, clinical laboratory assessments, ECGs, 
and vital signs did not show significant abnormalities. 
 
 
The risk to participants in this trial will be minimized by adherence to the eligibility criteria, 
close clinical monitoring, regular safety data reviews, and pre-specified rules for automatically 
stopping the study should unanticipated safety issues suddenly arise. 
No reproductive toxicology studies have been performed for LTP001. Women of child-bearing 
potential will be only enrolled if they use highly effective contraception methods. 
Additional details about potential risks of LTP001 can be found in the Investigator's Brochure. 
Procedural risks 
Cardiac catheterization is a safe procedure when performed by an experienced medical team. 
But, there may be some possible risks such as bleeding, infection, and blood clots. A heart 
attack or a stroke can happen in very rare situations. Right heart catheterization (RHC) is 
regularly employed to monitor the course of PAH. RHC may be performed without radiation 
but for optimal placement of the catheter, the investigator can employ x-ray to double-check 
the positioning of the catheter when measurements are made. RHC does not employ contrast 
media. RHC is required to calculate PVR, which is the primary efficacy assessment and is 
performed at screening (up to Day 1) and at the end of treatment. 
Other procedures in the study are non-invasive: 
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Echocardiography or ultrasound imaging of the heart uses high-frequency sound waves to view 
soft tissues and does not involve ionizing radiation. Ultrasound imaging has been in widespread 
clinical use globally for over 20 years with an excellent safety record. There are no known 
adverse safety risks, but ultrasound use does produce slight bioeffects on the body as the tissue 
heats slightly when the acoustic waves enter the body and can also produce small pockets of 
gas in tissue. A hand-held transducer is placed on the skin to produce the image and its 
application will be limited to the region of interest (chest to perform cardiac exam) to minimize 
any discomfort and risk of cavitation. 
Other procedures in the study are non-invasive. Participants are under observation when they 
perform the 6MWT. 
Participants will maintain standard of care treatment for PAH. Should they require a change of 
PAH directed therapy due to progression of their PAH related symptoms, they will be 
discontinued from the study. 
LTP001 is, based on its mechanism of action, not likely to interfere with immune-defense and 
should not impair the response to vaccines. If participants require vaccinations, e. g. against 
COVID-19, those can be administered according to the applicable vaccination 
recommendations. Also, treatment with LTP001 is unlikely to increase the risk of being infected 
with SARS-CoV-2, the virus causing COVID-19. 
Women of child-bearing potential and sexually active males must be informed that taking the 
study treatment or some of the procedures, such as cardiac catheterization, may involve 
unknown or known risks to the fetus if pregnancy were to occur during the study, and agree that 
in order to participate in the study they must adhere to the contraception requirements outlined 
in the exclusion criteria. If there is any question that the participant will not reliably comply, 
they should not be entered or continue in the study. 
Potential benefits 
PAH is a progressive disease ultimately leading to cardiac failure and death if untreated. 
Preclinical data suggest that LTP001 may reduce pulmonary artery pressure and thus may 
control or reverse disease progression. However, LTP001 has not been used outside a Phase I 
study in healthy volunteers, thus, efficacy has not been proven and there is no proven direct 
medical benefit for participants in this study. There is also no other SMURF1 inhibitor drug 
tested in clinical studies. Participants randomized to the LTP001 treatment arm may benefit in 
the current study if LTP001 proves to be safe and effective. 
4.5.1 
Blood sample volume 
A volume smaller than a typical blood donation is planned to be collected over a period of 
34 weeks, from each participant as part of the study. The approximate volumes are mentioned 
in the ICF. Additional samples may be required for safety monitoring. 
Timings of blood sample collection are outlined in the assessment schedule (Table 8-1). 
A summary blood log is provided in the central laboratory manual. Instructions for sample 
collection, processing, storage and shipment information are also available in the laboratory 
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See the Section 8.5.3.2 on the potential use of residual samples. 
4.5.2 
Risks and benefits of off-site visits 
Participants are not anticipated to be exposed to greater risks when participating in off-site 
assessments. OHPs will perform assessments according to the same processes and instructions 
defined in the protocol and study manuals for onsite visits, thus data integrity is also expected 
to be comparable to onsite assessments. Safety management in an off-site setting will adhere to 
the same quality standards as for the traditional onsite model and remains under the 
responsibility of the investigator (refer to Section 3.1.1). 
4.6 
Rationale for Public Health Emergency mitigation procedures 
In addition to the planned off-site procedures, in the event of a Public Health Emergency as 
declared by Local or Regional authorities (i.e. pandemic, epidemic or natural disaster), 
mitigation procedures to ensure participant safety and trial integrity may be implemented. 
If allowable by a local Health Authority and depending on operational capabilities, phone calls, 
virtual contacts (e.g. tele consult) or additional visits by OHPs to the participant´s home, can 
replace onsite study visits (in addition to the already planned off-site visits), for the duration of 
the disruption until it is safe for the participant to visit the site again. 
Notification of the Public Health Emergency should be discussed with Novartis prior to 
implementation of mitigation procedures, and permitted/approved by Local or Regional Health 
Authorities and Ethics Committees as appropriate. 
5 
Study Population 
The study population will be comprised of male and female participants with pulmonary arterial 
hypertension. 
Approximately 44 participants will be randomized in the study. Approximately 40 participants 
are expected to complete the study. 
The investigator must ensure that all participants being considered for the study meet the 
following eligibility criteria. No additional criteria should be applied by the investigator in order 
that the study population will be representative of all eligible patients. 
Participant selection is to be established by checking through all eligibility criteria at screening. 
A relevant record (e.g., checklist) of the eligibility criteria must be stored with the source 
documentation. 
Deviation from any entry criterion excludes a participant from enrollment into the study. 
Details on re-screening are located in Section 8.1. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study. 
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3. Male and female patients ≥ 18 and ≤ 75 years of age on the day of Informed Consent 
signature. 
4. History of PAH belonging to one of the following subgroups of the World Health 
Organization (WHO) Clinical Classification Group 1: 
• Patients with idiopathic pulmonary arterial hypertension (IPAH)  
• Hereditary pulmonary arterial hypertension  
• Congenital heart disease (surgically repaired at least 12 months prior to screening)  
• Drug or toxin induced (for example, anorexigen use, or methamphetamine use). 
5. Resting mean pulmonary arterial pressure (mPAP) > 25 mmHg; pulmonary capillary 
wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP)  < 15 mmHg, 
as determined by right heart catheterization within 20 days of randomization. 
6. Pulmonary Vascular Resistance (PVR) > 6 Wood Units (WU) corresponding to 
480 dynes s/cm5, as determined by right heart catheterization (RHC) within 20 days of 
randomization. 
7. WHO Functional Class II-III 
8. At least one 6MWT distance must be between 150 and 550 m (inclusive). The qualifying 
test needs to be within 20 days of randomization. To meet the above criterion additional 
6MWT may be performed up to a maximum of 3 tests in total prior to dosing; the minimal 
time difference between two tests should be at least 4 h. 
9. Standard of care therapy which is stable at least 6 weeks prior to baseline RHC and 
qualifying 6MWT at screening (and up to Day 1 pre-dose). Standard of care includes one 
or more of the following treatments: 
• prostacyclin analogues and receptor agonists 
• endothelin receptor antagonists 
• phosphodiesterase type 5 inhibitors 
• soluble guanylate cyclase stimulators  
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
enrollment, or within 30 days, whichever is longer; or longer if required by local 
regulations. 
2. History of hypersensitivity to any of the study treatments or excipients  
3. Patients with pulmonary hypertension (PH) in the WHO Clinical Classification 
Groups 2-5, and any PAH Group 1 subgroups that were not covered by Inclusion Criterion 
#4. 
4. Participants with a history of left sided heart disease, chronic left sided heart failure, 
congenital or acquired valvular disease compromising left ventricular function and/or 
pulmonary venous hypertension or symptomatic coronary disease (asymptomatic, 
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5. Patients with obstructive lung disease defined as: FEV1/FVC < 60% and FEV1 < 60% of 
predicted value after bronchodilator administration as well as patients with moderate or 
severe restrictive lung disease: Total Lung Capacity < 70% of predicted value. Testing 
must have occurred within 24 months of screening. If historical testing is not available, 
then lung function testing must be conducted during the screening period. 
6. Acute or chronic impairment (other than dyspnea), which would limit the ability to 
comply with study requirements, including interference with physical activity; execution 
of study procedures such as 6MWT (e.g., angina pectoris, claudication, musculoskeletal 
disorder, multiple sclerosis, need for walking aids). 
7. Any surgical or medical condition which, in the opinion of the investigator, may place the 
patient at higher risk from his/her participation in the study, or is likely to prevent the 
patient from complying with the requirements of the study or completing the study. The 
investigator should make this determination in consideration of the patient’s medical 
history and/or clinical or laboratory evidence of any of the following: 
• Moderate or severe hepatic failure (Child-Pugh classification stage B or C) 
• Significant renal impairment with an estimated creatinine clearance < 30 mL/min as 
calculated by the CKD-EPI formula  
8. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless 
of whether there is evidence of local recurrence or metastases. 
9. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception while 
taking study treatment and until End of Study visit (30 days post-last treatment). Highly 
effective contraception methods include: 
· Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
· Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before 
taking study treatment. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment. 
· Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant 
· Use of oral, (estrogen and progesterone), injected, or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), 
or other forms of hormonal contraception that have comparable efficacy (failure rate 
< 1%), for example hormone vaginal ring or transdermal hormone contraception. 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Women are considered post-menopausal if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate history 
of vasomotor symptoms). Women are considered not of child bearing potential if they are 
post-menopausal or have had surgical bilateral oophorectomy (with or without 


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hysterectomy) or total hysterectomy at least six weeks ago. In the case of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment is she considered not of child bearing potential. 
10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test. 
11. Sexually active males must use a condom during intercourse while taking drug and for 
24 hours after stopping study medication and should not father a child in this period. 
A condom is required to be used also by vasectomized men in order to prevent delivery of 
the drug via seminal fluid. In addition, male participants should not donate sperm for the 
time specified above.  
12. Recently conducted (the program should have been completed at least 8 weeks prior to 
screening) or planned cardio-pulmonary rehabilitation program based on exercise training 
during the conduct of the study.  
13. Required or planned transplant or heart/lung surgery. 
14.
. 
15. Any of the following: 
x Known family history of long QT syndrome 
x Known presence of long QT syndrome 
x Current use of any medications which prolong the QT interval  
16. 
 
6 
Treatment 
6.1 
Study treatment 
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for participant numbering, prescribing/dispensing, and taking study treatment are 
outlined in Section 6.3. 
Refer to the ‘Dietary restrictions and smoking’ section (See Section 6.2.4.1) for details of 
dosing and food intake. 
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6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug  
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
LTP001  mg 
Oral Use 
Double-blind, 
patient-specific 
kits 
Global 
LTP001 
mg 
Oral Use 
Double-blind, 
patient-specific 
kits 
Global 
Placebo to 
LTP001  mg 
Oral Use  
Double-blind, 
patient-specific 
kits 
Global 
Placebo to 
LTP001
 mg 
Oral Use 
Double-blind, 
patient-specific 
kits 
Global 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug and control drug are included in this trial. 
6.1.3 
Treatment arms/group 
Participants will be assigned on study Day 1 to one of the following two treatment arms/groups 
in a ratio of 3:1: 
LTP001  mg administered 
 (
 
) or placebo to LTP001 (
 
 administered 
 
. 
6.1.4 
Post Trial Access 
An open label extension (OLE) study is prepared and patients will be offered to participate if 
in the current study there is no emerging safety concern (safety signal or signal of clinical 
worsening of PAH more than under placebo). Further details of post trial access will be detailed 
in the corresponding OLE study protocol. 
For participants who enroll in the OLE study, Week 29 (EOS visit) should be skipped. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant is enrolled into the study must be recorded 
on the appropriate electronic Case Report Forms. 
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Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a participant or allowing a new medication to be started. If the participant is 
already enrolled, contact Novartis to determine if the participant should continue participation 
in the study. 
COVID-19 vaccinations and any other vaccinations with registered vaccines are allowed as 
recommended for the patient population by the applicable regulations and guidelines. 
 
 
 
 
 
 
 
 
 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
Endothelin receptor antagonists, prostacyclin analogues and receptor agonists, soluble 
guanylate cyclase stimulators and/or phosphodiesterase type 5 inhibitors for PAH treatment are 
allowed if participants have been on a stable dose for at least 6 weeks prior to the baseline Right 
Heart Catheterization and the last 6MWT prior to randomization. The dose(s) should remain 
unchanged during the study. 
x Treatment with diuretics is allowed and may be adjusted during the study within the 
following limits:  
x No other diuretic is added 
x No parenteral diuretic is added 
x The oral diuretic dose will not increase more than double from initial stable dose level 
prior to the first dose and will not be changed within 7 days prior to a RHC 
assessment (if dose adjustment is required, consider to reschedule RHC visit). 
x Single administration of medication for diagnostic purposes (such as use for acute 
vasodilator testing during the RHC procedure) is allowed. 
x IV prostacyclin analogues daily dose no more than 20% change from initial stable dose 
level as determined at the time of screening. 
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6.2.2 
Prohibited medication 
Participants should remain stable on their PAH-specific background therapy during the study. 
Unless there is intolerance to background therapy (PDE5i, prostacyclin analogues and receptor 
agonists, ERA, and sGC stimulators, refer to Section 6.2.1) should be kept stable during the 
study. Note that a required change in PAH-directed therapy due to clinical worsening of PAH 
should result in treatment discontinuation and appropriate management of the participant with 
the PAH directed therapy as per the investigators discretion and the participant's need. 
In terms of treatments required for other conditions or adverse events, there are no known drug 
interaction signals with LTP001 at the dose level under investigation and participants should be 
treated as per the discretion of the investigator. Also there are no known pharmacodynamic 
adverse interactions with other treatments identified as yet. 
 
 
Table 6-2 
 
Drugs which are known to prolong the QT interval are prohibited for use throughout the study 
duration.  
6.2.3 
Rescue medication 
Rescue medication is defined as an additional medication, or change in the dose of an existing 
medication. 
A clinical worsening of PAH requiring a change in dose of an existing PAH-specific 
medication, or the addition of a new PAH specific medication, may fulfill criteria for 
discontinuation for study treatment (see Section 9.1.1). PAH-specific medications include: all 
ERAs, PDE5i, sGC stimulators and oral, intravenous or subcutaneous prostacyclin analogues 
and receptors agonists. For allowed modifications of PAH directed therapies and adjustments 
of diuretic therapy please refer to Section 6.2.1. 
Use of rescue medications must be recorded on the Concomitant medications/Significant non-
drug therapies eCRF after signing the informed consent. 
6.2.4 
Restriction for study participants 
For the duration of the study, participants should be informed and reminded of the restrictions 
outlined in this section. 
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6.2.4.1 
Dietary restrictions and smoking 
1. Participants should be encouraged to maintain a healthy diet and abstain from the use of 
alcohol or (recreational) drugs. Smoking status will be collected as part of the participant 
demographics. 
2. 
 
 
  
6.2.4.2 
Other restrictions 
No significant change in physical exercise program from the beginning of the study until after 
the Week 27 visit. 
6.3 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section (See Section 6.1.1). 
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the IRT and obtaining the medication number(s). The study medication has a 2-part 
label (base plus tear-off label). Immediately before dispensing the medication kit to the 
participant, site personnel will detach the outer part of the label from the packaging and affix it 
to the source document. 
Where delivery of IMP directly to a participant's secure off-site location (e.g. home) is permitted 
by national and local governing regulations then dispatch of IMP from the site to the participant 
will be performed under the accountability of the Investigator. The provisioning of supply will 
be for a maximum of a 120 day supply. In this case, regular contacts (every 4 weeks or more 
frequently if needed) will occur between the site and the participant for instructional purposes, 
safety monitoring, and discussion of the participant's health status until the participant's next 
visit to the study site.  
6.3.1 
Handling of study treatment and other treatment 
6.3.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
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The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
field monitors during site or remote monitoring visits, and at the completion of the trial. 
Since study treatment is administered at home and when at the clinical site, participants will be 
asked to return all unused study treatment and packaging at each visit during the treatment 
period or at the time of discontinuation of study treatment. 
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the Novartis 
monitor or to the Novartis address provided in the investigator folder at each site. 
6.3.1.2 
Handling of other treatment 
It should be checked at each visit if other concomitant PAH specific therapy has been kept 
stable as specified in the study eligibility criteria (Section 5) and in Section 6.2.1. 
6.3.2 
Instruction for prescribing and taking study treatment 
LTP001 should be taken daily at approximately the same time each day 
. On 
clinic visit days, the participant should take LTP001 during the clinic visit prior to post-dose 
PK samples (when applicable), when instructed by the study staff. 6MWT and RHC 
assessments should be executed at approximately the same time after drug administration each 
time (+/- 1 hour). 
 
. 
If vomiting occurs during the course of treatment, participants should not take the study 
treatment LTP001 again before the next scheduled dose. 
Participants should be instructed not to make up missed doses. A missed dose is defined as a 
case when the full dose is not taken within 12 hours after the approximate time of the usual 
daily dosing. That day's dose should be omitted and the participant should continue treatment 
with the next scheduled dose. 
For visit days, the dose administered on the day of PK sample collection to the participant will 
be recorded on the Dosage Form eCRF. For visits without PK samples, the first day the 
participant is seen by an off-site health professional during the visit window, or the first day of 
a visit to the clinical site should be the dose recorded in the Dosage Form eCRF. 
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Novartis will provide the site with a participant study card to hand over to all study participants 
who receive a dose of study medication (LTP001 or placebo), which will state that the 
participant is participating in a clinical study and may have received an investigational product. 
This participant study card will also include the contact information of the Study 
Doctor/Investigative Site. Designated study staff will instruct study participants to present this 
card to a medical care provider if they have any medical issues during the course of the study. 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
6.4 
Participant numbering, treatment assignment, randomization 
6.4.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened. The Participant No. consists of the 
Center Number (Center No.);as assigned by Novartis to the investigative site with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the informed consent form, the participant is assigned 
to the next sequential Participant No. available. 
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No. 
6.4.2 
Treatment assignment, randomization 
On study Day 1, all eligible participants will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or his/her delegate will contact 
the IRT after confirming that the participant fulfills all the inclusion/exclusion criteria. The IRT 
will assign a randomization number to the participant, which will be used to link the participant 
to a treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the participant. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. 
A participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. 
These randomization numbers are linked to the different treatment arms, which in turn are 
linked to medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Global Clinical Supply (GCS) using a validated system that 
automates the random assignment of medication numbers to packs containing the study 
treatment. 
The randomization scheme for participants will be reviewed and approved by a member of the 
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6.5 
Treatment blinding 
Participants, investigator staff (including OHPs) , persons performing the assessments, and the 
Novartis Clinical Trial Team (CTT) will remain blinded to the identity of the treatment from 
the time of randomization until database lock except for unblindings listed in Table 6-3. 
Unblinding a single participant at site for safety reasons (necessary for participant management) 
will occur via an emergency system in place at the site. As a result, the participant should be 
discontinued from the study treatment. 
The DMC members will be un-blinded as per the procedures described in the DMC charter. 
The randomization codes associated with participants from whom PK samples are taken will be 
disclosed to PK analysts who will keep PK results confidential until database lock. 
Randomization codes may be also disclosed to biomarker analysts (concerned with target 
engagement markers or pathway engagement markers) who also will keep the blind. 
The following method will be used to maintain the blind: 
• the identity of the treatments will be concealed by the use of study treatment that are all 
identical in packaging, labeling, schedule of administration, appearance, taste, and odor. 
At the time of safety review/interim analysis for efficacy, the Novartis CTT may create and 
review unblinded interim reports. 
Table 6-3 
Blinding and unblinding plan 
Role 
Time or Event 
Randomization 
list generated 
Treatment 
allocation & 
dosing 
Safety event 
(single subject 
unblinded) 
Interim 
Analysis & 
dose 
escalation 
Participants 
B 
B 
UI 
B 
Site staff 
B 
B 
UI 
B 
Unblinded site staff (see text 
for details)  
B 
UI 
UI 
UI 
Drug Supply and 
Randomization Office 
UI 
UI 
UI 
UI 
Statistician/statistical 
programmer/data analysts 
B 
B 
UI 
UI 
Independent committees 
used for assessing interim 
results 
B 
UI 
UI 
UI 
All other sponsor staff not 
identified above 
B 
B 
UI 
UI 
Unblinded sponsor staff (see 
text for details) 
B 
UI 
UI 
UI 
B Remains blinded 
NA Not applicable 
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6.6 
Dose escalation and dose modification 
Investigational dose adjustments and/or interruptions are not permitted. 
6.7 
Additional treatment guidance 
6.7.1 
Treatment compliance 
The investigator/site staff must promote compliance by instructing the participant to take the 
study treatment exactly as prescribed and by stating that compliance is necessary for the 
participant’s safety and the validity of the study. The participant must also be instructed to 
contact the investigator if he/she is unable for any reason to take the study treatment as 
prescribed. Compliance will be assessed by the investigator and/or study personnel at each visit 
using pill counts and information provided by the participant. This information should be 
captured in the source document at each visit. All study treatment dispensed and returned must 
be recorded in the Drug Accountability Log. 
Off-site treatment compliance will be assessed by the OHP and details of which will be shared 
with the investigator. 
6.7.2 
Recommended treatment of adverse events 
At present there is insufficient information to provide specific recommendations regarding 
treatment of adverse events (AEs). If participants experience a deterioration of their 
PAH condition investigators should determine if they need to be treated with additional PAH 
directed therapy. Study treatment discontinuation criteria as defined in Section 9.1 should be 
observed. 
6.7.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely. 
Most often, discontinuation from study treatment and knowledge of the possible treatment 
assignments are sufficient to treat a study participant who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a participant, he/she must provide 
the requested participant identifying information and confirm the necessity to break the 
treatment code for the participant. The investigator will then receive details of the 
investigational drug treatment for the specified participant and a fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
study team that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide: 
• protocol number 
• name (if available) 
• participant number 


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In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her level of understanding. If the participant is capable of doing so, he/she 
must indicate agreement by personally signing and dating the written informed consent 
document.  
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH E6 GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational treatment can 
be found in the Investigator's Brochure (IB). This information will be included in the participant 
informed consent and should be discussed with the participant during the study as needed. Any 
new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an investigator 
notification or an aggregate safety finding. New information might require an update to the 
informed consent and then must be discussed with the participant. 
The following informed consents are included in this study: 
x Main study consent, which also included:  
x 
 
 
x 
 
x As applicable, Pregnancy Outcomes Reporting Consent for female participants or the 
female partners of any male participants who took study treatment 
x 
 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
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Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information. 
 
 
 
 
 
 
 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
The study includes the option for the participant to have certain study procedures performed 
off-site by an off-site healthcare professional instead of at the study site, for which a separate 
signature is required if the participant agrees. It is required as part of this protocol that the 
Investigator presents this option to the participant, as permitted by national and local governing 
regulations. The process for obtaining consent should be exactly the same as described above 
for the main informed consent. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.). 
8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. 
The following visits may be conducted at an off-site location as allowed by local laws and 
regulations: Visit 120 (Week 9), Visit 140 (Week 17), Visit 150 (Week 21), and Visit 199 
(Week 29).  
For all visits, assessments may occur throughout the visit window over multiple days, as needed, 
except where defined. For Day 1 and Week 25 visits with timed PK draws, only PK samples 
need to be taken post-dose. 
On clinic visit days, the participant should take LTP001 during the clinic visit prior to post-dose 
PK samples (when applicable), when instructed by the study staff. RHC assessments and 
6 minute walk test assessments should be executed at approximately the same time after drug 
administration each time (+/- 1 hour). 
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Participants who discontinue from study treatment are to return for the end of treatment visit as 
soon as possible, and attend the follow-up visits as indicated in the Assessment Schedule. 
Participants who discontinue from study or withdraw their consent/oppose the use of their 
data/biological samples should be scheduled for a final evaluation visit if they agree, as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications not previously reported must be recorded on the eCRF. 
The “X” in the table denotes the assessments to be recorded in the clinical database or received 
electronically from a vendor. The “S” in the table denotes the assessments that are only in the 
participant’s source documentation and do not need to be recorded in the clinical database. 


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Table 8-1 
Assessment Schedule 
Period Screening 
Treatment 
EOS 
Visit Name Screening
2 
Treatment 
EOT 
EOS20 
Visit Numbers1 
1 
100 
11
0 
12
0 
13
0 
14
0 
15
0 
160 
1999 
Days -56 to -1 
1 
29 
+5 
57 
+5 
85 
+5 
11
3 
+5 
14
1 
+5 
169 
+5 
199 
±5 
Weeks 
-8 to -1 
1 
5 
9 
13 17 21 
25 
29 
Time (post-
dose) 
- 
Predos
e 
0mi
n 
15mi
n 
45mi
n 
120mi
n 
- 
- 
- 
- 
- 
- 0mi
n 
15mi
n 
45mi
n 
120mi
n 
- 
Informed 
consent21 
X 
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
Inclusion / 
Exclusion criteria 
X 
X 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
Medical 
history/current 
medical 
conditions 
X 
   
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
Physical 
Examination 
S 
   
  
  
  
 
S3 
  
  
  
  
  
 
  
  
  
S3 
Lung Function 
Testing 
X4 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
Body Height 
X 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
Body Weight 
X 
X 
  
  
  
  
X 
X 
X 
X 
X 
X 
  
  
  
  
X 
Body 
Temperature 
X 
X 
  
  
  
  
X 
X 
X 
X 
X 
X 
  
  
  
  
X 
Blood Pressure 
and Pulse Rate 
X 
X 
  
  
  
  
X 
X 
X 
X 
X 
X 
  
  
  
  
X 


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Period Screening 
Treatment 
EOS 
Visit Name Screening
2 
Treatment 
EOT 
EOS20 
Visit Numbers1 
1 
100 
11
0 
12
0 
13
0 
14
0 
15
0 
160 
1999 
Days -56 to -1 
1 
29 
+5 
57 
+5 
85 
+5 
11
3 
+5 
14
1 
+5 
169 
+5 
199 
±5 
Weeks 
-8 to -1 
1 
5 
9 
13 17 21 
25 
29 
Time (post-
dose) 
- 
Predos
e 
0mi
n 
15mi
n 
45mi
n 
120mi
n 
- 
- 
- 
- 
- 
- 0mi
n 
15mi
n 
45mi
n 
120mi
n 
- 
Electrocardiogra
m (ECG) 
X 
X 
  
  
  
  
X 
X 
X 
X 
X 
X 
  
  
  
  
X 
emPHasis-108 
X9 
X9 
  
  
  
  
X9 X9 X9 X9 X9 X
9 
  
  
  
  
  
PAH-SYMPACT8 
X9 
X9 
  
  
  
  
X9 X9 X9 X9 X9 X
9 
  
  
  
  
  
Dose 
administration11 
  
  
 
X 
  
  
 
X 
X 
X 
X 
X 
 
X 
  
  
  
  
Drug 
dispensation 
  
S 
  
  
  
 
S 
S 
S 
S 
S 
  
 
  
  
  
  
Collect study 
medication/ 
perform drug 
accountability12 
  
  
  
  
  
  
 
S 
S 
S 
S 
S 
S 
 
  
  
  
  
Pregnancy and 
assessments of 
fertility 
S 
S13 
  
  
  
  
S 
S 
S 
S 
S 
S 
  
  
  
  
S 
Hematology 
X14 
X 
  
  
  
  
X 
X 
X 
X 
X 
X 
  
  
  
  
X 
Clinical 
Chemistry 
X14 
X 
  
  
  
  
X 
X 
X 
X 
X 
X 
  
  
  
  
X 
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Period Screening 
Treatment 
EOS 
Visit Name Screening
2 
Treatment 
EOT 
EOS20 
Visit Numbers1 
1 
100 
11
0 
12
0 
13
0 
14
0 
15
0 
160 
1999 
Days -56 to -1 
1 
29 
+5 
57 
+5 
85 
+5 
11
3 
+5 
14
1 
+5 
169 
+5 
199 
±5 
Weeks 
-8 to -1 
1 
5 
9 
13 17 21 
25 
29 
Time (post-
dose) 
- 
Predos
e 
0mi
n 
15mi
n 
45mi
n 
120mi
n 
- 
- 
- 
- 
- 
- 0mi
n 
15mi
n 
45mi
n 
120mi
n 
- 
Coagulation 
Assays 
X14 
X 
  
  
  
  
X 
X 
X 
X 
X 
X 
  
  
  
  
X 
Urinalysis 
X14 
X 
  
  
  
  
X 
X 
X 
X 
X 
X 
  
  
  
  
X 
NT-proBNP 
  
X 
  
  
  
  
X 
X 
X 
X 
X 
X 
  
  
  
  
X 
Right heart 
catheterization 
X19 
  
  
  
  
  
  
  
  
 
X 
 
  
  
  
  
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Period Screening 
Treatment 
EOS 
Visit Name Screening
2 
Treatment 
EOT 
EOS20 
Visit Numbers1 
1 
100 
11
0 
12
0 
13
0 
14
0 
15
0 
160 
1999 
Days -56 to -1 
1 
29 
+5 
57 
+5 
85 
+5 
11
3 
+5 
14
1 
+5 
169 
+5 
199 
±5 
Weeks 
-8 to -1 
1 
5 
9 
13 17 21 
25 
29 
Time (post-
dose) 
- 
Predos
e 
0mi
n 
15mi
n 
45mi
n 
120mi
n 
- 
- 
- 
- 
- 
- 0mi
n 
15mi
n 
45mi
n 
120mi
n 
- 
Echocardiogram 
X 
  
  
  
 
X 
 
X 
  
 
X 
 
  
  
  
  
6-Minute Walk 
Test 
X19 
  
  
  
 
X 
 
X 
  
 
X 
 
  
  
  
  
Concomitant 
Medications/ 
Adverse Events 
As required 
Serious Adverse 
Events 
X 
Study 
completion 
information 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Visit structure given for internal programming purpose only 
2 All assessments during screening must be done at the clinic site. 
3 Short physical exam may be employed beginning at Week 5, unless complete physical exam is indicated. 
4 Only to be conducted if historical lung function testing within 24 months of screening is not available. 
5 
 
6 
. 
8 PROs to be completed by participants for 7 consecutive day intervals beginning 6 days prior to Day 1 and 7 day intervals around each visit from Weeks 5 to 25. The 
7th day of collection for each visit should occur during the Visit Window for Weeks 5 to Week 25.  
9 On clinic visit days, PROs are to be the first assessments performed. 
11 Dosing is daily from Day 1 to Week 25 including all visit and non-visit days. 
12 Collect unused study medication, perform drug accountability (pill count) and document compliance with protocol instructions. 
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Period Screening 
Treatment 
EOS 
Visit Name Screening
2 
Treatment 
EOT 
EOS20 
Visit Numbers1 
1 
100 
11
0 
12
0 
13
0 
14
0 
15
0 
160 
1999 
Days -56 to -1 
1 
29 
+5 
57 
+5 
85 
+5 
11
3 
+5 
14
1 
+5 
169 
+5 
199 
±5 
Weeks 
-8 to -1 
1 
5 
9 
13 17 21 
25 
29 
Time (post-
dose) 
- 
Predos
e 
0mi
n 
15mi
n 
45mi
n 
120mi
n 
- 
- 
- 
- 
- 
- 0mi
n 
15mi
n 
45mi
n 
120mi
n 
- 
13 As per local requirements (such as United Kingdom investigational sites), Day 1 Predose pregnancy tests can be serum and conducted with the investigator’s local lab 
in order to ensure results are available prior to first dosing. In UK investigational sites, a negative serum pregnancy test must be available no more than 7 days prior to 
first dosing. Where this is not required, a negative urine pregnancy test must be available prior to dosing on Day 1. 
14 Must occur 15 or more business days prior to planned randomization. 
15 +/-5 min 
16 +/- 15 min 
17 + 1 h 
19 To be completed within 20 days of randomization (and may occur up to pre-dose on Day 1) 
20 EOS visit may be skipped if participant joins the extension study associated with this protocol. 
21
 
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8.1 
Screening 
It is permissible to re-screen a participant if s/he fails the initial screening, if deemed feasible 
or necessary by the study site investigator. Participants who do not meet inclusion due to out of 
range PVR should not be re-screened. If a subsequent re-screen is required after the first 
permissible re-screening, the case should be discussed with the Sponsor. Additional 
re-screenings may be approved on a case-by-case basis. 
In the case where a safety laboratory assessment at screening is outside of the range specified 
in the eligibility criteria, the assessment may be repeated once prior to first dose of study 
treatment. If the repeat value remains outside of the specified ranges, the participant must be 
excluded from the study. 
8.1.1 
Eligibility screening 
8.1.1.1 
Lung Function Testing 
If historical lung function test results are not available within 24 months of screening, then lung 
function testing, as per investigator's local procedures, must be conducted during screening to 
confirm eligibility. 
The following parameters must be reviewed by the PI: 
• Total Lung Capacity (TLC) 
• Forced Vital Capacity (FVC) 
• Forced Expiratory Volume during the first second (FEV1) 
TLC can be done by either body or dilution methods. 
FEV1 and FVC must be measured after bronchodilator is administered. Note, the 
bronchodilator must be locally procured by the Investigator. 
Results for the TLC, FEV1, and FVC at screening or historical results must be captured on the 
appropriate Case Report Form. 
8.1.1.2 
Hepatitis screen, HIV screen 
Not applicable. 
8.1.1.3 
Alcohol test, Drug screen, Urine cotinine 
Not applicable. 


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8.1.2 
Information to be collected on screening failures 
Participants who sign an informed consent form and are subsequently found to be ineligible 
prior to randomization will be considered a screen failure. The reason for screen failure should 
be recorded on the appropriate Case Report Form. The demographic information, informed 
consent, and Inclusion/Exclusion pages must also be completed for screen failure participants. 
No other data will be entered into the clinical database for participants who are screen failures, 
unless the participant experienced a serious adverse event during the screening phase (see 
Section 10.1.3 for SAE reporting details). If the participant fails to be randomized, the IRT must 
be notified within 2 days of the screen fail that the participant was not randomized. 
Participants who are randomized and fail to start treatment, e.g. participants randomized in 
error, will be considered an early terminator. The reason for early termination should be 
recorded on the appropriate Case Report Form. 
8.2 
Participant demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with eCRF. 
Participant demographics: full date (only if required and permitted) or year of birth or age, sex, 
race/predominant ethnicity (if permitted) and relevant medical history/current medical 
conditions (until date of signature of informed consent) will be recorded in the eCRF. Where 
possible, the diagnosis and not symptoms should be recorded. Participant race/ethnicity data 
are collected and analyzed to identify any differences in the safety and/or efficacy profile of the 
treatment due to these characteristics. Smoking history will be recorded, as well.  
All prescription medications, over-the-counter drugs and significant non-drug therapies prior to 
the start of the study must be documented. See the Section 6.2.1 Concomitant Therapy for 
further details on what information must be recorded on the appropriate page of the eCRF. 
8.3 
Efficacy 
Pharmacodynamic samples will be collected at the time-points defined in the Assessment 
Schedule (Table 8-1). Pharmacodynamic samples includes the following assessments: 
x NT-proBNP 
x 
 
x 
 
x 
 
x 
 
Follow instructions outlined in the central laboratory manual regarding sample collection, 
numbering, processing, and shipment. 
Pharmacodynamic (PD) samples will be obtained and evaluated in all participants at all dose 
levels, including the placebo group. 
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8.3.1 
Echocardiography 
For the assessment of the impact of LTP001 on right heart structure and function, 
echocardiography will be performed at the time specified in the Assessment Schedule (Table 
8-1). 
The following parameters will be assessed: 
x Tricuspid annular plane systolic excursion (TAPSE) 
x Tricuspid annular systolic velocity (TASV) 
x Peak velocity of excursion (RV S') 
x Fractional area change (FAC) 
x 
 
 
  
The methods for assessment and recording are specified in the imaging charter and imaging 
manual. All echocardiography images will be centrally read by an imaging vendor. 
The coded medical images will be used primarily for analysis as described in this protocol; 
however, the images may also be used for the development and evaluation of new analysis 
methods directly related to the area of research that this study covers. Incidental findings are 
beyond the scope of central imaging vendor. If an investigator/radiologist recognizes any 
incidental finding in the images during the course of conducting the clinical trial, the 
investigator should follow up as part of his/her duty of care to ensure the safety and wellbeing 
of the participant. 
8.3.2 
Right Heart Catheterization (RHC) 
The RHC assessment is performed to assess several hemodynamic variables in pulmonary 
hypertension, including mPAP, PCWP, CO, PVR, and systemic vascular resistance (SVR). 
x RHC will be performed according to the local hospital procedures. Concomitant PAH 
medications that could affect hemodynamic measurements need to be taken on a standard 
schedule relative to the timing of the RHC. When possible, these medications should be 
taken at least 60 minutes prior to the start of the procedure. Exact timing of dosing of 
study drug should be recorded in the source document for catheterization. The timing of a 
patient’s concomitant medication and study treatment relative to catheterization should be 
the same for the subsequent catheterization. 
x The following hemodynamic parameters will be assessed when the patient is in a stable 
hemodynamic rest state (as demonstrated by three consecutive CO measurements within 
10% of each other) while the patient is breathing ambient air or oxygen:  
x RA, mPAP, PCWP, systolic and diastolic blood pressure, HR 
x CO (measured in triplicate preferably by the thermodilution technique) 
x Mixed venous blood gas measurement 
In all cases, the same technique must be used for the baseline and Week 25 RHC measurements. 
x The following parameters will be derived from the CO measurement:  
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• 
SVR in dyn·s/cm5 
• 
PVR in dyn·s/cm5 
A more detailed instruction manual on the course of the assessments will be provided 
separately. 
8.3.3 
Six Minute Walk Test (6MWT) 
A standardized 6MWT will be performed considering the guidance for the test procedures 
described by ERS and ATS guidelines (Holland et al 2014). The 6MWT measures how many 
meters a person can walk in 6 minutes. Refer to 6MWT Instructions Manual for further details. 
For the Borg score component, the participant will answer questions on a scale of one to ten in 
order to determine the participant's shortness of breath before the 6MWT. As soon as the test is 
complete, the participant will be asked to sit down and the SaO2, HR and Borg score values 
will be recorded. 
Resting values of oxygen saturation (%), heart rate (b/min), blood pressure and Borg score will 
be recorded in the eCRF before the test, at the end of the test and two minutes after the end of 
the test. Total distance walked (meters), the number and duration of any stops, and whether the 
patient completed the test will also be recorded in the eCRF. 
Requirement of rescue medication including oxygen therapy and any adverse events occurring 
during the 6MWT will be recorded. If the patient is on chronic oxygen therapy, oxygen should 
be given at the standard rate (and at the same rate during each 6MWT procedure) or as directed 
by the investigator. 
Before randomization, the 6MWT must be performed (between screening and pre-dose on 
Day 1). The qualifying 6MWT must meet Inclusion Criterion #8 and be within 20 days of 
randomization.  
Single 6MWTs will be performed according to the Assessment Schedule (Table 8-1). 
Every attempt should be made to conduct the 6MWT at about the same time of day. 
8.3.4 
Appropriateness of efficacy assessments 
• The right heart catheterization allows an estimation of the progression of PAH by 
measuring the right heart and pulmonary arterial pressures as well as cardiac function. 
RHC is commonly employed in studies with PAH as a sensitive functional assessment to 
assess disease progression. In the scope of the current study it allows the detection of 
improvement within a small study population. 
• Echocardiography is a commonly used technique to measure cardiac structure and 
functional parameters, is non-invasive and such allows more frequent monitoring without 
procedural risks. 
• The 6MWT is a well standardized and simple test to assess physical performance. 
8.4 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 


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For details on AE collection and reporting, refer to AE section (Section 10.1.1). 
As per Section 4.6, during a Public Health Emergency as declared by Local or Regional 
authorities (i.e. pandemic, epidemic or natural disaster), that limits or prevents on-site study 
visits, regular phone or virtual calls can occur (every 4 weeks or more frequently if needed) for 
safety monitoring and discussion of the participant´s health status until it is safe for the 
participant to visit the site again. 
Clinically notable safety findings are defined in Appendix 1, Section 16.1. 
Assessment 
Specification 
Physical examination 
A complete physical examination will include the 
examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, 
lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular, and neurological. If 
indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and 
pelvic exams will be performed. 
A short physical exam will include the 
examination of general appearance, heart, 
lungs, abdomen, and extremities (edema). A 
short physical exam can occur starting from 
Week 5 except where a complete physical 
examination is required (see above). 
Information for all physical examinations must 
be included in the source documentation at the 
study site. Clinically relevant findings that are 
present prior to signing informed consent must 
be recorded on the appropriate eCRF that 
captures medical history. Significant findings 
made after signing informed consent which meet 
the definition of an Adverse Event must be 
recorded as an adverse event. 
Vital signs 
Vital signs will include the collection of otic, oral 
or forehead body temperature (recorded in °C), 
blood pressure (BP) and pulse measurements. 
After the participant has been sitting for 
3 minutes, with back supported and both feet 
placed on the floor, systolic and diastolic BP will 
be measured using an automated validated 
device, e.g. OMRON with an appropriately sized 
cuff. In case the cuff sizes available are not 
large enough for the participant's arm 
circumference, a sphygmomanometer with an 
appropriately sized cuff may be used. 
Height and weight 
Height in centimeters (cm) and body weight (to 
the nearest 0.1 kilogram (kg) in indoor clothing, 
but without shoes) will be measured as specified 
in Table 8-1. 


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8.4.1 
Laboratory evaluations 
If participants cannot visit the site for safety lab assessments conducted through central labs, 
local lab collection may be used during a Public Health Emergency as declared by Local or 
Regional authorities (i.e. pandemic, epidemic or natural disaster), that limits or prevents on-site 
study visits. 
If participants cannot visit the site for protocol specified safety lab assessments, an alternative 
lab (local) collection site may be used. 
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate. 
In all cases, the Investigator must document in the source documents, the clinical considerations 
(i.e., result was/was not clinically significant and/or medically relevant) in allowing or 
disallowing the participant to continue in the study. 
A central laboratory will be used for analysis of all safety specimens collected. Details on the 
collection, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the central laboratory manual. 
Urinalysis 
A midstream urine sample (approx. 30 mL) will be obtained, in order to avoid contamination 
with epithelial cells and sediments, and allow proper assessments. 
Special clinical laboratory evaluations 
All abnormal lab results must be evaluated for criteria defining an adverse event and reported 
as such if the criteria are met. For those lab adverse events, repeated evaluations are mandatory 
until normalization of the result(s) or until the result is no longer considered to be clinically 
significant. 
Clinically notable laboratory findings are defined in Section 16.1. 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Erythrocyte, Mean 
Corpuscular Hemoglobin, Erythrocyte Mean 
Corpuscular HGB Concentration, Erythrocyte 
Mean Corpuscular Volume, Platelets, 
Erythrocytes (will only be assessed in case of 
abnormalities in the full blood count), 
Leukocytes, Erythrocyte Cell Morphology 
differential, Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils, Bands) 
Chemistry (Note: thyroid and endocrine function 
tests are to be conducted at all time points 
where clinical chemistry is indicated) 
Albumin, Alkaline phosphatase, ALT, AST, 
Gamma-glutamyl-transferase (GGT), Lactate 
dehydrogenase (LDH), Bicarbonate, Calcium, 
Magnesium, Phosphate, Chloride, Sodium, 
Potassium, Creatinine, Creatine kinase, Direct 
Bilirubin, Indirect Bilirubin, Total Bilirubin, Total 
Cholesterol, LDL Cholesterol, HDL Cholesterol, 
Total Protein, Triglycerides, Urea Nitrogen or 


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Test Category 
Test Name 
Urea, Uric Acid, Amylase, Lipase, Glucose (non-
fasting) 
Urinalysis 
Microscopic Panel (Erythrocytes, Leukocytes, 
Casts, Crystals, Bacteria, Epithelial cells) 
Macroscopic Panel (Dipstick) (Color, Bilirubin, 
Occult Blood, Macroscopic Blood, Glucose, 
Ketones, Leukocytes esterase, Nitrite, pH, 
Protein, Specific Gravity, Urobilinogen) 
Pregnancy Test 
Serum pregnancy test refer to 'Pregnancy and 
assessments of fertility' section 
Coagulation Assays 
Prothrombin Time (PT), International Normalized 
Ratio (INR), activated Partial Thromboplastin 
Clotting Time (aPTT) 
Liver Event Testing and Liver Follow-Up Testing 
Albumin, ALP, ALT, AST, CK, GGT, GLDH, INR, 
PT, and Total Bilirubin (TBIL). Test for hemolysis 
(haptoglobin, reticulocytes, unconjugated 
[indirect] bilirubin). 
These tests are in addition to routine testing, to 
be performed only in follow-up to safety events 
when indicated in Section 16.2 Liver safety 
monitoring. 
Renal follow-up 
Tests that may be done in addition to routine 
testing [i.e. serum chemistry & urinalysis), to be 
performed in case of follow-up to renal safety 
events when indicated in Section 16.3. Renal 
safety monitoring: 
Urine protein, albumin and creatinine (for urine 
protein;creatinine ratio (UPCR) and urine 
albumin;creatinine ratio (UACR)), repeat serum 
creatinine. Repeat standard chemistry testing 
and standard urinalysis (microscopic panel 
(casts, crystals, bacteria, epithelial cells, 
erythrocytes, leukocytes) and macroscopic 
panel (dipstick) (color, bilirubin, glucose, 
ketones, leukocyte esterase, blood, nitrites, pH, 
protein, specific gravity, urobilinogen)), urine 
sediment and microscopy 
Additional tests 
NT-proBNP (considered a pharmacodynamic 
biomarker) 
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8.4.2 
Electrocardiogram (ECG) 
The Fridericia QT correction formula (QTcF) must be used for clinical decisions. 
The investigator must calculate QTcF if it is not auto-calculated by the ECG machine. 
Single local 12 lead ECGs are collected. 
ECGs will be locally collected and evaluated. Interpretation of the tracing must be made by a 
qualified physician and documented on the appropriate eCRF. Each ECG tracing should be 
labeled with the study number, participant initials (where regulations permit), participant 
number, date, and kept in the source documents at the study site. Clinically significant 
abnormalities present at screening should be reported on the appropriate eCRF. Clinically 
significant findings must be discussed with Novartis prior to enrolling the participant in the 
study. New or worsened clinically significant findings occurring after informed consent must 
be recorded as adverse events. 
The original ECGs on non-heat-sensitive paper, appropriately signed, must be archived at the 
study site. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. For any ECGs with participant safety concerns, 
two additional ECGs must be performed to confirm the safety finding.  
Clinically significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or adverse events as appropriate. 
8.4.3 
Pregnancy and assessments of fertility 
A condom is required for all sexually active male participants to prevent them from fathering a 
child AND to prevent delivery of study treatment via seminal fluid to their partner up to 
24 hours after last study drug administration. In addition, male participants should not donate 
sperm for the duration of study treatment up to 24 hours after last study drug administration. 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements. 
If participants cannot visit the site to have serum pregnancy tests during a Public Health 
emergency as declared by Local or Regional authorities i.e. pandemic, epidemic or natural 
disaster, that limits or prevents on-site study visits, urine pregnancy test kits may be used. 
Relevant participants can perform the urine pregnancy test at home and report the result to the 
site. It is important that participants are instructed to perform the urine pregnancy test first and 
only if the test result is negative proceed with the administration of the study treatment. 
A communication process should be established with the participant so that the Site is informed 
and can verify the pregnancy test results (e.g., following country specific measures). 
Assessments of fertility 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of 
child-bearing potential must also be available as source documentation in the following cases: 
1. Surgical bilateral oophorectomy without a hysterectomy 


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2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, 
 testing is required of any female 
participant regardless of reported reproductive/menopausal status at screening. 
8.4.4 
Appropriateness of safety measurements 
 
 
 
 
Cardiac function and status is monitored by efficacy assessments including RHC, 
echocardiography, and 6MWT which are detailed under the efficacy measures in the study. 
Further safety assessments (hematology, serum chemistry, coagulation, ECGs, vital signs, 
physical exams) are standard for investigations monitoring general safety in Phase 2 clinical 
trials. 
8.5 
Additional assessments 
8.5.1 
Clinical Outcome Assessments (COAs) 
Patient reported outcomes (PROs) 
The two patient reported outcomes utilized in this study are emPHasis-10 and 
PAH-SYMPACT. EmPHasis-10 is a total of 10 questions on an ordinal scale to determine the 
impact pulmonary arterial hypertension has on aspects of health-related quality of life. 
PAH-SYMPACT is a validated PAH-specific scale that monitors patient symptoms and clinical 
experience that is sensitive to improvement. 
The Borg scale being used in conjunction with the 6MWT is also a PRO, but is handled 
separately, as described in Section 8.3.3. 
On visit days and when required, the participant must be given the PRO measures to be 
completed at the scheduled visit before any clinical assessments are conducted. Participant’s 
refusal to complete all or any part of a PRO measure should be documented in the study data 
capture system and should not be captured as a protocol deviation. Handling of protocol 
deviations can be modified if needed per study protocol. 
Participant questionnaires should be completed in the language most familiar to the participant. 
If self-administered: 
The participant should be given sufficient space and time to complete the PRO measures. 
The site personnel should check PRO measures for completeness and ask the participant to 
complete any missing responses. The responses stored electronically in the database will be 
considered the source file. 
Completed measures (including when using paper PRO measures and any unsolicited 
comments written by the participant) must be reviewed and assessed by the investigator for 
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responses which may indicate potential AEs or SAEs before any clinical study examinations. 
This assessment should be documented in study source records. If AEs or SAEs are confirmed, 
study investigators should not encourage the participant to change responses reported in the 
completed questionnaires. Study investigators must follow reporting instructions outlined in 
Section 10.1.1 of the study protocol. 
8.5.2 
Pharmacokinetics (PK) 
Follow instructions outlined in the central laboratory manual regarding sample collection, 
numbering, processing and shipment. See the potential use of residual samples for more 
information (See Section 8.5.3.2) 
PK samples will be evaluated in all participants providing samples except the placebo group. 
Samples taken for pharmacokinetic analysis will be processed to plasma and concentrations of 
LTP001 will be quantified by LC-MS-MS. Samples will be collected on Day 1 and Week 25, 
as per the assessment schedule (Table 8-1). 
A non-validated method may be used for metabolite investigations/ exploratory work. 
Concentrations will be expressed in mass per volume units and will refer to the free base. 
Concentrations below the lower limit of quantification (LLOQ) will be reported as “zero” and 
missing data will be labeled as such in the Bioanalytical Data Report. 
For standard pharmacokinetic abbreviations and definitions, see the list provided in 
Section 12.5.1. 
The following pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental analysis with Phoenix WinNonlin (Version 8 or 
higher): Cmax and Tmax, from the plasma concentration-time data. 
8.5.3 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.5.3.1 
 
 
 
 
8.5.3.2 
 
 
 
 
 
 
 
 
 
8.5.4 
 
 
 
 
 
 
 
 
 
 
 
 
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9 
Discontinuation and completion 
9.1 
Discontinuation from study treatment and from study 
9.1.1 
Discontinuation from study treatment 
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study drug administration, if any) 
and can be initiated by either the participant or the investigator. 
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
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Discontinuation from study treatment is required under the following circumstances: 
• Participant decision 
• Pregnancy 
• Any situation in which continued study participation might result in a safety risk to the 
participant 
• Deterioration of PAH requiring hospitalization 
• Development of heart failure symptoms consistent with pulmonary hypertension WHO 
Functional Class IV (symptoms at rest; severe symptoms at exercise) 
• Lung transplantation required 
• Atrial septostomy required 
• Additional PAH directed therapy required beyond the scope of allowed concomitant 
medication Section 6.2.1) due to disease progression 
• Adverse event that is graded severe by the investigator and considered study drug related 
• If a liver or renal event occurs, follow guidelines outlined in Section 16.2 
(Appendix 2) and Section 16.3 (Appendix 3) regarding discontinuation of study treatment. 
If discontinuation from study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from study treatment and 
record this information. 
Participants who discontinue from study treatment agree to return for the end of treatment and 
follow-up visits indicated in the Assessment Schedule (refer to Section 8). 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the 
participant. This telephone contact should preferably be done according to the study visit 
schedule. 
After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
9.1.2 
Discontinuation from study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the Assessment Schedule (refer to Section 8). 


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9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue from study treatment or discontinue from study or withdraw 
consent/oppose to the use of their data/biological samples, the investigator must show "due 
diligence" by documenting in the source documents steps taken to contact the participant, e.g. 
dates of telephone calls, registered letters, etc. A participant should not be considered as lost to 
follow-up until due diligence has been completed. 
9.2 
Withdrawal of informed consent/Opposition to use 
data/biological samples 
Withdrawal of consent/opposition to use data/biological samples occurs when a participant: 
• Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be as per local regulations (e.g. in writing) and recorded in the source 
documentation. 
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g. to respond to data queries) and potentially other country-specific restrictions. It is therefore 
very important to ensure accurate recording of withdrawal vs. discontinuation based on the 
protocol definitions of these terms. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their consent/ 
exercise data privacy rights and record this information. The Investigator shall clearly document 
if the participant has withdrawn his/her consent for the use of data in addition to a study 
discontinuation. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table (refer to Section 8). 
Further details on withdrawal of consent or the exercise of participants' data privacy rights are 
included in the corresponding informed consent form. 


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9.3 
Study stopping rules 
Overall study stopping rules 
• Three or more (in different participants) similar study-treatment (LTP001) related SAEs; 
(Exception: SAEs that are related to worsening of PAH (i.e. lack of efficacy by LTP001)). 
• The Sponsor considers that the number and/or severity of AEs, abnormal safety 
monitoring tests or abnormal laboratory findings justify putting the study on hold. The 
sponsor may trigger a safety review in such instances at any time during the study. 
In these cases, ad hoc internal experts in collaboration with the DMC and with representative 
site investigators (if deemed necessary) will carefully evaluate the safety data of the entire 
study. If time permits – after consultation of the DMC – the sponsor may ask the DMC to 
undertake a separate review and provide recommendations to the sponsor. The experts (and 
investigators if felt needed) will recommend whether the study can be continued, should be 
terminated or if other safety measures need to be taken. 
The findings and recommendations will be documented and will be made available to all 
investigators, their respective Institutional Review Board/Independent Ethics Committee 
(IRB/IEC), as appropriate. 
Any subjects currently being dosed will be allowed to continue dosing during the safety review 
unless otherwise advised by the sponsor, as long as they have not met an individual 
discontinuation rule or have an ongoing severe or serious adverse event of the same type. 
The study may continue following the safety review, if the investigators and Sponsor agree it is 
safe to proceed in consultation with the DMC. Any restart of the study following a full safety 
review will be notified to the health authorities or submitted as a substantial amendment, 
depending on the region and applicable local requirements. 
9.4 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that of the last participant visit following the decision. 
For participants that are enrolled in an extension study the corresponding rules of the extension 
study protocol apply. If the last participant enrolls in the extension study protocol, then the final 
visit in this protocol for that participant will be considered their Study Completion visit.  
9.5 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study drug development 


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In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a participant who discontinued from study treatment. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the participant’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 
10 
Safety monitoring, reporting and committees 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The severity grade 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant 
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4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/permanently discontinued 
6. Its outcome  
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
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Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity  
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are 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 dependency or abuse (please refer to the 
ICH-E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety immediately, without undue delay, under no 
circumstances later than within 24 hours of learning of its occurrence. Detailed instructions 
regarding the submission process and requirements are to be found in the investigator folder 
provided to each site. Information about all SAEs is collected and recorded on the Serious 
Adverse Event Report Form; all applicable sections of the form must be completed in order to 
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1. SAEs occurring after the participant has provided informed consent until the time the 
participant is deemed a Screen Failure must be reported to Novartis. 
2. Randomized OR Treated Participants: SAEs collected between time participant signs ICF 
until 30 days after the participant has discontinued from study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, and under no circumstances later than 24 hours of the 
investigator receiving the follow-up information. An SAE occurring at a different time interval 
or otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the 30 day period should only be reported to Novartis Safety if the 
investigator suspects a causal relationship to study treatment, unless otherwise specified by 
local law/regulations. 
10.1.4 
Pregnancy reporting 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the investigator to collect and report information regarding the pregnancy. 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the investigational 
treatment any pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
If a female partner of a male trial participant who took study treatment in this study becomes 
pregnant, pregnancy outcomes should be collected. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother. 
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
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10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer. 
Medication errors are usually unintentional, although a participant can intentionally ‘commit’ 
a medication error due to a lack of medical knowledge or sound judgment 
 
) or there is an accidental drug omission by 
an HCP). This section can be edited as per trial need. 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported 
to Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
eCRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
Please refer to Table 16-1 in Appendix 2 for complete definitions of liver laboratory triggers 
/liver events. 
Once a participant is exposed to study treatment, every liver event defined in Section 16.1 
should be followed up by the investigator or designated personnel at the trial site, as summarized 
below. Since deterioration of PAH may result in increases of liver values it should be checked 
if an increase of liver values might be secondary to a deterioration of right heart failure. 
Liver chemistry tests (i.e. ALT, AST, TBL, PT/INR, ALP and G-GT) should be repeated to 
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confirm the elevation. Increased liver values considered secondary to deterioration of right heart 
function are not considered liver events 
• Liver chemistry repeats will be performed using the central laboratory. If results will not 
be available from the central laboratory, then the repeats can also be performed at a local 
laboratory to monitor the safety of the participant. If a liver event is subsequently reported, 
any local liver chemistry tests previously conducted that are associated with this event 
should have results recorded on the appropriate eCRF. 
• If the initial elevation is confirmed and a liver event is suspected, close observation of the 
participant will be initiated, including consideration of treatment interruption if deemed 
appropriate. 
• Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section, Section 9.1.1), if appropriate 
• Hospitalization of the participant if appropriate 
• Thorough follow-up of the liver event should include as per the investigator’s discretion to 
allow for a causality assessment: serology tests, imaging and pathology assessments, 
hepatologist’s consultancy; obtaining more detailed history of symptoms and prior or 
concurrent diseases, history of concomitant drug use, exclusion of underlying liver 
disease.  
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF. 
10.2.2 
Renal safety monitoring 
Once a participant is exposed to study treatment, the following two categories of abnormal renal 
laboratory alert values should be assessed during the study period: 
• Serum creatinine increase > 25% compared to baseline 
• Any one of the following:  
• New onset dipstick proteinuria ≥ 3+, OR 
• New onset dipstick hematuria ≥ 3+ (after excluding menstruation, UTI, extreme 
exercise, or trauma) 
Abnormal renal event findings should be confirmed within 5 days. 
Once a participant is exposed to study treatment, renal laboratory alerts or renal safety events 
should be monitored and followed up by the investigator or designated trial staff. Please see 
Table 16-4 for further guidance. 
10.3 
Committees 
10.3.1 
Data monitoring committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. Note: the trial statistician will be employed as a member 
of the DMC. The DMC will assess at defined intervals the progress of the clinical trial, safety 


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data and critical efficacy variables, and recommend to Novartis whether to continue, modify or 
terminate a trial. 
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency and documentation of DMC reports, minutes and recommendations will be described 
in a separate charter that is established between Novartis and the DMC. 
The DMC will also advise the Sponsor in case an unplanned safety review is triggered and 
requires a decision to stop or continue the study (as per Section 9.3). 
11 
Data Collection and Database management 
11.1 
Data collection 
All other data captured for this study will have an external originating source (either written or 
electronic) with the eCRF not being considered as source. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on eCRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.1.1 
Data collection for offsite procedures 
The OHPs will enter data at off-site visits into electronic source documentation forms contained 
in an eSource DDC platform, which has been validated for use in clinical research. Where paper 
source documentation exists, images of documentation will be uploaded electronically into the 
same platform as certified copies, and the original documentation will then be sent to the 
investigator.  
Data contained in the platform are available to site and sponsor staff based on role-based access 
and permissions and will be stored in a robust and secure cloud-based back-end environment. 
Only sponsor staff who are responsible for field monitoring activities will have access to the 
source data, which may include some personally identifiable information, consistent with the 
access that is provided to a field monitor in a traditional onsite clinical trial model. 


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Relevant data in the eSource DDC platform may be manually transcribed by site staff into the 
study EDC system.  
Certified copies of data in the eSource DDC platform will be provided to investigator and/or 
site personnel, and promptly and regularly uploaded into the participant’s medical records, 
according to local guidelines. 
Investigators will have continuous, near real time access to this study and all participant records 
within this study in the eSource DDC platform, with the ability to add, edit, review and sign 
forms within participant records.  
The platform maintains a secure, GCP-compliant audit trail and uses measures such as 
encryption and access controls to ensure that data privacy and security is maintained.  
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of 
Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
and statistician. Any changes to the database after that time can only be made after written 
agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis/delegated CRO representative will review the protocol and data capture requirements 
(i.e. eSource DDE or eCRFs) with the investigators and their staff. During the study, Novartis 
employs several methods of ensuring protocol and GCP compliance and the quality/integrity of 
the sites’ data. The field monitor will visit the site to check the completeness of participant 


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records, the accuracy of data capture / data entry, the adherence to the protocol and to Good 
Clinical Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits.  Continuous remote monitoring of each site’s data 
may be performed by a centralized Novartis/ delegated CRO/ CRA organization. Additionally, 
a central analytics organization may analyze data & identify risks & trends for site operational 
parameters, and provide reports to Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
For all analysis sets, participants will be analyzed according to the study treatment(s) received. 
The safety analysis set will include all participants who received any study drug. 
The PK analysis set will include all participants with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact PK data. 
The PD analysis set will include all participants with available PD data and no protocol 
deviations with relevant impact on PD data. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively by treatment group and overall utilizing the safety set. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles will also be presented. 


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Relevant medical histories and current medical conditions at baseline will be listed by treatment 
group. 
12.3 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The duration of exposure (in weeks) by treatment group and overall will be summarized using 
the safety set. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed according to the Anatomical Therapeutic Chemical (ATC) 
classification system, by treatment group. 
12.4 
Analysis supporting primary objectives 
12.4.1 
Definition of primary endpoint(s) 
The primary endpoint of the study is PVR, defined as the resistance against blood flow from 
the pulmonary artery to the left atrium measured in dyn·s·cm−5. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
Primary endpoint – Pulmonary Vascular Resistance (PVR) 
The change from baseline in PVR at Week 25 will be analyzed using a Bayesian approach 
(Fisch et al 2015) with Analysis of Covariance. The model includes treatment and WHO 
functional class as fixed effects and baseline value as a covariate. Contrast for treatment 
difference will be provided together with 80% two-sided credible intervals under Bayesian 
framework and the posterior probability that the treatment effect better than placebo will be 
derived. 
To derive the prior distribution for the change from baseline in the placebo group, a 
meta‑analysis (Neuenschwander et al 2010) on the change from baseline in PVR at Week 17/24 
for the placebo groups (64 participants) from two historical clinical trials was conducted  
(Table 12-1). From this meta-analysis, the prior distribution for the change from baseline in 
PVR in the placebo group is a normal distribution with mean 38.5 dyn·s·cm−5 and standard 
deviation 86.7 dyn·s·cm−5, which corresponds to approximately 8 participants for the placebo 
group. This prior was used as a weakly informative prior for the placebo group at Week 25. 


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Table 12-1 
Historical data used for the meta-analysis to determine the informative 
prior on PVR for the placebo group 
Trial 
N 
Treatment 
Change from 
baseline (SE) 
Selexipag PII 
42 (3:1) 
Selexipag (n=32) 
-129.8 (54.8) 
Sotatercept PII 
(PULSAR) 
106 (~2:1) 
Placebo (n=32)* 
-16 (35.3) 
* Placebo arm represents patients on Standard of Care which may include Selexipag. 
12.4.3 
Handling of intercurrent events of primary estimand 
Not applicable. 
12.4.4 
Handling of missing values not related to intercurrent event 
Missing data will not be imputed. 
12.4.5 
Sensitivity analyses 
The primary analysis will be repeated assuming a non‑informative prior for placebo treatment 
group. This would allow us to capture the results without using any historical control data. 
In the event of protocol deviations relevant for inclusion criteria or documented as any 
deviations from the standardized procedures for PVR collection, the primary analysis will be 
repeated excluding these subjects. 
The underlying normality assumption for analysis of covariance (ANCOVA) will be evaluated. 
If normality assumption is not met, then alternative methods will be considered such as 
Hodges-Lehmann, or log-transformed data. 
12.4.6 
Supplementary analysis 
Not applicable. 
12.5 
Analysis supporting secondary objectives 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
Change from baseline for 6MWT will be analyzed based on mixed model repeated measures, 
adjusting for effects of treatment, visit as categorical factors and treatment*visit and 
baseline*visit interactions. Model based estimates of the mean effect will be reported for each 
treatment group along with the treatment difference, the 2-sided 80% confidence interval for 
treatment difference, and one-sided p-value.  


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Other efficacy endpoints including RHC, echocardiography parameters, PROs (emPHasis-10 
and PAH-SYMPACT scores) and NT-proBNP will be summarized as change from baseline by 
visit and treatment group. Time to clinical worsening will be analyzed using survival models 
(i.e., Kaplan-Meier, cox regression) if adequate number of events occur during the study to 
characterize the survival curve. The hazard ratio and the corresponding 80% confidence 
intervals will be computed using the appropriate method. 
If normality assumption is violated for any of the continuous outcomes, then appropriate 
transformation (i.e., log-transformed) of the data will be considered. 
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings will be presented by treatment 
group and tables will be presented by treatment group and overall. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
The on-treatment period lasts from the date of first administration of study treatment to the EOS 
visit (about 30 days after the date of the last actual administration of any study treatment). 
Adverse events 
All adverse events summarized will be displayed by treatment group and overall. All adverse 
events listing will be presented by treatment group and participant. 
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of double-blind 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways: 
• by treatment, primary system organ class and preferred term. 
• by treatment, primary system organ class, preferred term and maximum severity. 
• by treatment, Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation. In case of sparse 
events in any of these categories occur, only a listing will be provided if deemed adequate. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 


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Vital signs 
All vital signs data will be listed by treatment group, participant, and visit/time and if ranges 
are available, abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics and graphical presentations (e.g. boxplots) will be provided by treatment and 
visit/time. 
12-lead ECG 
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each participant 
during the study. ECG data will be read and interpreted (locally). 
Categorical Analysis of QT/QTc interval data based on the number of participants meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented. In addition, a listing of these participants will be produced (by treatment 
group). 
All ECG data will be listed by treatment group, participant and visit/time, abnormalities will be 
flagged. Summary statistics and graphical presentations (e.g. boxplots) will be provided by 
treatment and visit/time. 
Clinical laboratory evaluations 
All laboratory data will be listed by treatment group, participant, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by by 
visit/time for treatment group, and overall. Shift tables using the low/normal/high/ (low and 
high) classification will be used to compare baseline to the worst on-treatment value. 
12.5.3 
Pharmacokinetics 
Descriptive summary statistics of LTP001 plasma concentration data will be provided by 
treatment, and visit/sampling time point, including the frequency (n, %) of concentrations below 
the LLOQ and reported as zero. 
Summary statistics will include mean (arithmetic and geometric), standard deviation (SD), 
coefficient of variation (CV) (arithmetic and geometric), median, minimum, and maximum. 
Descriptive summary statistics for LTP001 PK will include mean (arithmetic and geometric), 
SD, and CV (arithmetic and geometric), median, minimum, and maximum. An exception to this 
is Tmax where median, minimum, and maximum will be presented. 
Table 12-2 
Non-compartmental pharmacokinetic parameters 
Cmax 
The maximum (peak) observed plasma, blood, 
serum, or other body fluid drug concentration 
after single dose administration (ng x mL-1) 
Tmax 
The time to reach maximum (peak) plasma, 
blood, serum, or other body fluid drug 
concentration after single dose administration 
(h) 


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12.5.4 
PK/PD relationships 
No preplanned analyses is considered.
 
 
.   
12.6 
Analysis of exploratory endpoints 
12.6.1 
 
 
 
 
 
12.6.2 
 
 
 
 
 
 
 
 
 
12.7 
Interim analyses 
An unblinded interim analysis (IA) will be planned for this trial. 
The IA will be performed primarily to assess futility (non-binding) on PVR endpoint when 
approximately 20 participants complete the treatment period (Week 25). In addition, this IA 
will be utilized to evaluate safety, and efficacy relevant to other endpoints.  
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
Pulmonary Vascular Resistance (PVR) 
Approximately 44 participants including dropouts are planned to be randomized in a 3:1 ratio 
to receive LTP001 vs. placebo on top of Standard of Care (SoC). Dropout rate is considered to 
be around 10%. 
The sample size calculation was based on the primary endpoint of change from baseline in PVR 
at Week 25. The criteria for this calculation is based on dual criteria: 
1. An average change from baseline for PVR over placebo is 100 dyn·s·cmí5 and 
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2. 90% level of proof that the change from baseline for PVR in the LTP001 group is better 
than placebo. 
With a non-informative prior for the LTP001 group, and the obtained weakly informative prior 
for the placebo group, a sample size of 40 (3:1 ratio of LTP001: placebo) provides 
approximately 86% chance (power) of meeting the success criterion. Refer to Section 12.4.2 
for further details. With approximately 20 participants completing the study at interim, the 
probability of considering stopping early for futility (non-binding) is approximately 47% in 
case of a placebo‑like drug and approximately 1% in case the true treatment difference for PVR 
is 200 dyn·s·cm−5, which is the statistically significant difference between drug and placebo in 
this PAH population. 
Assumptions related to PVR variability will be evaluated at the time of interim analyses to 
consider re-estimation of sample size as appropriate. 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.). 


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For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
13.5 
Participant Engagement 
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the time-points indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis. 
• Thank You letter 
• Plain language trial summary - after CSR publication 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 


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Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request. 
Beshay S, Sahay S, Humbert M (2020) Evaluation and management of pulmonary arterial 
hypertension. Respir Med p. 106099. 
Fisch R, Jones I, Jones J, et al (2015) Bayesian Design of Proof-of-Concept Trials. Ther Innov 
Regul Sci p. 155-162. 
Hemnes AR, Humbert M (2017) Pathobiology of pulmonary arterial hypertension: 
understanding the roads less travelled. Eur Respir Rev. 
Holland AE, Spruit MA, Troosters T, et al (2014) An official European Respiratory 
Society/American Thoracic Society technical standard: field walking tests in chronic 
respiratory disease. Eur Respir J p. 1428-46. 
 
Murakami K, Mathew R, Huang J, et al (2010) Smurf1 ubiquitin ligase causes downregulation 
of BMP receptors and is induced in monocrotaline and hypoxia models of pulmonary arterial 
hypertension. Exp Biol Med (Maywood) p. 805-13. 
Neuenschwander B, Capkun-Niggli G, Branson M, et al (2010) Summarizing historical 
information on controls in clinical trials. Clin Trials p. 5-18. 
Rothman AM, Arnold ND, Pickworth JA, et al (2016) MicroRNA-140-5p and SMURF1 
regulate pulmonary arterial hypertension. J Clin Invest p. 2495-508. 
 
 
Wilkins MR, Aman J, Harbaum L, et al (2018) Recent advances in pulmonary arterial 
hypertension. F1000Res. 
 
 
Zhu H, Kavsak P, Abdollah S, et al (1999) A SMAD ubiquitin ligase targets the BMP 
pathway and affects embryonic pattern formation. Nature p. 687-93. 
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16 
Appendices 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs 
Systolic blood pressure > 165 mm Hg or < 80 mm Hg in absence of arterial hyper- or 
hypertension at baseline 
Diastolic blood pressure > 109 mm Hg or < 50 mm Hg in absence of arterial hyper- or 
hypertension at baseline 
Pulse rate > 99 bpm or < 50 bpm and change by 20 bpm or more from baseline 
QTcF increase by > 60 ms 
All QTcF > 500 ms 
QTcF > 480 ms if normal at baseline 
QRS-Duration > 120 ms when normal at baseline. 
PR - value > 220 ms when normal at baseline 
AV-block > Grade 2a 
Values need to be noted and their clinical significance in light of the underlying PAH condition 
needs to be considered (does condition cause symptoms; is condition a sign for disease 
progression; is condition a potential side effect of LTP001 or other PAH directed therapy?) 


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16.2 
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements 
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
Please refer to Table 16-1 in Appendix 5 for complete definitions of liver laboratory triggers. 
Once a participant is exposed to study treatment, every liver event defined in Table 16-1 should 
be followed up by the Investigator or designated personnel at the trial site, as summarized 
below. Since deterioration of PAH may result in increases of liver values it should be checked 
if an increase of liver values might be secondary to a deterioration of right heart failure. Liver 
chemistry tests (i.e. ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm elevation. Increased 
liver values considered secondary to deterioration of right heart function are not considered 
liver events. 
1. Liver chemistry repeats will be performed using the central laboratory. If results will not 
be available from the central laboratory, then the repeats can also be performed at a local 
laboratory to monitor the safety of the participant. If a liver event is subsequently reported, 
any local liver chemistry tests previously conducted that are associated with this event 
should have results recorded on the appropriate CRF. 
2. If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
3. Discontinuation of the investigational drug (refer to the Discontinuation of study 
treatment Section 9.1.1 Discontinuation from study treatment), if appropriate 
4. Hospitalization of the participant if appropriate 
5. Causality assessment of the liver event 
6. Thorough follow-up of the liver event should include, as per the investigator's discretion 
to allow for a causality assessment: serology tests, imaging and pathology assessments, 
hepatologist’s consultancy; obtaining more detailed history of symptoms and prior or 
concurrent diseases, history of concomitant drug use, exclusion of underlying liver 
disease. 
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF. 
 
Table 16-1 
Liver event and laboratory trigger definitions 
  
Definition/ threshold 
Liver laboratory triggers 
If ALT, AST and total bilirubin normal at 
baseline: 
• 
ALT or AST > 5 × ULN 
• 
ALP > 2 × ULN (in the absence of known 
bone pathology) 
• 
Total bilirubin > 3 × ULN (in the absence of 
known Gilbert syndrome) 
• 
ALT or AST > 3 × ULN and INR > 1.5 


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• 
Potential Hy’s Law cases (defined as ALT or 
AST > 3 × ULN and Total bilirubin > 2 × ULN 
[mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN) 
• 
Any clinical event of jaundice (or equivalent 
term) 
• 
ALT or AST > 3 × ULN accompanied by 
(general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with 
eosinophilia 
• 
Any adverse event potentially indicative of a 
liver toxicity 
If ALT or AST abnormal at baseline: 
• 
ALT or AST > 3x baseline or > 300 U/L 
(whichever occurs first) 
Notify Novartis study lead and medical lead of any finding of a liver event identified not 
explained by PAH worsening for further follow-up assessments. 
 
Table 16-2 
Follow up requirements for liver laboratory triggers - ALT, AST, TBL 
 
ALT 
TBL 
Liver Symptoms 
Action 
ALT increase without bilirubin increase: 
 
 
If normal at 
baseline: 
ALT > 3 x ULN 
Normal 
For 
participants with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL 
None 
• 
No change 
to study 
treatment 
• 
Measure 
ALT, AST, 
ALP, GGT, 
TBIL, INR, 
albumin, CK, 
and GLDH in 
48-72 hours. 
• 
Follow-up for 
symptoms. 
If elevated at 
baseline: 
ALT > 2 x 
baseline 
or > 300 U/L 
(whichever 
occurs ﬁrst) 
 
If normal at 
baseline: 
ALT > 5 x ULN 
for more than two 
weeks 
Normal 
For 
participants with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL 
None 
• 
Interrupt 
study 
treatment 
• 
Measure 
ALT, AST, 
ALP, GGT, 
TBIL, INR, 
albumin, CK, 
and GLDH in 
48-72 hours. 
If elevated at 
baseline: 
ALT > 3 x 
baseline 
or > 300 U/L 
(whichever 
occurs ﬁrst) for 


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Table 16-3 
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia 
Criteria 
Actions required 
Follow-up monitoring 
Total Bilirubin (isolated) 
 
 
>1.5 – 3.0 ULN 
• 
Maintain treatment 
• 
Repeat LFTs within 48-72 
hours 
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline 
> 3 - 10 × ULN (in the absence 
of known Gilbert syndrome) 
• 
Interrupt treatment 
• 
Repeat LFT within 48-72 
hours 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline (ALT, AST, total 
bilirubin, Alb, PT/INR, ALP and 
GGT) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
 
ALT 
TBL 
Liver Symptoms 
Action 
more than two 
weeks 
• 
Follow-up for 
symptoms. 
• 
Initiate close 
monitoring 
and workup 
for competing 
etiologies. 
• 
Study 
treatment can 
be restarted 
only if 
another 
etiology is 
identiﬁed and 
liver enzymes 
return to 
baseline. 
 
If normal at 
baseline: 
ALT > 8 x ULN 
Normal 
None 
ALT increase with bilirubin increase: 
 
If normal at 
baseline: 
ALT > 3 x ULN 
TBL > 2 x ULN 
(or INR > 1.5) 
For participants 
with Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at 
baseline: 
ALT > 2 x 
baseline 
or > 300 U/L 
(whichever 
occurs ﬁrst) 
 
If normal at 
baseline: 
ALT > 3 x ULN 
Normal or 
elevated 
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain 
If elevated at 
baseline: 
ALT > 2 x 
baseline 
or > 300 U/L 
(whichever 
occurs ﬁrst) 


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Protocol No. CLTP001A12201 
 
Criteria 
Actions required 
Follow-up monitoring 
> 10 x ULN 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize the participant 
• 
Establish causality 
• 
Record the AE and 
contributing factors(e.g. 
conmeds, med hx, lab)in 
the appropriate CRF 
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolution (frequency at 
Investigator discretion) 
Any AE potentially indicative of 
a liver toxicity 
• 
Consider study treatment 
interruption or 
discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors(e.g. 
conmeds, med hx, lab)in 
the appropriate CRF 
Investigator discretion 
 
Based on Investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease 


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Protocol No. CLTP001A12201 
 
16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up 
Renal safety parameters will be checked at all visits. Careful monitoring of deterioration of 
renal function or of pathologic changes in the urinalysis is required. The below definitions 
mandate to classify a renal parameter deviation as a renal event. Further guidance for the follow-
up of abnormal renal function parameters and renal events will be provided in the investigator 
portal under Renal Events guidance document. 
Table 16-4 
Specific renal alert criteria and actions 
Serum Event 
Serum creatinine 
increase > 25% fold 
compared to baseline 
Follow up within 1-2 
days 
Please review 
Section 8.4.1  
Urine Event 
New onset dipstick 
proteinuria ≥3+ OR 
New onset dipstick 
hematuria ≥3+ (after 
excluding 
menstruation, urinary 
tract infection, 
extreme exercise, or 
trauma) 
Follow up within 2-5 
days 
Please review 
Section 8.4.1  
For all renal events: 
Document contributing factors in the eCRF: 
co-medication, other co-morbid conditions, 
and additional diagnostic procedures 
performed 
Monitor subject regularly (frequency at 
investigator’s discretion) until either: 
Event resolution: sCr within 20% of baseline 
or 
Event stabilization: sCr level with ±20% 
variability over last 2 months 
Further recommendations on the follow-up for 
renal events can be found in the investigator 
portal (Follow-up for renal events document). 
 


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16.4 
Appendix 4: Calculation of Pulmonary Vascular Resistance 
(PVR) 
 
 
PVR = 
𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 (𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚)−𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃(𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚)
𝐶𝐶𝐶𝐶 (
𝐿𝐿
min ⬚)
 𝑥𝑥 80 
 
PVR = Pulmonary Vascular Resistance 
mPAP = Mean Pulmonary Arterial Pressure 
PCWP = Pulmonary Capillary Wedge Pressure 
CO = Cardiac Output 

SAP_001.pdf: 
Clinical Development 
LTP001 
CLTP001A12201 / NCT05135000
A randomized, participant- and investigator-blinded, 
placebo-controlled study to investigate efficacy, safety and 
tolerability of LTP001 in participants with pulmonary 
arterial hypertension  
Statistical Analysis Plan (SAP) 
Document type: 
SAP Amendment 2 
Document status: 
Final 
Release date: 
05-Jun-2024
Number of pages: 
25 
Property of Novartis 
 Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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SAP 
 
Study No. CLTP001A12201 
 
 
 
Document History – Changes compared to previous final version of SAP 
CCI


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SAP 
 
Study No. CLTP001A12201 
 
 
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SAP 
 
Study No. CLTP001A12201 
 
 
 
Table of contents 
Table of contents ................................................................................................................. 4 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design ............................................................................................................ 7 
1.2 
Study objectives, endpoints and estimands ............................................................. 8 
1.2.1 
Primary estimand(s) .............................................................................. 10 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ......................................................................... 10 
2.1.1 
General definitions ................................................................................ 10 
2.2 
Analysis sets .......................................................................................................... 10 
2.2.1 
Subgroup of interest .............................................................................. 12 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 12 
2.3.1 
Patient disposition ................................................................................. 12 
2.3.2 
Demographics and other baseline characteristics ................................. 12 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 13 
2.4.1 
Study treatment / compliance ................................................................ 13 
2.4.2 
Prior, concomitant and post therapies ................................................... 13 
2.5 
Analysis supporting primary objective(s) .............................................................. 14 
2.5.1 
Primary endpoint(s) ............................................................................... 14 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 14 
2.5.3 
Handling of intercurrent events ............................................................. 14 
2.5.4 
Handling of missing values not related to intercurrent event ............... 14 
2.5.5 
Sensitivity analyses ............................................................................... 15 
2.5.6 
Supplementary analyses ........................................................................ 15 
2.6 
Analysis supporting secondary objectives ............................................................. 15 
2.6.1 
Secondary endpoint(s) ........................................................................... 15 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 17 
2.6.3 
Handling of intercurrent events ............................................................. 18 
2.6.4 
Handling of missing values not related to intercurrent events .............. 18 
2.6.5 
Sensitivity analyses ............................................................................... 18 
2.6.6 
Supplementary analyses ........................................................................ 18 
2.7 
Safety analyses....................................................................................................... 18 


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2.7.1 
Adverse events (AEs) ............................................................................ 18 
2.7.2 
Deaths .................................................................................................... 19 
2.7.3 
Laboratory data ..................................................................................... 19 
2.7.4 
Other safety data ................................................................................... 19 
2.8 
Pharmacokinetic endpoints .................................................................................... 20 
2.9 
PD and PK/PD analyses ........................................................................................ 21 
2.10 
Patient-reported outcomes ..................................................................................... 21 
2.11 
 
2.12 
Other Exploratory analyses.................................................................................... 22 
2.13 
Interim analysis ...................................................................................................... 23 
3 
Sample size calculation ..................................................................................................... 24 
4 
Change to protocol specified analyses .............................................................................. 24 
5 
Reference ........................................................................................................................... 25 
 
List of tables 
Table 2-1 
Protocol deviation codes and analysis sets ............................................ 11 
Table 2-2 
Historical data used for the meta-analysis to determine the 
informative prior on PVR for the placebo group .................................. 14 
Table 2-3 
Clinical notable criteria for QTcF (Fridericia's formula) ...................... 20 
Table 2-4 
 
 
List of figures 
Figure 1-1 
Study design scheme ............................................................................... 8 
 
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List of abbreviations 
AE 
ANCOVA 
BMI 
CO 
CRF 
CSR 
DMS 
FAS 
FEV1 
HR 
IA 
LLOQ 
MAR 
MedDRA 
mg 
mL 
mPAP 
NT-proBNP 
OHP 
PD 
PK 
PPS 
PRO 
PVR 
QTcF 
SAP 
SAS 
SD 
SoC 
TAPSE 
TASV 
TFLs 
TTCW 
WHO 
PAH 
SAP 
6MWD 
6MWT 
Adverse Event 
Analysis of covariance 
Body Mass Index 
Cardiac Output 
Case Report Form 
Clinical Study Report 
Document Management System 
Full Analysis Set 
Forced Expiratory Volume in the first second 
Heart Rate 
Interim Analyses 
Lower Limit of Quantification 
Missing at random 
Medical Dictionary for Drug Regulatory Affairs 
Milligram(s) 
Milliliter(s) 
Mean Pulmonary Arterial Pressure 
N-terminal fragment of the prohormone B-type Natriuetic Peptide 
Off-site Healthcare Professional 
Pharmacodynamic(s) 
Pharmacokinetics 
Per-Protocol Set 
Patient-reported Outcomes 
Pulmonary Vascular Resistance 
QT interval corrected by Fridericia’s formula 
Statistical Analysis Plan 
Statistical Analysis System 
Standard Deviation 
Standard of Care 
Tricuspid Annular Plane Systolic Excursion 
Tricuspid Annular Systolic Velocity 
Tables, Figures, Listings 
Time to Clinical Worsening 
World Health Organization 
Pulmonary Arterial Hypertension 
Statistical Analysis Plan 
Six Minute Walk Distance 
Six Minute Walk Test 


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1 
Introduction 
The Reporting and Analysis documents contain detailed information to aid the production of 
Statistics & Programming input into the Clinical Study Report (CSR) for trial 
“CLTP001A12201”. 
This Statistical Analysis Plan (SAP) has been developed in accordance with Clinical Trial 
Protocol CLTP001A12201 (Amended Protocol Version 02, released on 01-Mar-2022), and 
describes the implementation of the statistical analysis planned in the protocol.  
1.1 
Study design 
This is a randomized, participant- and investigator-blinded, placebo-controlled, parallel group 
study of LTP001 or placebo on top of standard of care in participants with PAH.  
Standard of care includes one or more of the following treatments: prostacyclin analogues or 
receptor agonists (if I.V., dose adjustments must be within 20% of initial stable dose), 
endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and soluble guanylate 
cyclase stimulators.  
The study design is described in Figure 1-1. A screening period of 8 weeks will be used to 
access eligibility prior to randomization. Approximately 44 eligible participants with PAH will 
be randomized in a 3:1 ratio to either oral LTP001 or placebo daily for 24 weeks in order to 
achieve 40 patients who complete the treatment period.  
An unblinded interim analysis is planned for when approximately 20 participants complete the 
24-week treatment period, and may include analyses to assess sample size, efficacy, PK, PD, 
or safety. 


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Figure 1-1 
Study design scheme 
Participants may be allowed to roll over from this study to enter the open label extension study 
upon approval from health authorities and review boards.  
1.2 
Study objectives, endpoints and estimands  
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
x 
To assess the efficacy of LTP001 in 
participants with pulmonary arterial 
hypertension (PAH). 
x 
Change from baseline right heart catheterization PVR at 
Week 25 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
x 
To evaluate the effect of LTP001 on 
Six Minute Walk Distance (6MWD) 
x 
Change from baseline in 6MWD at Weeks 13 and 25 
x 
To evaluate the effect of LTP001 on 
hemodynamic parameters other than 
PVR 
x 
Right heart catheterization assessments including 
RV pressures, pulmonary artery pressures, wedge pressure, 
and cardiac output at Week 25 
x 
To assess the effect of LTP001 on 
measurements of right ventricular 
function 
x 
Change from baseline in tricuspid annular plane systolic 
excursion (TAPSE) by echocardiography at Weeks 5, 13, and 
25 
Change from baseline in tricuspid annular systolic velocity 
(TASV) by echocardiography at Weeks 5, 13, and 25 
Change from baseline of peak velocity of excursion (RV S') 
by echocardiography at Weeks 5, 13, and 25 
Change from baseline in fractional area change (FAC) by 
echocardiography at Weeks 5, 13, and 25 
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Objective(s) 
Endpoint(s) 
x 
To assess the impact of LTP001 on 
patient reported outcomes (PRO) 
x 
Change from baseline in EmPHasis-10 and PAH-SYMPACT 
at Weeks 13 and 25 
x 
To assess the safety and tolerability 
of LTP001. 
x 
AEs, SAEs, vital signs, ECGs, safety laboratory 
measurements 
x 
To assess the impact of LTP001 on 
Time to Clinical Worsening (TTCW). 
x 
Time to any of the following: 
x Death 
x +RVSLWDOVWD\KGXHWRZRUVHQLQJRI3$+
Worsening of PAH is defined by the following right heart 
failure related signs and symptoms: syncope or near 
syncope, cyanosis, increase of breathlessness, clinically 
relevant deterioration of exercise capacity, decrease of 
oxygen saturation, increased peripheral edema, 
hepatomegaly, and ascites  
x Worsening of PAH resulting in need for lung 
transplantation or balloon atrial septostomy 
x Initiation of parenteral prostanoid therapy, chronic 
oxygen therapy, or any other PAH-specific therapies or 
need for increase of diuretics for more than 4 weeks due 
to worsening of PAH 
x Disease progression (switch in modified New York Heart 
Association/WHO FC by at least one grade) . 
x Significant drop in 6MWD (15% from baseline or more) 
due to PAH-worsening 
x 
To investigate the pharmacokinetics 
(PK) of LTP001 
x 
Cmax and tmax (Day 1 and Week 25)   
x 
To assess the impact of LTP001 on 
the N-terminal fragment of the 
prohormone B-type natriuetic peptide 
(NT-proBNP) 
x 
N-terminal fragment of the prohormone B-type natriuetic 
peptide 
Exploratory objective(s) 
Endpoint(s) for exploratory objective(s) 
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1.2.1 
Primary estimand(s) 
Not applicable.  
2 
Statistical methods 
2.1 
Data analysis general information 
2.1.1 
General definitions  
Investigational treatment will be LTP001 or placebo. 
Date of first administration of study treatment (Day 1) will be defined as the date of the first 
actual administration of LTP001 or placebo. 
Date of last administration of study treatment will be defined as the date of the last actual 
administration of LTP001 or placebo. 
Baseline will be defined as the Day 1 assessment. If this datum is not available, the last pre-
dosing assessment will be considered. 
Study day will be defined as the number of days since the date of first dose of study treatment 
(LTP001 or placebo). The date of first dose of study treatment will be defined as Day 1 and the 
day prior to first dose of will be defined as Day -1. 
Therefore, for a particular date, study day will be calculated as follows: 
for dates on or after the date of first dose of study treatment, 
 
Study day = Assessment date – Date of first dose administration + 1 
The on-treatment period lasts from the date of first administration of study treatment to the End 
of Study (EOS) visit or the date of last randomized dose if EOS visit is not available. The EOS 
visit is a follow-up visit that is approximately 30 days after the date of the last actual 
administration of investigational treatment. For participants who will be enrolled into the open 
label extension (OLE) study, their EOS visits will be skipped. 
2.2 
Analysis sets  
For all analysis sets, participants will be analyzed according to the study treatment(s) received. 
The safety analysis set will include all participants who received any study drug. 
The PK analysis set will include all participants with at least one available valid (i.e., not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact PK data. Participants in the placebo arm will be excluded from 
PK analysis set. 
The PD analysis set will include all participants with available PD data and no protocol 
deviations with relevant impact on PD data. 
The analysis sets and protocol deviation codes are related as Table 2-1. 


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Table 2-1 
Protocol deviation codes and analysis sets 
Category   
  Deviation code 
Text description of deviation 
Data exclusion 
Subjects are excluded from Safety analysis in case of these PDs:  
Exclude subject from Safety 
analysis set  
WITH01 
Subject withdrew consent but 
continue to receive study 
medication 
Y 
Subjects are excluded from PK analysis in case of these PDs: 
Exclude subject from PK 
analysis set 
WITH01 
Subject withdrew consent but 
continue to receive study 
medication 
Y 
 
 
 
 
 
Y 
Subjects are excluded from PD analysis in case of these PDs: 
Exclude subject from PD 
analysis sets 
WITH01 
Subject withdrew consent but 
continue to receive study 
medication 
Y 
INCL04 
Absence of history of PAH 
subgroups of clinical 
classification group 1 as 
defined in Protocol 
Y 
INCL05A 
Resting mPAP is <25 mmHg, 
PCWP or left ventricular end 
diastolic pressure >15 mmHg 
as determined by RHC 
Y 
 
 
 
INCL06A 
Pulmonary Vascular Resistance 
is <6 WU corresponding to 480 
dynes s/cm5 as determined by 
RHC 
INCL07  
Patient doesn't have PAH of 
WHO Functional Class II – III 
Y 
EXCL03 
Patients with PH in clinical 
classification groups 2-5 
(WHO) and any PAH group 1 
subgroups not covered by IE 4 
Y 
 
 
 
 
 
Y 
Protocol deviations mentioned above, and analysis sets will be reviewed in the data review 
meeting to decide inclusion or exclusion of participant(s) from analyses sets. Decisions 
regarding the exclusion of participants and/or participant data from analyses will be made prior 
to final database lock (DBL).  
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2.2.1 
Subgroup of interest 
Not applicable. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
A summary table will be presented including the number and percentage of participants  
• Who were randomized to treatment groups and overall 
• Who completed the study  
• Who discontinued from study (overall and by the primary reason for discontinuation) 
The number and percentage of participants in each analysis set will be tabulated by treatment 
group. The percentage will be based on all randomized participants. 
A listing of all participants excluded from any analysis sets will be provided with reasons for 
exclusion (i.e., including both protocol and non-protocol deviations) 
2.3.2 
Demographics and other baseline characteristics 
Demographics and other baseline data including disease characteristics will be summarized 
descriptively by treatment group and overall utilizing the safety set. Categorical data will be 
presented as frequencies and percentages. For continuous data, mean, standard deviation, 
median, minimum, and maximum will be presented. For selected parameters, 25th and 75th 
percentiles will also be presented. 
Participant demographics will include age, gender, race, ethnicity & BMI.  
The following clinical baseline characteristics will be summarized separately: 
• Time since PAH diagnosis 
• PAH classification 
• Standard of care 
• Smoking history 
• WHO functional Class 
• 6 Minute Walk Test and Borg Scale 
• PVR 
• Echocardiography parameters 
• Lung function test 
• NT-proBNP 
• Concomitant PAH medication (classified as per the inclusion criteria; prostacyclin 
analogues and receptor agonists 
• endothelin receptor antagonists 
• phosphodiesterase type 5 inhibitors 


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x soluble guanylate cyclase stimulators) 
Relevant medical history and current medical conditions at the baseline will be listed by the 
treatment group and participant. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
The Safety set will be used for treatment related summaries. Categorical data will be 
summarized as frequencies and percentages. For continuous data, N, mean, standard deviation, 
median, 25th and 75th percentiles, minimum, and maximum will be presented. 
2.4.1 
Study treatment / compliance 
On Day 1, all eligible participants will be randomized and assigned in a 3:1 ratio to receive 
either LTP001 or placebo. The study medication (LTP001 mg or placebo) will be taken daily 
at approximately the same time each day 
. LTP001 mg consists of 
 
.
 
 
The treatment period is for 24 weeks with participants' visits at week 1, week 5, week 9, week 
13, week 17, week 21, week 25. Participants are instructed to take the study treatment exactly 
as prescribed and to contact the investigator if he/she is unable for any reason to take the study 
treatment as prescribed.  
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the participant. The information will be captured in the 
source document at each visit. All study treatment dispensed and returned will be recorded in 
the Drug Accountability Log. Off-site treatment compliance will be assessed by the OHP and 
details of which will be shared with the investigator. 
Participants will be instructed not to make up missed doses. A missed dose is defined as a case 
when the full dose is not taken within 12 hours after the approximate time of the usual daily 
dosing. That day's dose should be omitted, and the participant should continue treatment with 
the next scheduled dose. 
Pill counts (including counts of dispensed/returned pills) will be listed by participants, and visits, 
with relevant information about compliance provided by the participant if data is available.  
2.4.2 
Prior, concomitant and post therapies 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment for participants in the safety set will be listed according to the Anatomical 
Therapeutic Chemical (ATC) classification system, by treatment group. 
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2.5 
Analysis supporting primary objective(s) 
2.5.1 
Primary endpoint(s) 
To assess the efficacy of LTP001 in participants with pulmonary arterial hypertension (PAH), 
the primary endpoint of the study will be the change from baseline in Pulmonary Vascular 
Resistance (PVR) at Week 25. PVR is defined as the resistance against blood flow from the 
pulmonary artery to the left atrium measured in dyn·s·cm−5. 
2.5.2 
Statistical hypothesis, model, and method of analysis  
The analysis will be performed on the  PD analysis set. The change from baseline in PVR at 
Week 25 will be analyzed using a Bayesian approach (Fisch, et al., 2015) The model includes 
treatment and WHO functional class as fixed effects and baseline value as a covariate. Contrast 
for treatment difference will be provided together with 80% two-sided credible intervals under 
Bayesian framework and the posterior probability that the treatment effect better than placebo 
will be derived. 
To derive the prior distribution for the change from baseline in the placebo group, a 
meta‑analysis (Neuenschwander, Capkun-Niggli, Branson, & Spiegelhalter, 2010) on the 
change from baseline in PVR at Week 17/24 for the placebo groups (64 participants) from two 
historical clinical trials was conducted (Table 2-2). From this meta-analysis, the prior 
distribution for the change from baseline in PVR in the placebo group is a normal distribution 
with mean 38.5 dyn·s·cm−5 and standard deviation 86.7 dyn·s·cm−5, which corresponds to 
approximately 8 participants for the placebo group. This prior was used as a weakly informative 
prior for the placebo group at Week 25. 
Table 2-2 
Historical data used for the meta-analysis to determine the informative 
prior on PVR for the placebo group 
Trial 
N 
Treatment 
Change from baseline 
(SE) 
Selexipag PII 
42 (3:1) 
Selexipag (n=32) 
-129.8 (54.8) 
Sotatercept PII 
(PULSAR) 
106 (~2:1) 
Placebo (n=32)* 
-16 (35.3) 
* Placebo arm represents patients on SoC which may include Selexipag. 
2.5.3 
Handling of intercurrent events  
Not applicable. 
2.5.4 
Handling of missing values not related to intercurrent event 
Missing data will not be imputed. 


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2.5.5 
Sensitivity analyses  
The primary analysis will be repeated assuming a non‑informative prior for placebo treatment 
group. This would allow us to capture the results without using any historical control data. 
Due to the fact that the WHO functional classification tents to be sparse, a model without WHO 
functional classification will be fitted. 
In the event of protocol deviations relevant for inclusion criteria or documented as any 
deviations from the standardized procedures for PVR collection, the primary analysis will be 
repeated excluding these subjects. 
An analysis of covariance (ANCOVA) will be conducted with treatment as fixed effect and 
baseline as covariate to support the result of the primary analysis.  
An analysis of residuals will be carried-out to assess model assumption. If the underlying 
normality assumption for analysis of covariance (ANCOVA) is not met, then alternative 
methods will be considered such as Hodges–Lehmann (Lehmann & Hodges, 1963) or log-
transformed data. 
2.5.6 
Supplementary analyses 
Not applicable. 
2.6 
Analysis supporting secondary objectives  
All analysis of secondary endpoints will be performed on the PD analysis set. Missing data for 
any reason will not be explicitly imputed and will be handled by the respective mixed effects 
model (if performed) which implicitly imputes missing data assuming missing at random 
(MAR).  
2.6.1 
Secondary endpoint(s) 
Six Minute Walk Test 
This measures how many meters a person can walk in 6 minutes. It includes total distance 
walked (6MWD), the number and duration of any stops in 6 minutes. Test performed at baseline 
and at visits on Week 13, and 25 will be used for analysis. 
Right Heart Catheterization (RHC) 
The RHC is performed to assess several hemodynamic parameters when the patient is in a stable 
hemodynamic rest state (as demonstrated by three consecutive cardiac output measurements 
with 10% of each other). The measurement is taken at baseline and at visit on Week 25. The 
assessed hemodynamic parameters include: 
• right atrial (RA) pressure 
• mean pulmonary artery pressure (mPAP) 
• pulmonary capillary wedge pressure (PCWP) 
• systolic and diastolic blood pressure (RV pressures) 


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• heart rate (HR) 
• cardiac output (CO) 
• systemic vascular resistance (SVR) 
• mixed venous blood gas measurement 
Echocardiography 
The echocardiography is performed to assess the impact of study drug on right heart structure 
and function. All echocardiography images will be centrally read by an imaging vendor. The 
measurement is taken at baseline and at visit on Week 5, 13, and 25. 
The assessed echocardiography parameters include: 
• Tricuspid annular plane systolic excursion (TAPSE) 
• Tricuspid annular systolic velocity (TASV) 
• Peak velocity of excursion (RV S´) 
• Fractional area change (FAC) 
Patient Reported Outcomes (PROs) 
The two patient reported outcomes utilized in this study are emPHasis-10 and in PAH-
SYMPACT. Change from baseline on Week 13, and 25 will be descriptively summarized. 
• The emPHasis-10 questionnaire (Yorke, et al., 2014) consists of 10 items that address 
breathlessness, fatigue, control and confidence. Each item is scored on a semantic 
differential six-point scale (0-5) and carries the same weight. Hence, a total emPHasis-10 
score is derived simply aggregating scores of the 10 items. It ranges from 0 to 50, with 
higher scores representing a higher symptom burden. 
• The PAH-SYMPACT questionnaire (Mccollister, et al., 2016) (Chin, et al., 2018) consists 
of 11 symptom items across two domains (cardiopulmonary and cardiovascular 
symptoms) and 11 impact items across two domains (physical and cognitive/emotional 
impacts). Symptom items and one item about the use of oxygen are assessed daily for one 
week; impact items are assessed on the last day of the week. Each item is scored on a five-
point scale (0-4) except for the item of using oxygen (scale 0-1). The total PAH-
SYMPACT score will be calculated as the sum of impact item scores and mean weekly 
symptom item scores. For each symptom item, its mean weekly score will be calculated as 
the average daily item score taken within the 7-day interval.  
NT-proBNP 
The N-terminal fragment of the prohormone B-type natriuetic peptide (NT-ProBNP) is 
reflective of right ventricular distress. Measurements collected at baseline and at visits on Week 
13, and 25 will be used for analysis. 
Time to clinical worsening (TTCW) 
TTCW will be defined as time to any of the following events: 
• Death 


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• Hospital stay (≥ 24 h) due to worsening of PAH.  
• Worsening of PAH resulting in need for lung transplantation or balloon atrial septostomy 
• Initiation of parenteral prostanoid therapy, chronic oxygen therapy, or any other PAH-
specific therapies or need for increase of diuretics for more than 4 weeks due to worsening 
of PAH 
• Significant drop in 6MWD (15% from baseline or more) due to PAH-worsening 
2.6.2 
Statistical hypothesis, model, and method of analysis 
6MWT 
Change from baseline in walked distance for 6MWT at visits will be analyzed based on mixed 
model repeated measures, adjusting for effects of treatment, visit as categorical factors and 
treatment*visit and baseline*visit interactions.  Model based estimates of the mean effect will 
be reported for each treatment group along with the treatment difference, the 2-sided 80% 
confidence interval for treatment difference, and one-sided p-value 
TTCW 
Time to clinical worsening will be analyzed using survival models (i.e., Kaplan-Meier, cox 
regression) if adequate number of events occur during the study to characterize the survival 
curve. Participants without the event will be considered as censored at the end of the time at 
risk. The hazard ratio and the corresponding 80% confidence intervals will be computed using 
the appropriate method. If there is no adequate number of events, the number (and percentage) 
of participants with clinical worsening will be summarized by treatment and overall. 
Echocardiography 
Descriptive statistics (N, mean, SD, CV% mean, geometric mean, CV% geometric mean, 
median, min, and max) summarizing echocardiography parameters and their changes from 
baseline will be summarized by visit for treatment group and overall.  
Panels of individual spaghetti plots over time/visit for each echocardiography parameter will be 
provided. 
All echocardiography parameters will be listed by participant, and visit and if ranges are 
available, abnormalities will be flagged. 
PROs 
For emPHasis-10, total score and change from baseline of total score will be summarized by 
visit for treatment and overall. For PAH-SYMPACT, the total score and change from baseline 
will be summarized by visit for treatment and overall. 
NT-proBNP   
NT-proBNP (visits on week 13 and 25) will be analyzed based on mixed model repeated 
measures, adjusting for the baseline, treatment groups, visit and treatment-by-visit interaction. 
Model based estimates of the mean effect will be reported for each treatment group along with 


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the treatment difference, the 2-sided 80% confidence interval for treatment difference, and one-
sided p-value. Depending on the distribution of NT-proBNP data, the analysis for NT-proBNP 
might be through logarithms to reduce outliers and skewness. 
RHC  
RHC parameters and their change from baseline will be summarized by visit for treatment group 
and overall.  
Echocardiography parameters, PROs, and RHC are all continuous variables. Summary statistics 
(including N, mean, SD, minimum, median, and maximum) of each parameter, and graphical 
presentations (e.g., boxplots) will be provided by visit/time for treatment group, and overall 
2.6.3 
Handling of intercurrent events  
Not applicable. 
2.6.4 
Handling of missing values not related to intercurrent events 
Missing data will be assumed MAR while imputing the missing values.  
2.6.5 
Sensitivity analyses 
For the analysis of 6MWT, missing measurement will be assumed MAR. Alternative 
assumptions may be explored to investigate the robustness of the results under plausible non-
missing at random situations. 
2.6.6 
Supplementary analyses 
Not applicable. 
2.7 
Safety analyses 
For all safety analyses, the safety set will be used. All listings will be presented by treatment 
group, and tables will be presented by treatment group and overall. Safety summaries (tables, 
figures) include only data from the on-treatment period except for baseline data which will also 
be summarized where appropriate (e.g. change from baseline summaries).  
The on-treatment period lasts from the date of first administration of study treatment to the EOS 
visit (about 30 days after the date of the last actual administration of any study treatment). 
2.7.1 
Adverse events (AEs) 
All adverse events summarized will be displayed by treatment group and overall. All adverse 
events listing will be presented by treatment group and participant.  
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of double-blind 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways. The definition of the on treatment period is defined in Section 2.1.1. 
• by treatment, primary system organ class and preferred term. 


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• by treatment, primary system organ class, preferred term and maximum severity. 
• by treatment, Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation. In case of sparse 
events in any of these categories occur, only a listing will be provided if deemed adequate. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
2.7.1.1 
Adverse events of special interest / grouping of AEs 
Not applicable. 
2.7.2 
Deaths 
The number and percentage of deaths, including on-treatment and post-treatment deaths, will 
be summarized by treatment group. 
2.7.3 
Laboratory data 
All laboratory data will be listed by treatment group, participant, and visit/time and if normal 
ranges are available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a subject with any abnormal values. Descriptive statistics (N, mean, SD, 
minimum, median, and maximum) summarizing continuous laboratory results of clinical 
chemistry, hematology, urinalysis, and changes from baseline by visit/time for treatment group, 
and overall will be provided. Graphical presentations (e.g., boxplots) will be provided by 
visit/time and treatment.  
Shift tables using the low/normal/high/ (low and high) classification will be used to compare 
baseline to the worst on-treatment value for treatment group. 
2.7.4 
Other safety data 
2.7.4.1 
ECG data 
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each participant 
during the study. ECG data will be read and interpreted (locally).  
Categorical Analysis of QTcF (Fridericia’s formula) interval data based on the number of 
participants meeting or exceeding predefined limits in terms of absolute QT or QTc intervals or 
changes from baseline will be presented. The number and percentage of participants with 
clinical notable QTcF will be summarized by visit and treatment group and overall. A listing of 
these participants will be produced (by treatment group). The clinical notable criteria for QTcF 
(Fridericia’s formula) are indicated in Table 2-3. 


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Table 2-3 
Clinical notable criteria for QTcF (Fridericia's formula) 
ECG parameter (unit) 
Clinically notable range 
Notable value considering newly occurring or worsening cases 
QTcF (msec) 
QTcF (msec) 
 
> 500  
> 480 if normal at baseline 
 
Notable change from baseline 
QTcF (msec) 
> 60 
All ECG data will be listed by treatment group, participant and visit/time, abnormalities will be 
flagged. Summary statistics and graphical presentations (e.g., boxplots) will be provided by 
treatment and visit/time. 
2.7.4.2 
Vital signs 
Vital signs will include the collection of otic or oral body temperature (recorded in °C), blood 
pressure (BP) and pulse measurements. 
All vital signs data will be listed by treatment group, participant, and visit/time and if ranges 
are available, abnormalities will be flagged. Summary statistics (including N, mean, SD, 
minimum, median, maximum) of vital signs and changes from baseline will be provided by 
visit/time for treatment group and overall. Graphical presentations (e.g., boxplots) of vital signs 
will be provided by treatment and visit/time. 
2.8 
Pharmacokinetic endpoints   
All subjects within the PK analysis set will be included in the PK data analysis. 
The following pharmacokinetic parameters will be determined using PK blood samples 
collected at visits on
 
x LTP001 plasma concentration 
x Cmax and Tmax 
Cmax (in ng/mL) is the maximum (peak) observed plasma, blood, serum, or other body fluid 
drug concentration after single dose administration. Tmax (in hour) is the time to reach 
maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose 
administration. 
Descriptive summary statistics of LTP001 plasma concentration data will be provided by 
treatment, and visit/sampling time point. Summary statistics will include mean (arithmetic and 
geometric), standard deviation (SD), coefficient of variation (CV) (arithmetic and geometric), 
median, minimum, and maximum. Concentrations below LLOQ will be treated as zero in 
summary statistics and the frequency (n, %) of concentrations below the LLOQ will be reported. 
The geometric mean will not be reported if the dataset includes zero values. 
Descriptive summary statistics for LTP001 PK will include mean (arithmetic and geometric), 
SD, and CV (arithmetic and geometric), median, minimum, and maximum. An exception to this 
is Tmax where median, minimum, and maximum will be presented. 
CCI


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2.9 
PD and PK/PD analyses 
 
 
   
2.10 
Patient-reported outcomes 
Borg score 
For the Borg score component, the participant will answer questions on a scale of one to ten to 
determine the participant’s shortness of breath during the 6MWT. Larger score indicates higher 
breathing difficulty.  
The Borg score and change from baseline will be summarized by visit and treatment group on 
the PD analysis set. 
2.11 
 
 
 
 
  
 
CCI
CCI
CCI
CCI


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2.12 
Other Exploratory analyses 
 
 
 
 
 
 
 
CCI
CCI


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2.13 
Interim analysis 
An unblinded interim analysis (IA) will be carried-out when approximately 20 participants 
complete the treatment period (Week 25).  
This IA will be performed primarily to assess futility (non-binding) on PVR endpoint. The study 
may be stopped for futility if the posterior probability of the treatment effect no better than 
placebo is above 60%. Also, analysis for secondary efficacy endpoints, including right heart 
catheterization results, PROs, NT-proBNP, 6MWD, and TTCW will be performed as described 
in Section 2.6. 
Safety parameters including clinical safety laboratory, ECG, vital signs, and adverse events will 
be listed and descriptively summarized by treatment and visit/time, if appropriate. More 
detailed description of the analyses as described in Section 2.7 will be conducted.  The study 
will be stopped if there are three or more (in different participants) similar study-treatment 
(LTP001) related SAEs that are not related to worsening of PAH (i.e., lack of efficacy by 
LTP001) 
Additional interim analyses may be conducted to support decision making concerning the 
current clinical study, the sponsor’s clinical development projects in general or in case of any 
safety concerns. Unblinded interim analysis results will be reviewed by the clinical team.  
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3 
Sample size calculation 
Approximately 44 participants including dropouts are planned to be randomized in a 3:1 ratio 
to receive LTP001 vs. placebo on top of SoC. dropout rate is considered to be around 10%. 
The sample size calculation was based on the primary endpoint of change from baseline in PVR 
at Week 25. The criterion for this calculation is based on dual criteria: 
1. An average change from baseline for PVR over placebo is 100dyn·s·cm−5 and 
2. 90% level of proof that the change from baseline for PVR in the LTP001 group is better 
than placebo. 
With a non-informative prior for the LTP001 group, and the obtained weakly informative prior 
for the placebo group, a sample size of 40 (3:1 ratio of LTP001: placebo) provides 
approximately 84% chance (power) of meeting the success criterion if the true treatment effect 
over placebo is 200 dyn·s·cm−5.  
With approximately 20 participants completing the study at interim, the probability of 
considering stopping early for futility (non-binding) is approximately 44% in case of a 
placebo‑like drug and less than 3% in case the true treatment difference for PVR is 200 
dyn·s·cm−5, which is the statistically significant difference between drug and placebo in this 
PAH population. 
Assumptions related to PVR variability will be evaluated at the time of interim analyses to 
consider re-estimation of sample size as appropriate. 
4 
Change to protocol specified analyses 
No change from protocol specified analysis was made. 


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5 
Reference 
Chin, K. M., Gomberg-Maitland, M., Channick, R. N., Cuttica, M. J., Fischer, A., Frantz, R. 
P., . . . Badesch, D. B. (2018). Psychometric Validation of the Pulmonary Arterial 
Hypertension-Symptoms and Impact (PAH-SYMPACT) Questionnaire: Results of the 
SYMPHONY Trial. Chest, 154(4), 848-861. 
Fisch, R., Jones, I., Jones, J., Kerman, J., Rosenkranz, G. K., & Schmidli, H. (2015). Bayesian 
Design of Proof-of-Concept Trials. Therapeutic Innovation Regulatory Science, 155-162. 
Lehmann, E. L., & Hodges, J. L. (1963). Estimates of Location Based on Rank Tests. The 
Annals of Mathematical Statistics, 34, 598-611. 
Mccollister, D., Shaffer, S., Badesch, D. B., Filusch, A., Hunsche, E., Schuler, R., . . . 
Peacock, A. (2016). Development of the Pulmonary Arterial Hypertension-Symptoms and 
Impact (PAH-SYMPACT) questionnaire: a new patient-reported outcome instrument for 
PAH. 17(1). 
Neuenschwander, B., Capkun-Niggli, G., Branson, M., & Spiegelhalter, D. J. (2010). 
Summarizing historical Information on Controls in clinical Trials. Clinical Trials, 5-18. 
Yorke, J., Corris, P., Gaine, S., R. Gibbs, J., Kiely, D. G., Harries, C., . . . Armstrong, I. 
(2014). emPHasis-10: development of a health-related quality of life measure in pulmonary 
hypertension. 43(4), 1106-1113.