An Open-label Extension Study to Investigate Efficacy, Safety and Tolerability of LTP001 in Participants With Pulmonary Arterial Hypertension
Phase: PHASE2
Conditions: Pulmonary Arterial Hypertension
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
Clinical Trial Protocol Title: 
An open-label extension study to investigate efficacy, 
safety and tolerability of LTP001 in participants with 
pulmonary arterial hypertension 
Clinical Trial Protocol Number: CLTP001A12201E1 / NCT05764265
Version Number: v01 (Clean) 
Compound: LTP001 
Brief Title: Extension study of efficacy and safety of LTP001 in pulmonary arterial 
hypertension participants 
Study Phase: IIa 
Sponsor Name: Novartis 
Regulatory Agency Identifier Number(s): 2022-002007-38 
Approval Date: 30-Jan-2023 (content final) 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 5.0 dated 14-Jan-2022 

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
Amendment 01 (January 2023) .................................................................................................. 7 
1 
Protocol summary ................................................................................................................ 8 
1.1 
Summary .................................................................................................................. 8 
1.2 
Schema ................................................................................................................... 12 
1.3 
Assessment Schedule ............................................................................................. 12 
2 
Introduction ....................................................................................................................... 17 
2.1 
Study rationale ....................................................................................................... 17 
2.2 
Background ............................................................................................................ 17 
2.3 
Benefit/Risk assessment ........................................................................................ 18 
2.3.1 
Blood sample volume ............................................................................ 21 
3 
Objectives, endpoints, and estimands ................................................................................ 21 
3.1 
Primary estimands ................................................................................................. 22 
3.2 
Secondary estimands ............................................................................................. 22 
4 
Study design ...................................................................................................................... 23 
4.1 
Overall design ........................................................................................................ 23 
4.1.1 
Off-site procedures ................................................................................ 23 
4.2 
Scientific rationale for study design ...................................................................... 25 
4.3 
Justification for dose .............................................................................................. 26 
4.3.1 
Rationale for choice of background therapy ......................................... 26 
4.4 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 26 
4.5 
Rationale for public health emergency mitigation procedures .............................. 26 
4.6 
Purpose and timing of interim analyses/design adaptations .................................. 26 
4.7 
End of study definition .......................................................................................... 27 
5 
Study population ................................................................................................................ 27 
5.1 
Inclusion criteria .................................................................................................... 27 
5.2 
Exclusion criteria ................................................................................................... 27 
5.3 
Lifestyle considerations ......................................................................................... 28 
5.3.1 
Meals and dietary restrictions ............................................................... 28 
5.3.2 
Activity .................................................................................................. 29 
5.4 
Screen failures ....................................................................................................... 29 
5.4.1 
Participant numbering ........................................................................... 29 
6 
Study treatment(s) and concomitant therapy ..................................................................... 29 

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6.1 
Study treatment(s) .................................................................................................. 29 
6.1.1 
Additional study treatments .................................................................. 29 
6.2 
Preparation, handling, storage, and accountability ................................................ 30 
6.2.1 
Handling of study treatment .................................................................. 30 
6.2.2 
Handling of other treatment .................................................................. 31 
6.2.3 
Instruction for prescribing and taking study treatment ......................... 31 
6.3 
Measures to minimize bias: randomization and blinding ...................................... 31 
6.3.1 
Treatment assignment, randomization .................................................. 31 
6.3.2 
Treatment blinding ................................................................................ 31 
6.3.3 
Emergency breaking of assigned treatment code .................................. 31 
6.4 
Study treatment compliance .................................................................................. 32 
6.4.1 
Recommended treatment of adverse events .......................................... 32 
6.5 
Dose modification .................................................................................................. 32 
6.6 
Continued access to study treatment after the end of the study ............................. 32 
6.7 
Treatment of overdose ........................................................................................... 32 
6.7.1 
Reporting of study treatment errors including misuse/abuse ................ 32 
6.8 
Concomitant and other therapy .............................................................................. 33 
6.8.1 
Concomitant therapy ............................................................................. 33 
6.8.2 
Prohibited medication ........................................................................... 35 
6.8.3 
Rescue medicine.................................................................................... 35 
7 
Discontinuation of study treatment and participant discontinuation/withdrawal .............. 36 
7.1 
Discontinuation of study treatment ........................................................................ 36 
7.2 
Participant discontinuation from the study ............................................................ 37 
7.3 
Withdrawal of informed consent and exercise of participants’ data privacy 
rights ...................................................................................................................... 37 
7.4 
Lost to follow-up ................................................................................................... 38 
7.5 
Study stopping rules .............................................................................................. 38 
7.6 
Early study termination by the Sponsor................................................................. 38 
8 
Study Assessments and Procedures ................................................................................... 39 
8.1 
Screening ............................................................................................................... 39 
8.2 
Participant demographics/other baseline characteristics ....................................... 39 
8.3 
Efficacy assessments ............................................................................................. 39 
8.3.1 
Echocardiography ................................................................................. 40 
8.3.2 
Right heart catheterization .................................................................... 40 
8.3.3 
6-Minute Walk Test .............................................................................. 41 
8.3.4 
Appropriateness of efficacy assessments .............................................. 41 

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8.4 
Safety assessments ................................................................................................. 42 
8.4.1 
Electrocardiograms ............................................................................... 43 
8.4.2 
Clinical safety laboratory tests .............................................................. 43 
8.4.3 
Pregnancy testing .................................................................................. 45 
8.4.4 
Appropriateness of safety measurements .............................................. 46 
8.5 
Additional assessments .......................................................................................... 46 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 46 
8.6 
Adverse events (AEs), serious adverse events (SAEs), and other safety 
reporting ................................................................................................................. 47 
8.6.1 
Adverse events ...................................................................................... 47 
8.6.2 
Serious adverse events .......................................................................... 49 
8.6.3 
SAE reporting........................................................................................ 50 
8.6.4 
Pregnancy .............................................................................................. 51 
8.6.5 
Disease-related events and/or disease-related outcomes not 
qualifying as AEs or SAEs .................................................................... 51 
8.7 
Pharmacokinetics ................................................................................................... 51 
8.8 
 ............................................................................................................. 51 
8.8.1 
 52 
8.9 
Immunogenicity assessments................................................................................. 53 
8.10 
Health economics OR Medical resource utilization and health economics .......... 53 
9 
Statistical considerations ................................................................................................... 53 
9.1 
Analysis sets .......................................................................................................... 53 
9.2 
Statistical analyses ................................................................................................. 53 
9.2.1 
General considerations .......................................................................... 53 
9.2.2 
Participant demographics and other baseline characteristics ................ 53 
9.2.3 
Treatments ............................................................................................. 53 
9.3 
Primary endpoint(s)/estimand(s) analysis.............................................................. 53 
9.3.1 
Definition of primary endpoint(s) ......................................................... 54 
9.3.2 
Statistical model, hypothesis, and method of analysis .......................... 54 
9.3.3 
Handling of missing values not related to intercurrent event ............... 54 
9.3.4 
Sensitivity analyses ............................................................................... 55 
9.3.5 
Supplementary analysis ......................................................................... 55 
9.4 
Secondary endpoint(s)/estimand(s) analysis.......................................................... 55 
9.4.1 
Efficacy and/or pharmacodynamic endpoint(s) .................................... 55 
9.4.2 
Safety endpoints .................................................................................... 55 
9.4.3 
Patient reported outcomes ..................................................................... 55 
9.5 
Exploratory endpoint(s)/estimand(s) analysis ....................................................... 55 
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9.5.1 
 55 
9.5.2 
 56 
9.6 
(Other) Safety analyses .......................................................................................... 56 
9.7 
Other analyses ........................................................................................................ 56 
9.8 
Interim analysis ...................................................................................................... 56 
9.9 
Sample size determination ..................................................................................... 56 
10 Supporting documentation and operational considerations ............................................... 57 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations................... 57 
10.1.1 
Regulatory and ethical considerations .................................................. 57 
10.1.2 
Informed consent process ...................................................................... 58 
10.1.3 
Data protection ...................................................................................... 59 
10.1.4 
Committees structure ............................................................................ 60 
10.1.5 
Data collection and database management ........................................... 60 
10.1.6 
Source documents ................................................................................. 61 
10.1.7 
Publication policy.................................................................................. 62 
10.1.8 
Protocol adherence and protocol amendments ...................................... 62 
10.2 
Appendix 2: Abbreviations and definitions ........................................................... 64 
10.2.1 
List of abbreviations .............................................................................. 64 
10.2.2 
Definitions ............................................................................................. 66 
10.3 
Appendix 3: ECG values and vital signs ............................................................... 69 
10.3.1 
Clinically notable laboratory values and vital signs ............................. 69 
10.4 
Appendix 4: Participant Engagement .................................................................... 70 
10.5 
Appendix 5: Liver safety monitoring .................................................................... 71 
10.5.1 
Liver event and laboratory trigger definitions & follow-up 
requirements .......................................................................................... 72 
10.6 
Appendix 6: Renal safety monitoring .................................................................... 75 
10.6.1 
Specific Renal Alert Criteria and Actions and Event Follow-up .......... 75 
11 References ......................................................................................................................... 76 
List of tables 
Table 1-1 
Objectives and related endpoints ............................................................ 8 
Table 1-2 
Assessment Schedule ............................................................................ 14 
Table 3-1 
Objectives and related endpoints .......................................................... 21 
Table 4-1 
Rationale for study design ..................................................................... 25 
Table 6-1 
Investigational drugs ............................................................................. 29 
Table 6-2 
 35 
Table 8-1 
Safety Assessments ............................................................................... 42 
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Table 8-2 
Clinical Laboratory Evaluations ........................................................... 44 
Table 10-1 
Liver event and laboratory trigger definitions ...................................... 72 
Table 10-2 
Follow up requirements for liver laboratory triggers - ALT, AST, 
TBL ....................................................................................................... 72 
Table 10-3 
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia ............................................................................... 74 
Table 10-4 
Specific renal alert criteria and actions ................................................. 75 
List of figures 
Figure 1-1 
Study Schema ........................................................................................ 12 

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Protocol No. CLTP001A12201E1 
 
Amendment 01 (January 2023) 
Amendment rationale 
The primary purpose of this amendment is to incorporate safety follow-up visits at Weeks 9 and 
17 in response to feedback received by Health Authorities. 
The protocol appendix and Safety Assessments table was updated with further guidance for 
renal alert criteria and follow-up guidelines. 
Inclusion criterion #4 was removed to avoid the exclusion of subjects who may have progressed 
on placebo. 
This amendment also corrects for administrative inconsistencies and adds further protocol 
clarifications to ensure data quality. 
Changes to the protocol 
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 and Health Authority 
approval according to local regulations 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 No. CLTP001A12201E1 
 
1 
Protocol summary 
1.1 
Summary 
Protocol Title: 
An open-label extension study to investigate efficacy, safety and tolerability of LTP001 in 
participants with pulmonary arterial hypertension 
Brief Title: 
Extension 
study 
of 
efficacy 
and 
safety 
of 
LTP001 
in 
pulmonary 
arterial 
hypertension participants 
Purpose: 
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. 
Study Indication /Medical Condition: 
Pulmonary arterial hypertension 
Treatment type: 
Drug 
Study type: 
Interventional 
Objectives, Endpoints, and Estimands: 
Table 1-1 
Objectives and related endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To assess the long-term safety of LTP001 in 
participants with pulmonary arterial 
hypertension (PAH). 
• 
AEs, SAEs, vital signs, ECGs, safety 
laboratory measurements 
Secondary 
 
• 
To assess the effect of LTP001 on the 
6MWD 
• 
Change in 6MWD from baseline over time 
• 
To evaluate the effect of LTP001 on 
hemodynamic parameters derived from 
RHC including PVR, RA pressures, mean 
PA pressure, PCWP, CO, SVR. 
• 
Change from baseline over time for each 
parameter 

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Objectives 
Endpoints 
x 
To assess the effect of LTP001 on 
measurements of right ventricular function 
(RVF) in participants with PAH 
x 
Change from baseline in tricuspid annular 
plane systolic excursion (TAPSE) by 
echocardiography 
x 
Change from baseline in tricuspid annular 
systolic velocity (TASV) by 
echocardiography 
x 
Change from baseline of peak velocity of 
excursion (RV S') by echocardiography 
x 
Change from baseline in fractional area 
change (FAC) by echocardiography 
x 
To assess the impact of LTP001 on patient 
reported outcomes (PRO) in participants 
with PAH. 
x 
Change from baseline in EmPHasis-10 and 
PAH-SYMPACT 
x 
To assess the impact of LTP001 on Time to 
Clinical Worsening (TTCW) in participants 
with PAH. 
x 
Death 
x 
+RVSLWDOVWD\KGXHWRZRUVHQLQJRI
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 
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 assess the impact of LTP001 on the N-
terminal fragment of the prohormone B-type 
natriuretic peptide (NT-proBNP). 
x 
N-terminal fragment of the prohormone B-
type natriuretic peptide 
Exploratory 
 
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Protocol No. CLTP001A12201E1 
 
Objectives 
Endpoints 
Trial Design: 
Please refer to Section 1.2 Schema for study design figure. 
This is a non-randomized, open-label extension study, over 52 weeks, with LTP001 without a 
control treatment arm. Participants will be presented the opportunity to consider the extension 
study at the End of Treatment (EOT) visit of the parent study CLTP001A12201. At the EOT 
visit of the parent study, the investigator will determine the eligibility for the extension study 
(i.e. that none of the treatment discontinuation criteria were met and that the assessments at the 
EOT of the parent study were completed according to the parent protocol). Participants who are 
eligible and want to participate in the extension study will need sign an informed 
consent to receive the extension study treatment. As not all assessment results will be available 
(e.g. lab assessments) at the same visit date, the investigator will re-assess/reconfirm the 
eligibility as soon as the outstanding results are received. Patients can directly transition 
into  treatment in this extension study without un-blinding the previous treatment in the parent 
study. The safety and efficacy of LTP001 will be checked at the following visits: Weeks 5, 13, 
26, 39, and 52, as specified in the schedule of activities. Safety and tolerability assessments will 
take place at each visit. 6MWT and echocardiography will be assessed at Weeks 26 and 52. 
RHC will be assessed at Week 26. 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 
all visits. Participants will have safety follow-up phone calls at Weeks 9 and 17, and may be 
invited for unscheduled assessments at the site if deemed necessary. Following the end of the 
treatment period, participants will have one safety follow-up phone call approximately 30 days 
after the end of treatment visit at Week 56. 
The safety and efficacy profile of LTP001 that is observed in this extension study as well as the 
parent study, CLTP001A12201, will determine continuation of the extension study. 
Brief Summary: 
The purpose of this study is to measure the long-term safety and efficacy profile of LTP001 in 
participants with pulmonary arterial hypertension (PAH). The study offers participants who had 
completed the CLTP001A12201 double-blind parent study in PAH an opportunity to receive 
LTP001 (whether they were on LTP001 or not). Unblinding of the treatment received in 
CLTP001A12201 is not planned. 
x The study duration will be up to 54 weeks. 
x The treatment duration will be up to 52 weeks. 
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x The visit frequency will include visits at weeks 1, 5, 13, 26, 39, 52, and 56. 
Treatment of interest 
The treatment of interest is LTP001  mg daily on top of allowed standard of care treatment for 
PAH. The dose of the allowed concomitant medication should remain stable during the trial. 
Number of Participants: 
The study population is comprised of male and female adults with PAH. A total of 
approximately 40 participants are planned to complete the parent study CLTP001A12201 and 
meet the study entry criteria for this open label extension study. 
Key Inclusion criteria: 
x Written informed consent must be obtained before any assessment is performed. 
x Participant is currently completing the Novartis-sponsored study CLTP001A12201 in 
PAH and completed key efficacy and safety procedures up to the end of treatment of the 
parent study, without meeting discontinuation criteria in the parent study. 
x Willingness and ability to comply with scheduled visits, treatment plans and any other 
study procedures. 
x In the opinion of the Investigator the participant would benefit from LTP001 treatment. 
Key Exclusion criteria: 
x History of hypersensitivity to the study treatment. 
x Required or planned transplant or heart/lung surgery. 
x Acute or chronic impairment (other than dyspnea), which would limit the ability to 
comply with study requirements, including interference with physical activity or execution 
of study procedures such as 6MWT (e.g., angina pectoris, claudication, musculoskeletal 
disorder, need for walking aids). 
x Permanent discontinuation of Novartis drug in the parent study due to toxicity or disease 
progression, non-compliance to study procedures, withdrawal of consent or any other 
reason. 
Treatment Groups: 
Active treatment: LTP001 administered as  mg once daily 
 (
 
). Investigational study 
treatment dose adjustments and/or interruptions are not permitted. 
Data Monitoring/Other Committee: 
Yes; the DMC instituted for the parent study will also receive data from this extension study 
(see Section 10.1.4 Committees Structure). 
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Key words: 
Pulmonary arterial hypertension, pulmonary vascular resistance, 6 minute walk distance, time 
to clinical worsening, SMURF1 inhibitor, echocardiography, patient reported outcomes 
1.2 
Schema 
Figure 1-1 
Study Schema 
1.3 
Assessment Schedule 
The Assessment Schedule lists all of the assessments when they are performed. All data 
obtained from these assessments must be supported in the participant’s source documentation. 
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. 
Participants should be seen for all visits/assessments as outlined in the Assessment Schedule or 
as close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. 
Participants who discontinue from study treatment are to complete 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 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 events and concomitant medications not previously reported must be recorded on 
the CRF. 
PRO measures must be completed before any assessments are performed at any given visit. 
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As per Section 4.5, 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), 
alternative methods of providing continuing care may be implemented by the Investigator as 
the situation dictates. If allowable by a local health authority, national and local regulations and 
depending on operational capabilities, phone calls, virtual contacts (e.g. tele consultation) or 
visits by site staff/ off-site healthcare professional(s) staff to the participant´s home, can replace 
certain protocol assessments, for the duration of the disruption until it is safe for the participant 
to visit the site again. If the Investigator delegates tasks to an off-site healthcare professional, 
the Investigator must ensure the individual(s) is/are qualified and appropriately trained to 
perform assigned duties. The Investigator must oversee their conduct and remain responsible 
for the evaluation of the data collected. 

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Table 1-2 
Assessment Schedule 
Period 
Baseline 
 
 
Extension Treatment Up To Month 12 
 
Visit Name 
Transition Period 
 
 
Treatment 
EOT 
Post Study Safety Contact 
Visit Numbers1 
12 
1002 
110 
 
120 
 
130 
140 
150 
 
Days 
-14 to -1 
1 
29 
±7 
57 
±10 
85 
±10 
113 
±10 
176 
±10 
267 
±10 
358 
±10 
Last treatment +30 
-0 +7 
Weeks 
-2 to -1 
1 
5 
±1 
9 
±2 
13 
±2 
17 
±2 
26 
±2 
39 
±2 
52 
±2 
57 
-0 +1 
Informed consent3,4 
X 
  
  
 
  
 
  
  
  
  
Inclusion / Exclusion criteria 
X 
  
  
 
  
 
  
  
  
  
Physical Examination 
  
  
S 
S8 
S 
S8 
S 
S 
S 
  
Body Weight 
  
  
X 
X8 
X 
X8 
X 
X 
X 
  
Body Temperature 
  
  
X 
X8 
X 
X8 
X 
X 
X 
  
Blood Pressure and Pulse 
Rate 
  
  
X 
X8 
X 
X8 
X 
X 
X 
  
Electrocardiogram (ECG) 
  
  
X 
X8 
X 
X8 
X 
X 
X 
  
Dose administration5 
  
X 
X 
X8 
X 
X8 
X 
X 
X 
  
Drug dispensation 
  
X 
X 
 
X 
 
X 
X 
  
  
Collect study medication/ 
perform drug 
accountability5 
  
  
X 
X8 
X 
X8 
X 
X 
X 
  
Urinalysis 
  
  
X 
X8 
X 
X8 
X 
X 
X 
  
Pregnancy and 
assessments of fertility 
  
  
S 
S8 
S 
S8 
 
S 
S 
S 
  
Hematology 
  
  
X 
X8 
X 
X8 
 
X 
X 
X 
  
Clinical Chemistry 
  
  
X 
X8 
X 
X8 
 
X 
X 
X 
  

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Period 
Baseline 
 
 
Extension Treatment Up To Month 12 
 
Visit Name 
Transition Period 
 
 
Treatment 
EOT 
Post Study Safety Contact 
Visit Numbers1 
12 
1002 
110 
 
120 
 
130 
140 
150 
 
Days 
-14 to -1 
1 
29 
±7 
57 
±10 
85 
±10 
113 
±10 
176 
±10 
267 
±10 
358 
±10 
Last treatment +30 
-0 +7 
Weeks 
-2 to -1 
1 
5 
±1 
9 
±2 
13 
±2 
17 
±2 
26 
±2 
39 
±2 
52 
±2 
57 
-0 +1 
Coagulation Panel 
  
  
X 
X8 
X 
X8 
 
X 
X 
X 
  
NT-proBNP 
  
  
X 
 
X 
 
X 
X 
X 
  
emPHasis-10 and PAH-
SYMPACT6 
  
  
X7 
 
X7 
 
X7 
X7 
X7 
  
Right Heart 
Catheterization4 
  
  
  
 
  
 
X 
  
  
  
6-Minute Walk Test4 
  
  
  
 
  
 
X 
  
X 
  
Echocardiogram4 
  
  
  
 
  
 
X 
  
X 
  
Concomitant Medications/ 
Adverse Events 
 
X 
Study completion 
information 
  
  
  
 
  
 
  
  
X 
  
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Protocol No. CLTP001A12201E1 
 
Period 
Baseline 
 
 
Extension Treatment Up To Month 12 
 
Visit Name 
Transition Period 
 
 
Treatment 
EOT 
Post Study Safety Contact 
Visit Numbers1 
12 
1002 
110 
 
120 
 
130 
140 
150 
 
Days 
-14 to -1 
1 
29 
±7 
57 
±10 
85 
±10 
113 
±10 
176 
±10 
267 
±10 
358 
±10 
Last treatment +30 
-0 +7 
Weeks 
-2 to -1 
1 
5 
±1 
9 
±2 
13 
±2 
17 
±2 
26 
±2 
39 
±2 
52 
±2 
57 
-0 +1 
Safety Follow up Call 
  
  
  
S 
  
S 
  
  
  
S 
 
 
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 Baseline and Day 1 can be on the same day or within a 14-day transition period 
3 
 
4 Assessment must be performed onsite. All other assessments may be performed at an off-site location. 
5 Collect unused study medication, perform drug accountability (pill count) and document compliance with protocol instructions. 
6 PROs to be completed by participants for 7 consecutive day intervals around each visit from Weeks 5 to 52. The 7th day of collection for each visit 
should occur during the Visit Window for Weeks 5 to Week 52. 
7 On clinic visit days, PROs are to be the first assessments performed. 
8 Safety follow-up phone call at Weeks 9 and 17 may require unplanned safety assessment, if deemed necessary by the PI. PI may omit safety 
assessments per their discretion (optional). 
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2 
Introduction 
2.1 
Study rationale 
The purpose of this study is to study the long term safety and efficacy profile of LTP001 in 
participants with PAH. The study offers participants who had completed the CLTP001A12201 
double-blind parent study in PAH an opportunity to stay on or start receiving treatment with 
LTP001. 
2.2 
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 (PDE5i), 
endothelin receptor antagonists (ERAs), soluble guanylate cyclase (sGC) stimulators and 
prostacyclin analogues and receptor agonists) leave 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 (FIH) 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 2.3 and the 
Investigator's Brochure. 
 
 
 
 
 
 
 
 
 
2.3 
Benefit/Risk assessment 
Potential risks are based on the mechanism of action, the nonclinical toxicology data, and the 
safety data from the FIH 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 
 
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Clinical data 
Single doses of LTP001 
mg, 
 mg,  mg,  mg,  mg, 
 mg and 
 mg were well 
tolerated and did not show safety signals for LTP001 in the first in human study. 
Multiple doses of LTP001  mg,  mg,  mg, 
 mg and 
 mg once daily and 
 mg bid were 
well tolerated. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
, 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. 
However, 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. PVR was the primary efficacy assessment of the 
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parent study, CLTP001A12201, and is performed at Week 26 in the current study, which allows 
the assessment of the 1-year effect of LTP001 of those participants who received LTP001 
already in the parent study, and the 6-month effect on PVR of those who received placebo in 
the parent study. This data is considered very important to assess the long-term effect of LTP001 
on PVR in patients with PAH. 
Other procedures in the study are non-invasive: 
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. 
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 unless the investigator judges that the patient benefits from LTP001 
treatment despite the need for added PAH therapy and discusses the situation with the Novartis 
medical lead for the study (Section 6.8.1.1). 
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, the clinical data with LTP001 is still limited. 
It has been used in a Phase I study in healthy participants. It is used in the parent study, 
CLTP001A12201, for this extension study as well as in clinical investigations in other 
indications, such as lung fibrosis. Thus, when this extension study starts, whilst there will be a 
safety record in healthy and PAH participants, efficacy may not yet be proven in PAH 
participants. 

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2.3.1 
Blood sample volume 
A volume smaller than a typical blood donation is planned to be collected over a period of 
52 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 1-1). 
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 
manual. 
3 
Objectives, endpoints, and estimands 
Table 3-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To assess the long term 
safety of LTP001 in 
participants with pulmonary 
arterial hypertension (PAH). 
• 
 AEs, SAEs, vital signs, ECGs, safety laboratory 
measurements 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To evaluate the effect of 
LTP001 on 
hemodynamic parameters 
derived from RHC including 
PVR, RA pressures, mean 
PA pressure, PCWP, CO, 
SVR. 
• 
Change from baseline at week 26 for each parameter 
• 
To assess the effect of 
LTP001 on the 6MWD 
• 
Change in 6MWD from baseline over time 
• 
To assess the effect of 
LTP001 on measurements of 
right ventricular function 
(RVF) in participants with 
PAH 
• 
Change from baseline in tricuspid annular plane systolic 
excursion (TAPSE) by echocardiography 
Change from baseline in tricuspid annular systolic velocity 
(TASV) by echocardiography 
Change from baseline of peak velocity of excursion (RV S') 
by echocardiography 
Change from baseline in fractional area change (FAC) by 
echocardiography 
• 
To assess the impact of 
LTP001 on patient reported 
outcomes (PRO) in 
participants with PAH. 
• 
Change from baseline in EmPHasis-10 and PAH-
SYMPACT 

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Objective(s) 
Endpoint(s) 
x 
To assess the impact of 
LTP001 on Time to Clinical 
Worsening (TTCW) in 
participants with PAH. 
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 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) 
3.1 
Primary estimands 
Not applicable 
3.2 
Secondary estimands 
Not applicable 
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4 
Study design 
4.1 
Overall design 
Please refer to Section 1.2 Schema for study design figure. 
This is a non-randomized, open-label extension study over 52 weeks with LTP001 without a 
control treatment arm. Participants will be presented the opportunity to consider the extension 
study at the End of Treatment (EOT) visit (Week 25) of the parent study CLTP001A12201. 
The investigator will assess if the participant will continue by verifying that the participant has 
completed the parent study as planned. Moreover, at the EOT the investigator will determine 
the eligibility for the extension study (i.e. that none of the treatment discontinuation criteria 
were met and that the assessments at the EOT of the parent efficacy study were completed 
according to the parent protocol). The patient may directly continue into the extension study. 
If the patient does not directly continue in the extension study, the time between the end of 
treatment assessments in the parent study and the enrollment in the extension study i.e. during 
the transition period should be kept to a minimum (it should not exceed 14 days). 
Participants who are eligible and want to participate in the extension study will need to have 
signed an informed consent in order to receive the extension study treatment. In case of a direct 
transition into the extension study after the end of treatment visit in the parent study, as not all 
assessment results will be available (e.g. the central lab assessments) at the same day the 
investigator will re-assess/reconfirm the eligibility as soon as outstanding results are received. 
The safety and efficacy of LTP001 will be checked at the following visits: Weeks 5, 13, 26, 39 
and 52, as specified in the Assessment Schedule. Safety and tolerability assessments will take 
place at each visit. RHC will be performed at week 26, 6MWT and echocardiography will be 
assessed at Weeks 26 and 52. PAH-SYMPACT and emPHasis-10 will be collected for 7 days 
intervals with the seventh day of collection occurring within the allotted visit window for all 
Treatment visits (Weeks 5, 13, 26, 39 and 52). Participants will have safety follow-up phone 
calls at Weeks 9 and 17, and may be invited for safety assessment at site if deemed necessary. 
The PI may exercise their discretion in which safety assessments are required at these optional 
safety follow-up visits. Following the end of treatment period, participants will have one safety 
follow-up phone call approximately 30 days after the end of treatment visit at Week 52. 
The duration of the extension study is currently restricted to 52 weeks, but the study may be 
prolonged (via an amendment to the protocol) if the LTP001 development program in 
PAH continues and the benefit/risk assessment remains favorable for the patient population 
studied. The safety and efficacy profile of LTP001 that is observed in this extension study as 
well as the parent study, CLTP001A12201, will determine continuation of the extension study. 
4.1.1 
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, not mandated to be performed onsite, at an off-site location, as defined 
in Table 1-1. 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 

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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-participant shipment of study supplies 
• Direct-to-participant shipment of study treatment (refer to Section 6) 
• Electronic Source (eSource) Direct Data Capture (DDC) 
4.1.1.1 
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, but is 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 
4.1.1.2 
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 
regulations and guidelines. 
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 
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4.1.1.3 
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: 
• Secure videoconferencing which allows the participant, OHP and site personnel to be 
connected 
• Reminders to be automatically sent to participants (e.g. visit or dosing reminders) 
• eSource Direct Data Capture (DDC) (see Section 10.1.5.1) 
4.2 
Scientific rationale for study design 
Table 4-1 
Rationale for study design 
Study Design Aspect 
Rationale 
Open-label 
Design is to assess safety, and all participants 
will receive active treatment 
Eligibility 
All participants who completed CLTP001A12201 
treatment period and have not met study 
treatment discontinuation criteria are eligible to 
enroll. At the time of enrollment, efficacy of 
LTP001 is unknown, therefore all participants 
who may benefit can enroll in this extension 
protocol. 
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 
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4.3 
Justification for dose 
LTP001 will be administered once daily
 at a dose level of  mg. This is the same 
posology as used in the parent study, CLTP001A12201. 
In healthy participants, 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. 
4.3.1 
Rationale for choice of background therapy 
Participants will remain on the same background therapy as in the parent study, 
CLTP001A12201, (for details please refer to Section 6) and should not be changed during the 
extension study. Typically, 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 7.2) and subsequently return for the EOT assessments. However, if the investigator 
thinks that the participant should remain on study drug the Novartis medical monitor should be 
contacted to discuss the change of concomitant PAH medication and the reasons why it is 
thought to be beneficial for the participant to stay on study drug. 
4.4 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
This is an open label extension study, where all participants are planned to receive active 
treatment with LTP001. No control treatment is planned during this study. This allows all 
participants to potentially benefit from treatment, if LTP001 yields clinical benefit in PAH. 
4.5 
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 on-site 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. 
4.6 
Purpose and timing of interim analyses/design adaptations 
There are no prospectively planned interim analyses. Interim analyses may be conducted to 
support decision-making concerning the current clinical study, the sponsor’s clinical 
development projects in general, to provide regular safety updates or in case of any safety 
concerns. 
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4.7 
End of study definition 
The end of the study is defined as the date of the last visit of the last participant in the study. 
Study completion is defined as when the last participant finishes their last study visit and any 
repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator. 
5 
Study population 
The study population will be comprised of male and female participants with pulmonary arterial 
hypertension. 
Approximately 40 participants are expected to complete parent study CLTP001A12201 and 
meet the study entry criteria for this open label extension 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 participants. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Written informed consent must be obtained before any assessment is performed. 
2. Participant is currently completing the Novartis-sponsored study CLTP001A12201 in 
PAH and completed key efficacy and safety procedures up to the end of treatment of the 
core study, without meeting discontinuation criteria in the core study. 
3. Willingness and ability to comply with scheduled visits, treatment plans and any other 
study procedures. 
5. In the opinion of the Investigator would benefit from LTP001 treatment. 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. History of hypersensitivity to the study treatment. 
2. Sexually active males not committing to condom use precautions: 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 nor donate sperm. A condom 
is required to be used also by vasectomized men in order to prevent delivery of the drug 
via seminal fluid. 
3. Required or planned transplant or heart/lung surgery. 
4. 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 EOT visit (2 weeks 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. 

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x 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. 
x 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 
x 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 
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. 
5. 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. 
6. Acute or chronic impairment (other than dyspnea), which would limit the ability to 
comply with study requirements, including interference with physical activity or execution 
of study procedures such as 6MWT (e.g., angina pectoris, claudication, musculoskeletal 
disorder, need for walking aids). 
7. Permanent discontinuation of Novartis drug in the core efficacy study due to toxicity or 
disease progression despite active treatment, non-compliance to study procedures, 
withdrawal of consent or any other reason. 
5.3 
Lifestyle considerations 
For the duration of the study, participants should be informed and reminded of the restrictions 
outlined in this section. 
5.3.1 
Meals and dietary restrictions 
 
 
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5.3.1.1 
Dietary restrictions and smoking 
Participants should be encouraged to maintain a healthy diet and abstain from the use of alcohol 
or recreational drugs. Change in smoking status from parent study (CLTP001A12201) will be 
collected as part of the CRF. 
5.3.2 
Activity 
No significant change in physical exercise program from the beginning of the study until after 
Study Completion evaluation. 
5.4 
Screen failures 
A screen failure occurs when a participant who consents to participate in the clinical study is 
subsequently found to be ineligible and therefore not entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Information includes the 
screen failure details, eligibility criteria, and any serious adverse event (SAE). 
5.4.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled and is retained for the participant throughout his/her 
participation in the trial. The Participant No. consists of the Site Number (Site 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. 
6 
Study treatment(s) and concomitant therapy 
6.1 
Study treatment(s) 
Table 6-1 
Investigational drugs 
Investigational 
Drug (Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (Global 
or Local) 
LTP001 
mg 
Oral Use 
Open-label, 
participant-
specific kits 
Global 
LTP001  mg 
Oral Use 
Open-label, 
participant-
specific kits 
Global 
6.1.1 
Additional study treatments 
No other treatment beyond investigational drug is included in this trial. 
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6.2 
Preparation, handling, storage, and accountability 
Each study site will be supplied with study drug in packaging as described under Study 
treatment(s) Table 6-1. 
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 three-month supply. In this case, regular contacts (every 12 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. 
6.2.1 
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. 
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 the end of the study 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. 

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6.2.2 
Handling of other treatment 
It should be checked at each visit if other concomitant PAH specific therapy has been kept 
stable as specified in Section 6.8.1. 
6.2.3 
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 when instructed 
by the study staff. 6MWT and RHC assessment should be executed at approximately the same 
time after drug administration each time (tolerance window +/- 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. 
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. 
Novartis will provide the site with a participant study card to hand over to all study participants, 
which will state that the participant is participating in a clinical study and is receiving an 
investigational product. This participant study card will also include the contact information of 
the Study Doctor/Investigative Site. Designated study stuff 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. 
6.3 
Measures to minimize bias: randomization and blinding 
6.3.1 
Treatment assignment, randomization 
Not applicable 
6.3.2 
Treatment blinding 
Not applicable 
6.3.3 
Emergency breaking of assigned treatment code 
Emergency code breaks are not applicable, as the study medication is open-label. 
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6.4 
Study treatment compliance 
The investigator 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 (if applicable) 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. 
Remote treatment administration compliance will be assessed by the off-site healthcare 
professional and information provided to the Investigator and/or study personnel. 
6.4.1 
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 7.1 should be 
observed. 
Medication used to treat AEs must be recorded on the appropriate CRF. 
6.5 
Dose modification 
Investigational study treatment dose adjustments and/or interruptions are not permitted. 
6.6 
Continued access to study treatment after the end of the study 
Not applicable. 
6.7 
Treatment of overdose 
In the event of an overdose, the Investigator should: 
• Evaluate the participant to determine, in consultation with the medical monitor, whether 
study treatment should be interrupted or continued as per protocol. The participant should 
be checked for any adverse events and implementation of safety measures (e.g. additional 
visit for safety assessments/ additional assessments for safety) should be considered. 
The Novartis medical team, including the medical monitor, should be informed of any 
overdosing event. 
• Document the quantity of the excess dose as well as the duration of the overdose. 
6.7.1 
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 (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 

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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 CRF irrespective of whether or not associated with an AE/SAE. Study treatment 
errors and uses outside of what is foreseen in the protocol, 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. For more information on AE and SAE definition and 
reporting requirements, please see the respective sections. 
6.8 
Concomitant and other therapy 
6.8.1 
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. 
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 
enrolling 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 participant population by the applicable regulations and guidelines. 
LTP001 is not expected to be an inhibitor of cytochrome P450 enzymes at the exposures 
following a  mg dose. 
 
 See Section 6.8.2 for examples of 
 which are 
prohibited for use throughout the study duration. LTP001 is not expected to be an inhibitor of 
transporters tested to date. LTP001 is not expected to be a victim of transporter inhibition. 
6.8.1.1 
Permitted concomitant therapy requiring caution and/or action 
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 Case Report Forms. 
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. 
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PAH-directed concomitant medication 
ERAs, prostacyclin analogues and receptor agonists, sGC stimulators and/or PDE5i for PAH 
treatment are allowed. The dose(s) should remain unchanged during the study. In case the 
investigator reduces or increases the dose of a concomitant PAH directed therapy, or stops or 
starts a concomitant PAH directed therapy, please contact the Novartis medical monitor. 
Single administration of medication for diagnostic purposes (such as use for acute vasodilator 
testing during the RHC procedure) is allowed. 
IV prostacyclin analogues: If daily dose is increased by more than 20% change from initial 
study dose level please inform Novartis medical monitor. 
Overall, if an escalation of PAH directed therapy is required consider if this might be related to 
ineffective study drug treatment (Section 7.1). 
Treatment with diuretics is allowed and may be adjusted during the study with the following 
precautions: 
x Need for another diuretic to be added 
x A parenteral diuretic is added 
x The oral diuretic dose is more than doubled 
x Please inform the Novartis medical monitor and consider if the need for such treatment 
may point to ineffective study drug treatment 
Please do not change diuretic treatment within 7 days prior to a RHC assessment unless required 
for the safety of the participant. 
Other medications 
COVID-19 vaccinations and any other vaccinations with registered vaccines are allowed as 
recommended for the participant population by the applicable regulations and guidelines. 
LTP001 is not expected to be an inhibitor of cytochrome P450 enzymes at the exposures 
following a 
mg dose.
 
 
. 
LTP001 is not expected to be an inhibitor of transporters tested to date. LTP001 is not expected 
to be a victim of transporter inhibition. 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate Case Report Forms. 
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6.8.2 
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, ERAs, and sGC stimulators, refer to Section 6.8.1), doses should be kept stable during 
the study. Note that a required change in PAH-directed therapy due to clinical worsening of 
PAH might point to lack of efficacy of  LTP001 in the patient. Treatment discontinuation should 
be considered, and appropriate management of the participant with the PAH directed therapy 
as per the investigator's discretion and the participant's need instituted. 
In terms of treatments required for other conditions or adverse events, there are no known drug 
interaction signals with LTP001 potentially impacting the PK of other drugs 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. 
 
 
. 
Drugs which are known to prolong the QT interval are prohibited for use throughout the study 
duration. 
6.8.3 
Rescue medicine 
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. 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 6.8.1. 
Use of rescue medications must be recorded on the Concomitant medications/Significant non-
drug therapies CRF after signing the informed consent. 
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7 
Discontinuation of study treatment and participant 
discontinuation/withdrawal 
7.1 
Discontinuation of study treatment 
The investigator must also contact the IRT to register the participant’s 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. 
Discontinuation from study treatment is required under the following circumstances: 
• Participant decision 
• Pregnancy (if the participant decided to terminate the pregnancy, treatment with LTP001 
may be resumed after the abortion procedure if desired by the participant and agreed by 
the investigator and the Novartis medical monitor). 
• Any situation in which continued study participation might result in a safety risk to the 
participant 
• Development of heart failure symptoms consistent with pulmonary hypertension WHO 
Functional Class IV (symptoms at rest; severe symptoms at exercise) 
• If organ transplantation becomes necessary during the study treatment 
• Atrial septostomy required due to deterioration of PAH 
• Deterioration of PAH suggesting ineffectiveness of LTP001 as per the judgement of the 
investigator 
• Adverse event that is graded severe or serious by the investigator and considered study 
drug related. If the investigator believes it is beneficial for the participant to stay on study 
drug (e. g. signs of PAH-improvement and adverse event appears well manageable) and 
the participant wishes to stay on study drug the investigator shall contact the Novartis 
medical monitor for further discussion. 
• If a liver or renal event occurs, follow guidelines outlined in Section 10.5 (Appendix 5) 
and Section 10.6 (Appendix 6) regarding discontinuation of study treatment. 
If discontinuation from study treatment occurs due to participant's decision, the investigator 
should make a reasonable effort to understand the primary reason for the participant’s 
discontinuation from study treatment and record this information. In those instances where 
study drug discontinuation criteria were waived as per the exceptions defined above the decision 
made as well as the rationale for it needs to be documented in writing in the Trial Master File. 
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 Table 1-1). 

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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 
7.2 
Participant discontinuation from the 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 Section 1.3 Schedule of Activities. 
7.3 
Withdrawal of informed consent and exercise of participants’ 
data privacy rights 
Withdrawal of consent/opposition to use of data and/or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and when a participant: 
• Explicitly requests to stop use of their data 
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 the 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. 

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If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/exercise data privacy rights should be made as detailed in Section 1.3. 
Further details on withdrawal of consent or the exercise of participants' data privacy rights are 
included in the corresponding informed consent form. 
7.4 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits or fail to 
respond to any site attempts to contact them without stating an intention to discontinue from 
study treatment or discontinue from study or withdraw consent (or exercise other participants’ 
data privacy rights), 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. 
7.5 
Study stopping rules 
Overall study stopping rules 
The study will be put on hold if the Sponsor considers that the number and/or severity of AEs, 
abnormal safety monitoring tests or abnormal laboratory findings justify it. 
In these cases, ad hoc internal experts in collaboration with the DMC (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 ultimate responsibility on the decision to terminate the 
study is with the sponsor. 
The findings and recommendations of the internal experts and DMC (and investigators if felt 
needed) will be documented and will be made available to all investigators, their respective 
Institutional Review Board/Independent Ethics Committee (IRB/IEC), as appropriate. 
Any participants 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. 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. 
7.6 
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 after review of recommendations from applicable board(s) (e. g. DMC) 
• Discontinuation of LTP001 development in PAH 

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x LTP001 fails to show adequate efficacy and safety profile in the ongoing PAH studies in 
the population studied 
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 Novartis depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 
8 
Study Assessments and Procedures 
x Study procedures and their timing are summarized in Section 1.3 Assessment Schedule. 
Protocol waivers or exemptions are not allowed. 
x Immediate safety concerns should be discussed with Novartis upon occurrence or 
awareness to determine if the participant should continue or discontinue study 
treatment. 
x Adherence to the study design requirements, including those specified 
in Section 1.3 Assessment Schedule, is essential and required for study conduct. 
x Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
8.1 
Screening 
Participants are only allowed to join this trial if they have successfully completed the treatment 
phase of CLTP001A12201, meet all of the inclusion/exclusion criteria, and have signed the 
informed consent for this trial. 
8.2 
Participant demographics/other baseline characteristics 
The demographic information from the subset of patients that enter the extension study from 
the parent study CLTP001A12201 will be used for demographics and baseline characteristics. 
When applicable (i.e., following a significant enrollment delay from the parentstudy end of 
treatment visit to the first visit of the extension study), study participants will be asked for any 
changes of their medical conditions, concomitant medication from the last visit of the parent 
study. 
8.3 
Efficacy assessments 
Pharmacodynamic samples will be collected at the time-points defined in the Assessment 
Schedule (Table 1-1). Pharmacodynamic samples includes the following assessments: 
NT-proBNP 
 
 
 
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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. 
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 1-1). 
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 
 
 
In all participants, the baseline and follow-up imaging will be performed where possible using 
the same ultrasound scanner and technologist. 
The methods for assessment and recording are specified in the imaging charter and imaging 
manual, also known as the subject scanning guide. 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 well-being 
of the participant. 
8.3.2 
Right heart catheterization 
The RHC assessment is performed to assess several hemodynamic variables in pulmonary 
hypertension, including mPAP, PCWP, CO, PVR, and systemic vascular resistance (SVR). 
The RHC Assessments Recommendation Manual provides further instruction on performing 
the RHC. 
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 
participant’s concomitant medication and study treatment relative to catheterization should 
be the same for the subsequent catheterization (tolerance window +/- 1 hour). 
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• The following hemodynamic parameters will be assessed when the participant is in a 
stable hemodynamic rest state (as demonstrated by three consecutive CO measurements 
within 10% of each other) while the participant is breathing ambient air or oxygen: 
• RA, mPAP, PCWP, systolic and diastolic blood pressure, HR 
• CO (measured in triplicate preferably by the thermodilution technique) 
• Mixed venous blood gas measurement 
In all cases, the same technique must be used as was used in the parent study, CLTP001A12201. 
• The following parameters will be derived from the CO measurement: 
• SVR in dyn·s/cm-5 
• PVR in dyn·s/cm-5 
8.3.3 
6-Minute Walk Test 
A standardized 6MWT will be performed considering the guidance for the test procedures 
described by ERS and ATS guidelines (Section 11). 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 
participant 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 participant 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. 
Single 6MWTs will be performed according the Assessment Schedule (Table 1-1). 
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. 

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8.4 
Safety assessments 
Safety assessments are specified below with the Assessment Schedule detailing when each 
assessment is to be performed. 
For details on AE collection and reporting, refer to AE section (Section 8.6.1). 
As per Section 4.5, 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 12 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. 
Table 8-1 
Safety Assessments  
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. 
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 CRF 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 or 
oral 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. 
Weight 
Body weight (to the nearest 0.1 kilogram (kg) in 
indoor clothing, but without shoes) will be 
measured as specified in Table 1-1. 

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8.4.1 
Electrocardiograms 
The Fridericia QT correction formula (QTcF) must be used for clinical decisions to assess 
eligibility. The investigator must calculate QTcF if it is not auto-calculated by the ECG 
machine. 
Single 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 CRF. 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 CRF. 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. ECG safety monitoring, 
or a review process, should be in place for clinically significant ECG findings during the study. 
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or adverse events as appropriate. 
8.4.2 
Clinical safety laboratory tests 
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. 
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). 
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. 

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Special clinical laboratory evaluations 
In addition to hematology and clinical chemistry safety laboratory and urinalysis, 
thyroid-specific assays, endocrine function tests, and coagulation assays will be obtained as per 
the Table 8-2 below. 
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 required to 
allow the determination of the outcome of the event where possible. 
Clinically notable laboratory findings are defined in Appendix 3 (Section 10.3). 
Table 8-2 
Clinical Laboratory Evaluations 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Ery. Mean Corpuscular 
Hemoglobin, Ery. Mean Corpuscular HGB 
Concentration, Ery. Mean Corpuscular Volume, 
Platelets, Erythrocytes, Leukocytes, Erythrocyte 
Cell Morphology (only to be assessed in case of 
abnormalities in the full blood count), Differential 
(Basophils, Eosinophils, Lymphocytes, 
Monocytes, Neutrophils, Bands) 
Chemistry 
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 
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) 
Coagulation 
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). 
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Test Category 
Test Name 
These tests are in addition to routine testing, to 
be performed only in follow-up to safety events 
when indicated in Section 10.5 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 10.6, 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, Leukocytes esterase, Macroscopic 
Blood, Nitrite Occult Blood, pH, Protein, Specific 
Gravity, Urobilinogen)), urine sediment & 
microscopy 
Additional tests 
NT-proBNP (considered a pharmacodynamic 
biomarker) 
Pregnancy Test 
Serum pregnancy test refer to 'Pregnancy 
testing' in Section 8.4.3 
8.4.3 
Pregnancy testing 
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. In addition, 
male participants should not donate sperm while taking drug and for 24 hours after stopping 
study medication. 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements. 
As per Section 4.5, 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 to have serum pregnancy tests, 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). 

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Assessments of fertility 
A woman is considered of childbearing potential from menarche and until becoming post 
menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. Medical documentation of oophorectomy, 
hysterectomy, or tubal ligation must be retained as source documents. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause and an appropriate clinical profile. 
In absence of the medical documentation confirming permanent sterilization, or if the post-
menopausal status is not clear, the investigator should use his medical judgment to appropriately 
evaluate the fertility state of the woman and document it in the source document. 
8.4.4 
Appropriateness of safety measurements 
 
 
 
 
Cardiac function and status are 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 
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. 
Participant questionnaires should be completed in the language most familiar to the participant. 
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 either captured on paper, and subsequently 
entered manually into the eCRF, or stored electronically in the database will be considered the 
source file. 
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Completed measures must be reviewed and assessed by the Investigator for 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, Investigators 
should not encourage the participant to change responses reported in the completed 
questionnaires. Investigators must follow reporting instructions outlined in Section 8.6 of the 
study protocol. 
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 participant 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. 
8.6 
Adverse events (AEs), serious adverse events (SAEs), and other 
safety reporting 
8.6.1 
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 8.6.2): 
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 

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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 
3. Its duration (start and end dates or ongoing) and the outcome must be reported 
4. Whether it constitutes a SAE (see Section 8.6.2 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 not recovered/not resolved (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 a participant 
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8.6.2 
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 
• life-threatening 
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, fetal death or a congenital abnormality or 
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. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
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8.6.3 
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, but under no 
circumstances later than within 24 hours of obtaining knowledge of the events (Note: If more 
stringent, local regulations regarding reporting timelines prevail). 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 
provide a clinically thorough report. 
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, but under no circumstances later than within 24 hours of the 
Investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). 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 
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8.6.4 
Pregnancy 
Pregnancies 
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 
date of delivery. 
8.6.5 
Disease-related events and/or disease-related outcomes not qualifying 
as AEs or SAEs 
Not applicable 
8.7 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this extension study. 
8.8 
 
 
 
 
 
 
 
 
 
 
 
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8.8.1 
 
 
 
 
 
 
 
 
 
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8.9 
Immunogenicity assessments 
Immunogenicity is not evaluated in this study. 
8.10 
Health economics OR Medical resource utilization and health 
economics 
Health economics and medical resource utilization and health economics parameters are not 
evaluated in this study. 
9 
Statistical considerations 
9.1 
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 that received any study treatment. 
The PD analysis set will include all participants who received study treatment and had no 
protocol deviations with relevant impact on PD data. 
9.2 
Statistical analyses 
9.2.1 
General considerations 
The safety analysis set will be used in the analysis of all safety variables. 
9.2.2 
Participant demographics and other baseline characteristics 
Demographic and baseline characteristics of all patients in the extension study will be 
summarized for the safety population. 
9.2.3 
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) will be summarized by means of descriptive statistics 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. 
9.3 
Primary endpoint(s)/estimand(s) analysis 
The primary aim of the study is to assess the long-term safety of LTP001 in participants with 
PAH. Safety assessment will include AEs, SAEs, vital signs, ECGs, and safety laboratory 
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9.3.1 
Definition of primary endpoint(s) 
Adverse events (AEs) 
Study emergent AEs in the extension study will be summarized and listed. Also, all study 
emergent AEs in both the parent study and extension study will be summarized. 
Consistent with the parent study CLTP001A12201 definitions, AEs starting after the first dose 
of study medication or events present prior to start of treatment but increased in severity based 
on preferred term will be classified as a treatment emergent AE. The following treatment 
emergent adverse events summaries will be produced: 
• by primary system organ class and preferred term 
• by primary system organ class, preferred term and maximum severity 
• by Standardized MedDRA Query (SMQ) and preferred term. 
The number and percentage of participants with adverse events will be summarized. 
Vital signs 
Vital signs data will be summarized by visit/time. 
Electrocardiogram (ECG) 
All ECG data, including PR, QRS, QT, QTcF and RR, will be listed by participant and 
visit/time, and abnormalities will be flagged. Summary statistics will be provided by visit/time. 
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. 
Laboratory data 
All laboratory data will be listed by participant and visit/time, and abnormalities will be flagged 
if normal ranges are available. Summary statistics will be provided for each lab parameter at 
each visit. 
9.3.2 
Statistical model, hypothesis, and method of analysis 
The long-term safety of LTP001 will be evaluated in this extension study. 
All analyses will be based on frequency counts and summary statistics. No statistical models 
will be used. 
The primary analysis population will be the Safety analysis set. 
9.3.3 
Handling of missing values not related to intercurrent event 
Missing data will not be imputed. 

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9.3.4 
Sensitivity analyses 
Not applicable 
9.3.5 
Supplementary analysis 
Not applicable 
9.4 
Secondary endpoint(s)/estimand(s) analysis 
9.4.1 
Efficacy and/or pharmacodynamic endpoint(s) 
Change from baseline for efficacy endpoints including the right heart catheterization (RHC) 
parameters, 6-Minute Walk Distance (6MWD), and N-terminal fragment of the prohormone B-
type natriuetic peptide (NT-proBNP) will be descriptively summarized by visit/time for 
treatment group (treatment received in the parent study), and overall. The baseline measurement 
for the extension will be the baseline measurement taken during the parent study 
CLTP001A12201. Graphs (e.g., spaghetti plot) will be provided to show individual time 
courses of parameters for the extension study together with the parent study. 
Additionally, changes from baseline for efficacy endpoints will be descriptively summarized 
by visit/time for treatment group (treatment received in the parent study), and overall using a 
different baseline strategy: participants receiving LTP001 in the parent study will use the 
baseline of parent study as the baseline; participants switching from placebo in parent study to 
LTP001 in extension study will use the baseline of extension study as the baseline. 
Time to clinical worsening will be analyzed using survival analysis (i.e., Kaplan-Meier) and the 
corresponding 80% confidence interval will be computed using the appropriate method. 
9.4.2 
Safety endpoints 
Refer to Section 9.3.1. 
9.4.3 
Patient reported outcomes 
PROs (emPHasis-10 and PAH-SYMPACT scores) will be summarized as the original scores, 
as well as change from baseline, by time/visit. The baseline measurement for the extension 
study will be the baseline measurement of the parent study CLTP001A12201. Missing data may 
be imputed using a last observation carried forward approach (LOCF) as necessary. 
9.5 
Exploratory endpoint(s)/estimand(s) analysis 
9.5.1 
 
 
 
 
 
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9.5.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.6 
(Other) Safety analyses 
Not applicable 
9.7 
Other analyses 
Not applicable 
9.8 
Interim analysis 
Not applicable 
9.9 
Sample size determination 
Not applicable 
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10 
Supporting documentation and operational considerations 
10.1 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1 
Regulatory and ethical considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines 
• Applicable ICH Good Clinical Practice (GCP) guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (e.g. advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments/modifications to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The Investigator will be responsible for the following: 
Signing 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 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures 
Providing oversight of the conduct of the study at the site and adherence to requirements of 
21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations 
Inform Novartis immediately if an inspection of the clinical site is requested by a regulatory 
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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. 
10.1.2 
Informed consent process 
The Investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representatives will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data protection 
requirements, where applicable, and the IRB/IEC or study center. 
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. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the Informed Consent 
Form (ICF). 
A copy of the ICF(s) must be provided to the participant. 
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. 
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 upon obtaining consent and also 
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: 
 
 
 
 
 
 
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• As applicable, Pregnancy Outcomes Reporting Consent for female participants or the 
female partners of any male participants who took study treatment 
• Patient information sheet for female partners of any male participants who took study 
treatment 
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. 
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. 
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain a standard 
written informed consent due to limits that prevent an on-site visit, Investigator may conduct 
the informed consent discussion remotely (e.g. telephone, videoconference) if allowable by a 
local health authority. 
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.). 
10.1.3 
Data protection 
Participants will be assigned a unique identifier by Novartis. Any participant records or datasets 
that are transferred to Novartis will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used 
by Novartis in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Novartis, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
Novartis has appropriate processes and policies in place to handle personal data breaches 
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10.1.4 
Committees structure 
For the development of LTP001 in pulmonary arterial hypertension, with the start of the parent 
study, a DMC has been established. 
10.1.4.1 Data Monitoring Committee 
The parent study to this extension study will include a Data Monitoring Committee (DMC). 
The DMC will assess at defined intervals the progress of the clinical trial, safety data, and 
critical efficacy variables and recommend to Novartis whether to continue, modify, or terminate 
the trial and program. The DMC will be in place at least until the parent study is completed. 
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations are described 
in a separate charter that is established between Novartis and the DMC. 
10.1.5 
Data collection and database management 
10.1.5.1 Data collection for off-site procedures 
All data captured for this study will have an external originating source (either written or 
electronic) with the Case Report Form (CRF) 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 
CRF. 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 
Electronic Data Capture (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 entered into the 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. 
10.1.5.1.1 
Data collection for off-site procedures 
The OHPs will enter data at off-site visits into electronic source documentation forms contained 
in an eSource Direct Data Capture (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. 

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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. 
Relevant data in the eSource DDC platform may be manually transcribed by site staff into the 
study EDC system. Alternatively, the platform allows for configuration that enables data to be 
automatically exported 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. 
10.1.5.2 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. 
Baseline and study completion dates, as well as 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. 
Any changes to the database after that time can only be made after written agreement 
by Novartis development management. 
10.1.6 
Source documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. 

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The Investigator may need to request previous medical records or transfer records, depending 
on the study. Also, current medical records must be available. 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. 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 maintain accurate documentation (source data) that supports the 
information entered in the CRF. Study monitors will perform ongoing source data verification 
to confirm that data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory requirements. 
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 / CRA 
organization. Additionally, a central analytics organization may analyze data and identify risks 
and trends for site operational parameters, and provide reports to Novartis clinical teams to 
assist with trial oversight. 
10.1.7 
Publication policy 
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 participant 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.). 
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. 
Any data analysis carried out independently by the Investigator should be submitted 
to Novartis before publication or presentation. 
This is required in order to meet the EU Clinical Trial Regulation 536/2014, which is effective 
January 2022 for new protocols. 
Summary results of primary and secondary endpoints will be disclosed based upon the global 
Last Participant Last Visit (LPLV) date, since multinational studies are locked and reported 
based upon the global LPLV. 
10.1.8 
Protocol adherence and protocol amendments 
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 

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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. 
10.1.8.1 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. 
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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10.2 
Appendix 2: Abbreviations and definitions 
10.2.1 
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 
bid 
Twice a Day 
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 
CO2 
Carbon Dioxide 
COA 
Clinical Outcome Assessment 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
 
 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ERA 
Endothelin-Receptor Antagonist 
eSource 
Electronic Source 
FIH 
First in Human 
 
 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
h 
Hour 
hCG 
Human Chorionic Gonadotrophin 
HR 
Heart Rate 
I.V. 
intravenous 
IB 
Investigator's Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
CCI
CCI
CCI

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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 
 
 
LLN 
Lower Limit of Normal 
MedDRA 
Medical dictionary for regulatory activities  
mg 
Milligram(s) 
mL 
Milliliter(s) 
mPAP 
mean Pulmonary Arterial Pressure 
ng 
Nanogram(s) 
NT-
proBNP 
N-terminal fragment of the prohormone B-type Natriuetic Peptide 
NYHA 
New York Heart Association 
OHP 
Off-site HealthCare Professional 
OLE 
Open Label Extension 
p.o. 
Oral(ly) 
PA 
PosteroAnterior 
PAH 
Pulmonary Arterial Hypertension 
PCWP 
Pulmonary Capillary Wedge Pressure 
PD 
Pharmacodynamic(s) 
PDE5i 
Phosphodiesterase type 5 inhibitors 
PRO 
Patient Reported Outcomes 
 
 
 
 
 
 
PT 
Prothrombin Time 
PVR 
Pulmonary Vascular Resistence 
qd 
Once a Day 
QTcF 
QT interval corrected by Fridericia’s formula 
RA 
Right Atrium 
RVFAC 
Right Ventricular Fractional Area Change 
s.c. 
SubCutaneous 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
sGC 
soluble Guanylate Cyclase 
SMURF1 
SMAD-specific E3 Ubiquitin Protein Ligase 1 
SoA 
Schedule of Activities 
CCI
CCI
CCI
CCI

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SoC 
Standard of Care 
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 
10.2.2 
Definitions 
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. 
Cohort 
A group of individuals who share a common exposure, experience or 
characteristic, or a group of individuals followed-up or traced over time 
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 (e.g. 
100 mg once a day, 75 mg twice a day) 
Electronic Data Capture 
(EDC) 
Electronic data capture (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 
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 

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eSource Direct Data 
Capture (DDC) 
eSource DDC refers to the capture of clinical study data electronically, 
at the point of care. eSource Platform/Applications combines source 
documents and case report forms (eCRFs) into one application, 
allowing for the real time collection of clinical trial information to 
sponsors and other oversight authorities, as appropriate 
Healthy volunteer 
A person with no known significant health problems who volunteers to 
be a study participant  
Hybrid Trial Design 
A trial model incorporating both onsite (traditional site based) and offsite 
(decentralized) elements within the same study design. 
Intercurrent events 
Events occurring after treatment initiation that affect either the 
interpretation or the existence of the measurements associated with the 
clinical question of interest. 
Investigational drug/ 
treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
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) 
Part  
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single 
dose part and a multiple dose part, or a part in participants with 
established disease and in those with newly-diagnosed disease 
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. 
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 

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Screen Failure 
A participant who did not meet one or more criteria that were required 
for participation in the study 
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. 
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 different legal 
reason than consent. 

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10.3 
Appendix 3: ECG values and vital signs 
10.3.1 
Clinically notable laboratory values and vital signs 
The following clinically notable laboratory 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?) 
Clinically Notable Laboratory Values: 
Systolic blood pressure > 165 mm Hg or < 80 mm Hg in absence of arterial hyper- or 
hypotension at baseline 
Diastolic blood pressure > 109 mm Hg or < 50 mm Hg in absence of arterial hyper- or 
hypotension 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 study entry 
QRS-Duration > 120 ms when normal prior to  study enrolment. 
PR - value > 220 ms when normal at prior to study enrolment 
AV-block > Grade 2a 

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10.4 
Appendix 4: 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 

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10.5 
Appendix 5: 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 10-1 in Appendix 5 for complete definitions of liver laboratory triggers. 
Once a participant is exposed to study treatment, every liver event defined in Table 10-1 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 
• 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. 
• If the initial elevation is confirmed, 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 7.1), if appropriate 
• Hospitalization of the participant if appropriate 
• Causality assessment of the liver event 
• 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. 

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10.5.1 
Liver event and laboratory trigger definitions & follow-up requirements 
Table 10-1 
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 
• 
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 10-2 
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) 

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ALT 
TBL 
Liver Symptoms 
Action 
 
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. 
• 
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 elevated at 
baseline: 
ALT > 3 x 
baseline 
or > 300 U/L 
(whichever 
occurs ﬁrst) for 
more than two 
weeks 
 
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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Table 10-3 
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia 
Criteria 
Actions required 
Follow-up monitoring 
Total Biliruin (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) 
> 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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10.6 
Appendix 6: Renal safety monitoring 
10.6.1 
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. 
Table 10-4 
Specific renal alert criteria and actions 
Serum Event 
Serum creatinine increase > 25% fold compared 
to baseline 
Follow up within 1-2 days 
(Refer to Table 8-2) 
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 
(Refer to Table 8-2) 
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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