Conditions: Pulmonary Hypertension
Keywords: Six Minute Walk Distance Test (6 MWDT) Right Heart Catheterization (RHC) Pulmonary Vascular Resistance (PVR) Pulmonary Function Test (PFT) Mean Pulmonary Arterial Pressure (mPAP) Pharmacokinetics Pharmacodynamics Hyaluronan Hymecromone
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 17
Healthy volunteers: no

Brief summary:
This study is a prospective, randomized, double-blind, study of H01 (Hymecromone) in adults with pulmonary hypertension (PH). The primary objective of this study is to evaluate the safety and tolerability of oral H01 and the potential benefit of oral H01 on clinical measures of PH disease severity over 24 weeks.

Study Hypothesis:

Oral H01, at doses of 1600 mg per day, will be a safe and well-tolerated agent in adults with pulmonary hypertension over 24 weeks

Detailed description:
The study's objectives are to evaluate:

* The changes in clinical and functional measures (pulmonary function test, pulmonary vascular resistance, mean pulmonary arterial pressure, and 6 Minute Walk Distance Test) in adults with PH treated with oral H01
* The safety and tolerability of the use of oral H01 for PH over 24 weeks using health criteria/evaluations (Common Terminology Criteria for Adverse Events (CTCAE), quality of life (QOL) score, EMPHASIS-10 score and St George Respiratory Questionnaire (SGRQ) score)
* To investigate the clinical efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) markers (serum HA concentration, inflammatory markers and cytokines, NT-proBNP, and H01 and metabolite serum concentrations) in this population following oral H01 use

Arms:
arm 1: Treatment will be initiated. Participants will be administered 800 mg of oral H01 two times a day (total dose: 1600 mg/day). Participants will continue to be on treatment for 24 weeks and will be monitored with assessments. arm 2: Participants randomized to placebo will receive oral tablet placebo (inactive ingredients) two times a day. Participants will continue to be on placebo for 24 weeks and will be monitored with assessments.

Interventions: intervention 1: Hymecromone (H01) intervention 2: Placebo
Intervention descriptions: intervention 1: 800 mg oral H01 two times a day (total dose: 1600 mg/day). intervention 2: Oral tablet placebo (inactive ingredients) two times a day.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
Investigation of H01 in Adults With Pulmonary Hypertension 
Including Interstitial Lung Disease (The SATURN Study) 
Study Protocol and Statistical Analysis Plan 
NCT05128929 
September 30, 2022 


The SATURN Study [CONFIDENTIAL – DO NOT REDISTRIBUTE] 
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Short Title: 
Investigation of H01 in adults with pulmonary hypertension including interstitial lung 
disease (The SATURN Study). 
 
 
Study Description: A study of oral H01 in adults with pulmonary hypertension including 
interstitial lung disease 
 
 
Study Phase: 2a 
Product Name: H01 
Study Document: Protocol (September 30, 2022) 
Indication: Pulmonary Hypertension 
 
 
IND Number: 
 
 
 
Investigator: Roham Zamanian, MD 
 
 
 
 
 
CONFIDENTIAL: The information contained in this document, particularly unpublished data, is 
confidential property. It is provided to you in confidence as an investigator, potential investigator, or 
consultant, for review by you, your staff, and an applicable Institutional Review Board or Independent 
Ethics Committee. The information is only to be used by you in connection with authorized clinical studies 
of the investigational drug described in the protocol. You will not disclose any of the information to others 
without written authorization. 


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CONTENTS 
1 
BACKGROUND ................................................................................................................................ 5 
1.1 
Introduction ................................................................................................................................. 5 
1.2 
Study Overview .......................................................................................................................... 6 
1.3 
Scientific Rationale ..................................................................................................................... 8 
1.3.1 
Urgent need for pulmonary hypertension therapeutics ......................................................... 8 
1.3.2 
Discussion on pulmonary hypertension groups .................................................................... 8 
1.3.3 
Hyaluronan is an important driver of respiratory disease and pulmonary hypertension ...... 9 
1.3.4 
H01 is a novel approach to addressing pulmonary hypertension secondary to interstitial lung 
disease ……………………………………………………………………………………10 
2 
H01 PHARMACOLOGY ................................................................................................................. 11 
2.1 
Dose Rationale .......................................................................................................................... 11 
2.2 
Clinical Efficacy ....................................................................................................................... 12 
2.3 
Clinical Safety ........................................................................................................................... 13 
2.4 
Non-clinical Efficacy ................................................................................................................ 13 
2.5 
Non-clinical Safety ................................................................................................................... 15 
2.6 
Hypothesis ................................................................................................................................. 15 
3 
STUDY DESIGN .............................................................................................................................. 16 
3.1 
Study Treatment ........................................................................................................................ 16 
4 
ENDPOINTS .................................................................................................................................... 17 
4.1 
Primary Endpoint ...................................................................................................................... 17 
4.2 
Secondary Endpoints ................................................................................................................ 17 
4.3 
Exploratory Endpoints .............................................................................................................. 17 
5 
STUDY POPULATION ................................................................................................................... 17 
5.1 
Inclusion Criteria ...................................................................................................................... 18 
5.2 
Exclusion Criteria ..................................................................................................................... 18 
5.3 
Concomitant Medication ........................................................................................................... 20 
6 
SCHEDULE OF ASSESSMENTS ................................................................................................... 21 
7 
ASSESSMENTS ............................................................................................................................... 21 


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7.1 
Screening/Baseline Assessment ................................................................................................ 21 
7.2 
Laboratories for Central Study-specific Testing ....................................................................... 22 
7.3 
Clinical Improvement ............................................................................................................... 23 
8 
STUDY DRUG PROCEDURES ...................................................................................................... 23 
8.1 
Treatment Assignment .............................................................................................................. 23 
8.2 
Blinding ..................................................................................................................................... 23 
8.3 
Formulation of Test and Placebo Medications ......................................................................... 24 
8.4 
Possible Reasons for Discontinuation of Treatment ................................................................. 24 
9 
MONITORING AND REPORTING OF ADVERSE EVENTS ...................................................... 25 
9.1 
Adverse Events Definition ........................................................................................................ 25 
9.2 
Suspected Adverse Reaction Definition ................................................................................... 25 
9.3 
Serious Adverse Event or Serious Adverse Reaction Definition .............................................. 25 
9.4 
Unexpected Adverse Event or Reaction Definition .................................................................. 25 
9.5 
New Fact ................................................................................................................................... 26 
9.6 
Identification of Adverse Events .............................................................................................. 26 
9.7 
Follow-up of Adverse Events ................................................................................................... 27 
9.8 
Guidelines for Assessing Severity of an Adverse Event ........................................................... 27 
9.9 
Guidelines for Determining Causality ...................................................................................... 27 
9.10 
Serious Adverse Events ............................................................................................................ 28 
9.11 
Unexpected Non-serious Adverse Events ................................................................................. 28 
9.12 
Reporting to Health Authority .................................................................................................. 28 
9.12.1 Standard Reporting (IND Annual Report) .......................................................................... 28 
9.12.2 Expedited Reporting ........................................................................................................... 28 
9.13 
Protocol Violations ................................................................................................................... 29 
9.14 
Reasons for Early Termination ................................................................................................. 29 
9.14.1 Halting the Study ................................................................................................................ 29 
9.15 
Data Safety Monitoring ............................................................................................................. 30 
10 STATISTICAL METHODS AND CONSIDERATIONS ................................................................ 30 
10.1 
Analysis Population .................................................................................................................. 30 


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10.2 
Descriptive Statistics ................................................................................................................. 30 
10.3 
Analysis of Primary Endpoints ................................................................................................. 31 
10.4 
Analysis of Secondary Endpoints ............................................................................................. 31 
10.5 
Analysis of Exploratory Endpoints ........................................................................................... 31 
10.6 
Missing Data Handling ............................................................................................................. 32 
10.7 
Sample Size and Randomization .............................................................................................. 32 
11 DATA COLLECTION, RETENTION AND MONITORING ........................................................ 32 
11.1 
Data Collection Instruments ..................................................................................................... 32 
11.2 
Data Management Procedures .................................................................................................. 33 
11.3 
Data Quality Control and Reporting ......................................................................................... 33 
11.4 
Archival of Data ........................................................................................................................ 33 
11.5 
Availability and Retention of Investigational Records ............................................................. 34 
11.6 
Subject Confidentiality ............................................................................................................. 34 
12 ETHICAL CONSIDERATIONS ...................................................................................................... 34 
12.1 
IRB and HIPAA ........................................................................................................................ 34 
12.2 
Potential Participant Risks ........................................................................................................ 36 
12.3 
Potential Benefits ...................................................................................................................... 36 
13 Abbreviations .................................................................................................................................... 36 
14 References ......................................................................................................................................... 37 


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1 
BACKGROUND 
 
1.1 
Introduction 
 
This is a prospective, randomized, double-blind, study of H01 of 24 weeks in adults with pulmonary 
hypertension (PH) with an optional open-label extension  (extension to 48 weeks). The primary objective 
of this double-blinded study is to evaluate the clinical efficacy of H01 over 24 weeks. Secondary objectives 
are to investigate the safety and tolerability of H01 and pharmacokinetic (PK) and pharmacodynamic (PD) 
markers in this population. Following IRB approval and written informed consent, a total of 16 participants 
will be enrolled, randomized approximately 2:1 (H01 1600 mg/day : placebo), stratified by PH type, and 
treated for 24 weeks. Data from this study will inform future larger studies. Participants will have the 
opportunity to extend their participation an additional 24 weeks by consenting to an open-label extension 
. 
 
PH is characterized by remodeling of the pulmonary vasculature, resulting in narrowing and eventual 
obliteration of the lumen, leading to increased mean pulmonary arterial pressure (mPAP)1.While multiple 
therapies have been developed to address PH, there are no disease modifying therapies and morbidity and 
mortality remains high. 
 
Recent research has suggested that hyaluronan (HA), a key component of the extracellular matrix, plays 
an important role in the pathology of PH and has potential as a therapeutic target2,3. Hyaluronan is an 
extracellular matrix glycosaminoglycan capable of trapping large volumes of water and driving pro- 
inflammatory pathways and fibrosis4. The role of hyaluronan in pulmonary hypertension, lung 
inflammation, and fibrosis has been validated in multiple animal models2,3,5,6. Further, in these models, 
inhibition of hyaluronan synthesis with H01 led to significant reductions in hyaluronan and had positive 
effects on clinically relevant outcomes such as Right Ventricular Systolic Pressure (RVSP), the Fulton 
index and arterial oxygenation (Sp02). 
 
Hymecromone (H01) is a known inhibitor of HA that has been studied in models of respiratory the context 
of both inflammation and fibrosis. The purpose of this clinical trial is to study the safety and utility of H01 
in patients with pulmonary hypertension associated with chronic lung disease (selected from Groups 1 and 
3 PH). 
 
We hypothesize that oral H01, at doses of 1600 mg per day, will be a safe and well-tolerated agent in 
adults with pulmonary hypertension over 24 weeks. In addition, this study will investigate the potential 
benefit of oral H01 on clinical measures of PH disease severity including but not limited to: pulmonary 
vascular resistance, mean pulmonary arterial pressure, and the 6 Minute Walk Distance Test (6MWDT). 
 
 
 
 


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1.2 
Study Overview 
 
Protocol Title 
Investigation of H01 in adults with pulmonary hypertension including Interstitial Lung 
Disease (SATURN Study) 
IND # 
 
Study Design 
Phase 2a, double-blinded, approximately 2:1 randomized and stratified placebo- controlled 
study to evaluate the safety, tolerability, and efficacy of H01 in adults with pulmonary 
hypertension (PH), stratified between selected Group 1 and Group 3 PH types with optional 
open-label extension . 
Study 
Population 
Adults with confirmed diagnosis of Group 3 PH secondary to Interstitial Lung Disease (ILD) 
and Group 1 PH secondary to connective tissue disease, idiopathic, drugs and toxins, or 
hereditary PAH 
Study Drug 
400 mg H01 tablets [Isochol 400mg] and placebo 
Objectives 
1. Evaluate the change in clinical and functional measures in adults with PH treated with 
H01 
2. Evaluate the safety and tolerability of oral H01 in PH 
3. Evaluate the effect of H01 on serum biomarkers in PH 
Clinical Phase 
2a 
Primary 
Endpoint 
 Change in pulmonary vascular resistance (PVR) measured by right heart 
catheterization (RHC) from baseline to end of treatment (Week 24) of the blinded study 
Secondary 
Endpoints 
 The safety and tolerability of H01 in adults with pulmonary hypertension using the 
Common Terminology Criteria for Adverse Events (CTCAE) 
 Change in mean pulmonary arterial pressure (mPAP) by RHC from baseline to end of 
treatment (Week 24) of the blinded study 
 6 Minute Walk Distance Test (6 MWDT) from screening to end of treatment (Week 24) of 
the blinded study and through Week 48 of the open-label extension 
 Change in quality of life (QOL) score, EMPHASIS-10 score and St George Respiratory 
Questionnaire (SGRQ) score from baseline to end of treatment (Week 24)of the blinded study 
and through Week 48 of the open-label extension 
 Change in serum HA concentration from baseline to end of treatment (Week 24) of the 
blinded study and through Week 48 of the open-label extension 
 Change in NT-proBNP from baseline to end of treatment (Week 24) of the blinded study 
and through Week 48 of the open-label extension 
Exploratory 
Endpoints 
 Change in inflammatory markers (ESR, HSCRP) 
 Change in pro-inflammatory cytokines 
 Change in Forced Expiratory Volume in one second (FEV1) 
 Change in Forced Vital Capacity (FVC) from pulmonary function test (PFT) 
 Change in Total Lung Capacity (TLC) from pulmonary function test (PFT) 
 Change in Lung diffusion capacity (DLCO) from pulmonary function test (PFT) 
 Change in exhaled breath condensate (EBC) hyaluronan concentrations over the study 
period 
 Describe the pharmacokinetics (H01 and metabolite serum concentrations) 
 Describe HA fragment size 


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Planned 
sample size 
16 
Number of 
Sites 
1 
Duration of 
Participation 
Total study period of the blinded study: 28 weeks 
Total study period including open-label extension: 48 weeks 
 Screening Period: up to 4 weeks 
 Treatment Period of the blinded study: 24 weeks 
 Treatment Period including open-label extension: 48 weeks 
 Follow-up Period: 4 weeks after treatment period ends (Week 24) if not enrolled in the 
open-label extension 
Dose 
Schedule 
 Participants randomized to treatment will receive two H01 400 mg tablets BID (1600 
mg/day) for 24 weeks or through Week 48 if enrolled in the open-label extension 
 Participants randomized to placebo will receive two placebo tablets BID for 24 weeks 


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1.3 
Scientific Rationale 
 
1.3.1 Urgent need for pulmonary hypertension therapeutics 
 
Pulmonary hypertension (PH) is defined by a pulmonary vascular resistance (PVR) ≥3 WU associated 
with an increased mean pulmonary arterial pressure (mPAP >20 mmHg) at rest1. It can lead to right 
ventricle hypertrophy (RVH), right-sided heart failure and eventually death7 010). Idiopathic pulmonary 
fibrosis (IPF) is a form of restrictive interstitial lung disease (ILD) associated with extremely poor 
outcomes. IPF is characterized by parenchymal fibrosis that leads to impaired gas exchange8. PH, with a 
prevalence of about 40% in advanced disease9,10, is a common complication in IPF where it is strongly 
associated with increased morbidity and mortality10,11. It is classified as WHO Group 3 PH12. 
There are limited treatment options for patients with interstitial lung disease and PH, with lung 
transplantation being the only “curative” option. Despite the many pharmacological agents available to 
treat pulmonary arterial hypertension (PAH) (classified as Group 1 PH, where no lung parenchymal 
component is observed), these agents have been shown to be either ineffective or detrimental to patients 
with IPF + PH13. Consequently, it is essential to develop improved medical therapies for IPF+PH. 
1.3.2 Discussion on pulmonary hypertension groups 
 
This trial selects patients from Groups 1 and 3 PH based on the hypothesized utility of H01 in PH due to 
lung conditions associated with inflammation, vascular remodeling, and fibrosis. Brief discussion of these 
groups provides relevant context for selected inclusion/exclusion criteria. 
 
PH is broadly classified into 5 groups based on etiology, although there can also be overlap between groups. 
Group 1 (also referred to as pulmonary arterial hypertension (PAH)) includes patients with PAH secondary 
to connective tissue diseases, idiopathic PAH, hereditary PAH, and PAH secondary to selected other 
conditions (e.g. toxins, HIV, etc.). Although the prevalence of PAH is unknown in North America, several 
European registries have reported rates of 5 to 52 per million14,15. PAH is a proliferative vasculopathy, 
characterized by vasoconstriction, cell proliferation, fibrosis, and micro-thrombosis. Pathologic findings 
include hyperplasia and hypertrophy of all three layers of the vascular wall (intima, media, adventitia) in 
pulmonary arteries <50 microns (i.e., localizes to the small pulmonary muscular arterioles). In addition, 
fibrosis and in situ thrombi of the small pulmonary arteries and arterioles (plexiform lesions) can be 
seen16,17. The pathologic appearance of the small pulmonary arteries and arterioles is qualitatively similar 
in all patients with group 1 PAH. 
 
Over a dozen PAH specific therapies are available. They target components of five PAH relevant 
molecular pathways: voltage gated, L type calcium channels, nitric oxide cyclic guanosine 
monophosphate (cGMP), endothelin, and prostacyclin18. However, effective options for patients with 
group 1 PAH with co-existing lung disease are limited. These patients are primarily treated with 


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pulmonary vasodilators but outcomes remain poor. 
 
Group 3 PH is the second most common form of PH and is associated with increased morbidity and 
mortality19. The most common lung diseases resulting in PH are chronic obstructive pulmonary disease 
(COPD), interstitial lung disease (ILD) and obstructive sleep apnea (OSA) but PH is also associated with 
other diseases, such as cystic fibrosis and high altitude exposure. Among the etiologies of group 3 PH, the 
strongest evidence favors hypoxic pulmonary vasoconstriction (HPVC) with re-modelling of the 
pulmonary vascular bed. Group 3 PH has a very high morbidity and mortality19. PH in the setting of 
fibrotic lung disease is observed in up to 80% of patients with interstitial lung disease (ILD). The presence 
of PH is considered the single most significant predictor of mortality in patients with chronic lung 
disease10,11. 
The treatment of Group 3 PH has traditionally been to optimize treatment of the underlying lung disease 
and give long-term oxygen therapy to those who are hypoxic. The efficacy of pulmonary vasodilators in 
this group of patients is unclear. There have been mixed results from meta-analysis assessing the effects 
of vasodilators on exercise tolerance and quality of life20,21. Only recently has an acute vasodilator therapy 
with inhaled treprostinil been evaluated and approved for Group II PH.22 
In view of the poor prognosis associated with these conditions, and the lack of available specific therapy, 
further work is required to develop effective therapy. The only durable therapy for chronic lung diseases, 
such as ILD with PH, is lung transplantation. However, lung transplantation itself is associated with 
inferior outcomes in ILD+PH than for most other indications23. In addition, despite the many 
pharmacological agents available to treat pulmonary arterial hypertension (PAH), classified as Group 1 
PH, where no lung parenchymal component is observed, these agents have been shown to be either 
ineffective or detrimental to patients with IPF + PH13. Consequently, it is essential to develop improved 
medical therapies for PH in the setting of chronic lung diseases such as ILD. 
 
1.3.3 Hyaluronan is an important driver of respiratory disease and pulmonary hypertension 
 
Hyaluronan (HA), also known as hyaluronate or hyaluronic acid, is a glycosaminoglycan and a major 
component of the lung ECM24,25. Elevated hyaluronan has been reported in lung diseases including IPF and 
PAH26–30 and in PH associated with chronic obstructive pulmonary disease31. Furthermore, 
overexpression of hyaluronan synthase 2 (HAS2), an enzyme responsible for the synthesis of hyaluronan, 
has been implied in severe fibrosis29. In addition, increased hyaluronan has also been reported in 
autoimmune diseases. For example, in systemic sclerosis (SSc), elevated HA is present in both the skin32 
and associated with lung injury33,34. Elevated HA appears to be associated with progressive SSc affecting 
the lungs where it is associated with fibrosis35 and in patients with connective tissue disease (CTD) 
associated ILD36. These are consistent with increased HA observed in patients with Group 1 PH 26. 
Collectively, these studies point at a pathogenic role of HA in the PH associated with chronic lung diseases 
and suggest. that therapies targeting HA may serve as novel disease-modifying treatments for PH. 
 


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The inflammatory effects of HA are   dependent on   its   molecular   weight.   High   molecular weight 
HA (HMW-HA) of 1000 KDa is believed to have protective effects30. However, the breakdown of HA 
into low molecular weight (LMW) HA has been demonstrated to contribute to its pathobiological effects 
in the lung30. In line with this, increased LMW-HA fragments have been detected in an experimental 
model of PH associated with lung fibrosis2. 
1.3.4 H01 is a novel approach to addressing pulmonary hypertension secondary to interstitial lung 
disease 
 
H01, also known as 4-methylumbelliferone (4MU), is a small molecule inhibitor of HA synthesis. H01 
reduces HA levels primarily through two identified mechanisms. The first mechanism occurs through the 
extensive glucuronidation of H01 by UDP-glucuronyltransferases (UGTs) resulting in the depletion of 
UDP-glucuronic acid, one of the two substrates required for HA synthesis37,38. The second way that H01 
reduces HA levels is by downregulating HAS mRNA levels39. 4MU has been shown to inhibit HA 
production in multiple cell lines and tissue types40–44. 4MU has also been used in multiple animal models 
of cancer, fibrosis and autoimmunity39,45–51. Several studies have demonstrated that inhibition of HA using 
H01 prophylactically and therapeutically attenuated features of experimental PH including vascular 
remodelling and elevated right ventricle systolic pressure (RVSP, a surrogate for mPAP in mice). Using 
a mouse model of lung fibrosis and PH studies showed that a 2-week oral treatment with H01 inhibited 
RVSP and vascular remodelling2. These results were replicated in a mouse model exhibiting lung fibrosis, 
PH and airspace enlargement, where H01 treatment for 4 weeks was able to attenuate vascular remodelling 
and RVSP values3. Interestingly, in these studies, lung fibrosis was also attenuated. In addition to these 
highly-relevant pre-clinical studies in models that recapitulate features of Group 3 PH, H01 has been 
shown to be effective in models of acute lung injury5,6. 
In addition, H01 has demonstrated anti-fibrotic activity in other settings of inflammation (e.g., liver 
fibrosis). Independent of H01, HA inhibition has also been linked directly with meaningful clinical 
outcomes such as Forced Expiratory Volume (FEV1) in respiratory disease52. Taken together, these results 
point at elevated HA as a key feature in patients and experimental models of pulmonary hypertension. 
Furthermore, preclinical studies using H01 both prophylactically therapeutically demonstrates a beneficial 
effect of H01 in treating PH associated with lung fibrosis. These results underscore the use of H01 as a 
novel agent to treat Group 3 PH, where limited treatment options are available. 
Hymecromone (H01; 4-methylumbelliferone), a known inhibitor of HA synthesis, has been studied pre- 
clinically in inflammation and fibrosis53–55. In particular, H01 is of benefit in multiple models of airway 
inflammation5,6,56. Including in multiple pre-clinical mouse models of PH2,13. Hymecromone is an approved 
oral drug in Europe (European Union reference date [EURD] 07/27/1965) indicated in various diseases of 
the gallbladder and biliary tract (i.e. Biliary dyskinesia). It is hypothesized that its mechanism of action in 
biliary dyskinesia and autoimmunity may work, in part, via inhibition of hyaluronan biosynthesis. In regards 
to inhibition of HA, H01 is extensively glucoronidated by UDP- glucuronyltransferases (UGTs) which 
results in the depletion of UDP-glucuronic acid, a precursor necessary for HA synthesis.37,38 There is 
substantial evidence for the efficacy and safety of H01 based on its approved uses in multiple markets and 


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in multiple clinical trials57. A comprehensive review of H01 is available39. 
We propose a Phase 2a study of H01 in patients with Group 1 and Group 3 Pulmonary hypertension. This 
proof-of-concept study will generate data supporting the ultimate goal of investigating H01 as a safe, 
effective, oral treatment for patients with pulmonary hypertension. 
 
2 
H01 PHARMACOLOGY 
 
2.1 
Dose Rationale 
 
H01 is an approved oral drug in Europe (European Union reference date [EURD] 07/27/1965) for 
disorders of the biliary tract. H01 has been administered chronically in humans for 50+ years at doses up 
to 1800 mg/day PO with few observed adverse safety events. Based on the European package insert, the 
standard dosing regimens for adults in hepatobiliary conditions are 300-600 mg oral up to 3 times / day 
(900-1800 mg/day). 
 
Several clinical trials of H01 in humans have been published and all demonstrated safety during both short 
and long-term administration (Appendix B). The longest reported duration of administration was a study 
of oral administration for 6 months in patients (n=29)58. The highest dose administered in a clinical trial is 
3600mg for 4 days. 
 
To inhibit excess HA synthesis and alleviate respiratory distress, we propose to administer H01 800mg 
twice a day (1600 mg/day) PO for 24 weeks. Twice daily dosing was selected to facilitate outpatient 
adherence.  If the participants are enrolled in the open-label extension,  H01 is administered twice a day 
at dose of  800 mg (1600 mg/day) until Week 48. 
 
The selected dose of 1600 mg/day is consistent with non-clinical models of lung injury where human 
equivalent doses (HED) of H01 ranging from 120 mg/day PO to 2600 mg/day intra-peritoneal (IP) 
demonstrate notable functional improvements and reduced HA in bronchoalveolar lavage fluid2,5,6. In the 
Phase 1 dose range study recently completed at Stanford University, doses of 1200mg, 2400mg and 
3600mg per day doses over 4 days in healthy volunteers were well tolerated and led to decreases in sputum 
HA. 
 
Given the existing body of safety data for H01, and the relevance of the models suggesting 2600mg/day 
IP, characteristics of H01’s pharmacology, and the time necessary to see clinical efficacy in pulmonary 
hypertension patients, the decision was made to target 1600mg/day for 24 weeks. A BID regimen is 
selected over a QID regimen primarily to support patient compliance over a 24-week period. Participants 
enrolled in the open-label extension until week 48 will continue this BID regimen (800 mg twice a day). 
 
The results at this dose will inform the H01 development plan and larger scale dose-range studies. 
 
 


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2.2 
Clinical Efficacy 
 
Dozens of previous studies of H01 have established efficacy in the context of approved and currently 
marketed indications (hepatobiliary conditions)(reviewed in Nagy 201539) A recently completed Phase 1 
dose-range study demonstrated inhibition of hyaluronan in the sputum of healthy adults over 4 days 
(pharmacodynamic marker). 
 
The current study will be the first study to use the novel mechanism of HA inhibition to investigate the 
clinical efficacy in pulmonary hypertension. 


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2.3 
Clinical Safety 
 
In published clinical trials including more than 200 patients, H01 has demonstrated safety with over 28 
patient years of exposure. In these studies, H01 was safe and well tolerated. The safety profile of H01 is 
supported further by decades of marketing authorization approval in Europe, which is characterized by 
broader pharmacovigilance data. A principal European manufacturer reports awareness of more than 60 
clinical trials including 2638 patients (Grunenthal 2020). The main reported side effects for H01 in the 
product labels include diarrhea and allergic reactions. According to the WHO spontaneous reporting 
database59, investigated on August 8th, 2021, only 63 cases of adverse drug events to H01 have been 
reported since 1967 worldwide. The majority of reported adverse events concerned skin disorders (42.9%, 
mainly urticaria and pruritus), GI disorders (20.6%, mainly diarrhea), and immune system disorders 
(20.6%, mainly anaphylactic shock, angioedema or face edema). 
 
In fourteen randomized controlled trials, few side-effects were reported at doses up to 2400 mg/day PO39,60. 
In another study of H01 at 2400 mg/day in patients following surgical revision of biliary pathways, no 
serious adverse reactions were observed. 
 
2.4 
Non-clinical Efficacy 
 
H01 has been studied in multiple animal models of lung injury. Across these animal models, inhibition of 
HA synthesis with H01 led to a significant reduction in HA content, as well as clinically relevant outcomes. 
Five relevant studies are summarized below: 
 
• 
Bleomycin model of pulmonary hypertension and lung fibrosis. In 2017, Collum et al. 
published an article entitled “Inhibition of HA synthesis attenuates pulmonary hypertension 
associated with lung fibrosis”2. In an experimental model of lung fibrosis and pulmonary 
hypertension (PH), mice were treated i.p. with 0.035 U/g of bleomycin (BLM) or vehicle (PBS) 
twice a week for 4 weeks. This model of chronic injury presents with fibrotic deposition affecting 
the distal areas of the lung, which is more representative than the more common intra-tracheal (IT) 
instillation of bleomycin. On day 15, mice were provided with chow containing H01 at a dose of 
20 mg/kg/day or regular chow for the remainder of the experiment. To deliver 20 mg/kg/day, H01 
was added to the diet at a concentration of 125 mg/kg diet (assuming a mean body weight ~25 g 
and chow intake ~4 g per day). It was observed that blood oxygenation was reduced by 25% in the 
bleomycin-exposed mice on control chow, whereas only 5% oxygenation reduction was observed 
in the bleomycin-exposed and H01 treated group. This was consistent with improvised right 
ventricle systolic pressure (RVSP) values in BLM-exposed and H01 treated mice compared to 
BLM-exposed vehicle treated mice. RVSP is a surrogate value for mPAP in mice. Furthermore, 
hyaluronan (HA) levels observed by immunohistochemistry (IHC) showed increased HA 
deposition in bleomycin-exposed mice that were inhibited by H01 therapy. In line with this, 
bronchoalveolar lavage fluid (BALF) revealed a significant HA elevation in bleomycin-exposed 
mice that was attenuated from 1600 ng/mL HA to 1000 ng/mL HA by H01 treatment. These 


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observations were consistent with increased levels of the HA-synthases Has1, Has2 and Has3 
expression in bleomycin-exposed mice. H01 attenuated Has2 and Has3 but not Has1 expression. 
 
• 
Adenosine deaminase null mouse (Ada-/-) model of lung fibrosis and pulmonary hypertension 
in combined pulmonary fibrosis and emphysema (CPFE). In 2019, Collum et al. published an 
article entitled “Adenosine and hyaluronan promote lung fibrosis and pulmonary hypertension in 
combined pulmonary fibrosis and emphysema”3. Genetically engineered mice lacking adenosine 
deaminase (Ada-/-) were utilized as an experimental model of lung fibrosis and pulmonary 
hypertension (PH) in combined pulmonary fibrosis and emphysema (CPFE). Ada-/- mice received 
supplemental PEG-ADA, allowing them to live normally, from birth up to week 24. Starting on 
week 24, PEG-ADA was gradually reduced over 9 weeks and, starting on week 34, mice were 
provided with either control chow or medicated chow (H01 at a dose of 20 mg/kg/day) for 4 weeks. 
Ada-/- mice developed increased fibrosis in the lung as detected by Masson’s trichrome staining 
for collagen which was decreased upon H01 treatment. Arterioles from Ada-/- mice exhibited 
increased aSMA staining indicative of increased muscularization of the arterioles which resulted 
in an increased smooth muscle area/vessel ratio. Arterioles from H01-treated Ada-/- mice had 
significantly decreased aSMA staining and a more normalized smooth muscle area/vessel ratio. 
Ada-/- mice also had significantly decreased levels of arterial oxygenation (SpO2) which were 
normalized with H01 treatment. Importantly, bronchoalveolar lavage fluid (BALF) levels from 
Ada-/- mice contained HA levels that were significantly increased (> 10x) compared to normal 
mice while H01 treatment in Ada-/- mice were only ~3x above normal. In addition, in this study 
H01 was able to therapeutically reduce evidence of fibrotic matrix remodeling in these mice. 
• 
Hypoxia-induced Pulmonary Hypertension. In an unpublished study using mice lacking HAS2, 
investigators demonstrate that these mice are protected from the development of pulmonary 
hypertension, induced following chronic exposure to hypoxia (10% O2 for 28 days) with weekly 
Sugen (SU5416) injections. Similarly, in a model of hypoxia-sugen induced pulmonary 
hypertension, H01 administered starting on day 15 of 10% O2 halted vascular remodeling, 
perivascular HA accumulation and attenuated RVSP after 13 days of treatment. The hypoxia- 
sugen model of PH is able to recapitulate some of the features of patients with PAH, including 
elevated RVSP and vascular wall thickening without parenchymal lung disease. These studies 
underscore the role of HA synthesis in PH and highlight the capacity of H01 to halt the 
development of disease. 
 
• 
Staphylococcus enterotoxin B (SEB)-induced model of acute lung inflammation. In 2013, 
McKallip et al. published an article entitled “Treatment with the hyaluronic acid synthesis inhibitor 
4-methylumbelliferone suppresses SEB-induced lung inflammation”5. The effects of H01 on 
staphylococcus (SEB)-induced acute lung inflammation were investigated in vitro and in vivo. 
Culturing staphylococcal enterotoxin B (SEB)-activated immune cells with H01 led to reduced 
proliferation, reduced cytokine production as well as an increase in apoptosis when compared to 


The SATURN Study [CONFIDENTIAL – DO NOT REDISTRIBUTE] 
15 
 
 
untreated cells. In an in vivo model of lung inflammation, exposure to SEB led to significantly 
elevated levels of 1500 pg/mL hyaluronan (HA) in the bronchoalveolar lavage fluid (BALF). 
However, H01 treatment following SEB exposure significantly reduced BALF HA levels to 200 
pg/mL. Concomitant with the decrease in BALF, HA levels, mRNA levels of HAS1, HAS2 and 
HAS3 were also all significantly decreased. Furthermore, exposure of vehicle-treated mice to SEB 
led to an increase in the expression of various cytokines, such as IL‑1β, IL-2, IL-6, IFN-γ, and 
TNF-α, which are all reported to play a role in lung inflammation. In comparison, treatment of 
mice with H01 led to a significant reduction in the SEB-induced increase in all cytokines measured. 
 
• 
Lipopolysaccharide (LPS)-induced model of acute lung inflammation. In 2015, McKallip et 
al. published an article entitled “Treatment with the hyaluronic acid synthesis inhibitor 4- 
Methylumbelliferone suppresses LPS-induced lung inflammation”6. The effects of H01 on 
lipopolysaccharide (LPS)-induced acute lung inflammation were investigated in vitro and in vivo. 
Culturing LPS-activated immune cells with H01 led to reduced proliferation, reduced cytokine 
production, and an increase in apoptosis when compared to untreated cells. Treatment of mice with 
H01 (single dose of 450 mg/kg i.p., approximately 18000 mg/kg assuming a body weight of 25 g) 
led to protection from LPS-induced lung injury. Specifically, H01 treatment led to a reduction in 
LPS-induced HA synthase (HAS) messenger RNA (mRNA) levels HAS1 decreased from 9 to 1.5, 
HAS2 from 8 to 0.5, HAS3 from 13 to 1. Vascular permeability induced by LPS was reduced 
nearly 4-fold with H01 treatment while pro-inflammatory cytokine levels (IL-6, IFN-α and IFN-γ) 
were reduced by >90% with treatment. 
 
2.5 
Non-clinical Safety 
 
The acute toxicity of H01 is relatively low: the LD50 for oral administration is 7593 mg/kg in mice and 
6220 mg/kg in rats (highest doses tested; HED 37,000 mg/day and 61,000 mg/day, respectively). 
Protracted oral administration of 800-2400 mg/kg/day for 3 months in a dog model (HED 79,000 mg/day) 
and of 400-1000 mg/kg/day for 4 months in a rat model (HED 9700 mg/day), showed no toxicities in 
physical or behavioral measures (Cantabilin Label Italy - Attachment). No teratogenicity was observed in 
rat or rabbit at oral doses up to 1200 mg/kg/day (HED 23,000 mg/day). Toxicology tests on animals have 
not shown any toxic phenomena, abnormalities of growth or behavior. No cases of teratogenicity or fetal 
toxicity have been encountered. 
 
2.6 
Hypothesis 
 
We hypothesize that oral H01 at doses of 1600 mg per day for 24 weeks in the blinded study and for an 
additional 24 weeks as part of open-label extension  will be safe and well-tolerated and show evidence of 
clinical efficacy. We will conduct exploratory analyses in both the blinded study and open-label extension  
to further establish the correlation of changes in serum HA with meaningful clinical outcomes. 
 
 


The SATURN Study [CONFIDENTIAL – DO NOT REDISTRIBUTE] 
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3 
STUDY DESIGN 
 
3.1 
Study Treatment 
 
Participants will be randomized approximately 5:3 (Treatment:Placebo). Participants randomized to 
treatment will be given 800 mg oral H01 two times a day (total dose: 1600 mg/day). Participants 
randomized to placebo will receive oral tablet placebo (inactive ingredients) two times a day. Participants 
will be on treatment continuously for 24 weeks or 48 weeks if enrolled in the open-label extension.During 
the treatment period, participants will be monitored according to the schedule of assessments below. 
Participant a follow up will take place 30 days after the end of treatment at Week 24 if not enrolled in the 
open-label extension. 
 
 
 


The SATURN Study [CONFIDENTIAL – DO NOT REDISTRIBUTE] 
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4 
ENDPOINTS 
 
4.1 
Primary Endpoint 
 
• Change in pulmonary vascular resistance (PVR) measured by right heart catheterization (RHC) 
from baseline to end of treatment (Week 24) of the blinded study 
 
4.2 
Secondary Endpoints 
 
• The safety and tolerability of H01 in adults with pulmonary hypertension using the Common 
Terminology Criteria for Adverse Events (CTCAE) 
• Change in mean pulmonary arterial pressure (mPAP) by RHC from baseline to end of treatment 
(Week 24) of the blinded study 
• 6 Minute Walk Distance Test (6 MWDT) from screening to end of treatment (Week 24) of the 
blinded study or through Week 48 of the open-label extension 
• Change in quality of life (QOL) score, EMPHASIS-10 score and St George Respiratory 
Questionnaire (SGRQ) score from baseline to end of treatment (Week 24) of the blinded study or 
through Week 48 of the open-label extension 
• Change in serum HA concentration from baseline to end of treatment (Week 24) of the blinded 
study or through Week 48 of the open-label extension 
• Change in NT-proBNP from baseline to end of treatment (Week 24) of the blinded study or 
through Week 48 of the open-label extension 
 
4.3 
Exploratory Endpoints 
 
• Change in inflammatory markers and PH-specific biomarkers (ESR, HSCRP) 
• Change in pro-inflammatory cytokines 
• Change in Forced Expiratory Volume in one second (FEV1) 
• Change in Forced Vital Capacity (FVC) from pulmonary function test (PFT) 
• Change in Total Lung Capacity (TLC) from pulmonary function test (PFT) 
• Change in Lung diffusion capacity (DLCO) from pulmonary function test (PFT) 
• Change in exhaled breath condensate (EBC) hyaluronan concentrations over the study period 
• Describe the pharmacokinetics (H01 and metabolite serum concentrations) 
• Describe HA fragment size 
5 
STUDY POPULATION 
 
Adults with Group 1 PAH secondary to connective tissue disease, idiopathic, hereditary, toxins, or drugs 
and adults with Group 3 PH secondary to interstitial lung disease. Individuals interested in participating 
in the study will be screened for inclusion and exclusion criteria. If the patient meets criteria and consents 
to participate, they will be enrolled and undergo randomization. 
 


The SATURN Study [CONFIDENTIAL – DO NOT REDISTRIBUTE] 
18 
 
 
5.1 
Inclusion Criteria 
 
• 
Adults age 18 to 75 years inclusive; 
• 
WHO functional class II/III/IV despite treatment with maximally tolerated doses of 2 or more 
treatment modalities including PDE5 inhibitors, guanylate cyclase stimulators, endothelin receptor 
antagonists, and prostanoids when appropriate. 
• 
Baseline 6MWT>100 meters and <550 meters 
• 
Established diagnosis of Group 3 pulmonary hypertension secondary to interstitial lung disease 
OR established diagnosis of Group 1 pulmonary hypertension secondary to connective tissue 
disease, idiopathic, hereditary, drugs, or toxins. 
• 
Right heart catheterization at randomization showing precapillary pulmonary hypertension (mPAP 
≥ 25 mmHg and PVR > 400 dynes * sec * cm -5) and: 
o PCWP < 20 mmHg for Group 3 PH patients and Group 1 PAH patients 
• 
Participants on chronic medication for PAH, PH, or underlying lung disease must be on a stable 
and optimized dose for at least 90 days prior to the first dose of the study drug. 
• 
Female participants who are heterosexually active must use an acceptable method of contraception: 
condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with 
spermicide, IUD, or Hormone-based contraceptive 
• 
Be able to provide written informed consent and comply with requirements of the study 
 
5.2 
Exclusion Criteria 
 
• 
Participants with a diagnosis of PAH or PH for reasons other than the pulmonary hypertension 
primarily due to any of the following: 
o Group 2, 4, or 5 
o Group 1 due to HIV, veno-occlusive disease, porto-pulmonary hypertension, congenital 
heart disease 
o Group 3 due to severe chronic obstructive pulmonary disease (COPD) or obstructive sleep 
apnea (OSA) 
o Note: participants with overlapping syndromes will be evaluated on a case-by-case basis 
by the recruiting physician 
• 
Total Lung Capacity (TLC) <60% predicted 
• 
FEV1/FVC <50% predicted or FEV1 <55% predicted 
• 
Inability to safely attempt completion of the 6MWD test 
• 
Use of experimental PAH treatments within the past 3 months 
• 
Current systemic treatment with hymecromone 
• 
Left sided heart disease as defined by either a PCWP >20 mmHg and/or left ventricular ejection 
fraction <40% 
o Note: participants with abnormal left ventricular function attributable entirely to impaired 
left ventricular filling due to the effects of right ventricular overload (ie right ventricular 
hypertrophy and/or dilatation) are not excluded 


The SATURN Study [CONFIDENTIAL – DO NOT REDISTRIBUTE] 
19 
 
 
• 
Participants must not have 3 or more of the following left ventricular disease / dysfunction risk 
factors: 
o Body mass index (BMI) > 30kg/m2 
o History of essential hypertension requiring medication 
o Diabetes mellitus 
o Historical evidence of significant coronary disease established by any of the following: 
 
History of myocardial infarction 
 
History of percutaneous coronary intervention or coronary artery bypass graft 
 
Angiographic evidence of >50% stenosis in at least one coronary artery 
 
Positive stress test with imaging 
 
Stable angina 
• 
Significant valvular heart disease as determined by more than moderate findings on 
echocardiogram or history of valve replacement 
• 
Pregnant or actively breastfeeding 
• 
Female participants with childbearing potential not willing to use a form of birth control (including 
abstinence) during the study 
• 
Inability to undergo right heart catheterization 
• 
Acute pulmonary embolism within 90 days of randomization 
• 
Exacerbation of underlying lung disease or active pulmonary or upper respiratory infection within 
30 days of randomizations 
• 
Use of any inhaled tobacco products or significant history of drug abuse within 3 months prior to 
randomization 
• 
Subject is receiving >10L/min of oxygen supplementation by any mode of delivery at rest at 
baseline 
• 
Body mass index > 40kg/m2 
• 
Participants with history of dysphagia, achalasia, or difficulty swallowing capsules, tablets or pills 
• 
Participants with liver failure or AST or ALT greater than 2 times the upper limit of normal 
• 
Participants with total bilirubin levels greater than 2 times the upper limit of normal 
• 
Participants with CrCl <45 
• 
Use of any investigational drug/device, or participation in any investigational study with 
therapeutic intent within 30 days prior to randomization 
• 
Known allergy to hymecromone or any component of drug product (including rare hereditary 
problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption) 
• 
Known allergy to any component of placebo (including rare hereditary problems of galactose 
intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption) 
• 
Physician concern that participant may not adhere to the study protocol 
• 
Significant psychiatric, addictive, or other disorder that compromises the subject's ability to 
provide informed consent 
 
 
 


The SATURN Study [CONFIDENTIAL – DO NOT REDISTRIBUTE] 
20 
 
 
5.3 
Concomitant Medication 
 
To date, there are no known drug-drug interactions for H01. Metoclopramide, its derivatives and morphine 
are cited in one product label as potentially reducing the effect of H01. 
 
Participants can remain on an FDA approved PAH/PH background therapy if they have been on a stable 
regimen for a minimum of 90 days prior to randomization. 
 
Participants on a supportive therapy (e.g., anticoagulants, diuretics, oxygen) must have been on a stable 
and optimized dose for at least 30 days prior to the first dose of study drug. Exceptions are the 
discontinuation or dose changes of anticoagulants and / or dose change of diuretics. Participants on a 
chronic medication for underlying lung disease should be on a stable and optimized dose for > 30 days 
prior to the first dose of study drug. 
 
Participants may not newly initiate PAH/PH treatment from the first dose of study drug (Baseline) through 
study termination. Participants may not initiate pulmonary rehabilitation (rehab) within 90 days prior to 
the first dose of study drug and until the end of the study. 
 
All concomitant medications taken during the conduct of the study, including those taken for AEs or other 
medical events, should be recorded in the subject’s source documents and transcribed into the eCRF as 
required. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


The SATURN Study [CONFIDENTIAL – DO NOT REDISTRIBUTE] 
21 
 
 
 
6 
SCHEDULE OF ASSESSMENTS 
 
Schedule of Assessments for SATURN Trial 
Screen 
Active 
 
                                                   FU 
 
 
Screening 
Baseline 
Week 2 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 26** 
Week 28+ Week 36** Week 48 ** 
Visits 
0 
1 
2 
3 
4 
5 
6 
7 
Day« 
-30-0 
0 
14±3 
28±3 
56 ±3 
84±7 
140 ± 7 
168±7 
196±7 
210±3 
224±3 
280±7 
364±7 
Telephone or Email 
Contact 
 
 
X 
X 
 
X 
 
 
X** 
X ^ 
X** 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
History and physical 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
Symptom 
assessment/NYHA 
 
X 
X 
X 
X 
X 
X 
 
 
X** 
X+ 
X** 
X** 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X** 
X+ 
X** 
X** 
Vital Signs & Weight 
 
X 
 
X 
 
X 
 
 
X 
 
X** 
 
X** 
Physical Examination 
 
X 
 
X 
 
X 
 
 
X 
 
X** 
 
X** 
EMPHASIS-10 / 
SGQ 
 
X 
 
         X 
 
X 
 
 
X 
 
X** 
 
X** 
General Testing 
 
 
 
 
 
 
 
 
 
 
 
 
Comprehensive 
Metabolic Panel 
 
X 
 
X 
 
X 
 
 
 
 
X** 
 
X** 
CBC 
 
X 
 
X 
 
X 
 
 
X 
 
X** 
 
X** 
Pregnancy test (If 
Indicated)a 
 
X 
 
X 
X* 
X 
X* 
X* 
X 
X** 
 
X** 
X** 
 
X** 
12-Lead ECG 
 
X 
 
 
 
 
 
 
 
 
 
 
Endpoint assessment 
 
 
 
 
 
 
 
 
 
 
 
 
Right Heart 
Catheterization 
 
X 
 
 
 
 
 
 
 
 
 
 
Serum & EBC 
hyaluronan 
 
X 
 
X 
 
X 
 
 
X 
 
X** 
 
X** 
6 minute walk 
distance 
X 
 
 
X 
 
X 
 
 
X 
 
X** 
 
X** 
NT-pro-BNP 
 
X 
 
X 
 
X 
 
 
X 
 
X** 
 
X** 
PFT with ABG 
X 
 
 
 
 
 
 
X 
 
 
 
 
Inflammatory 
markers 
 
X 
 
X 
 
X 
 
 
X 
 
X** 
 
X** 
Serum and EBC drug 
levels 
 
X 
 
X 
 
X 
 
 
 
 
X** 
 
X** 
Study Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Medication Pill Count 
 
 
X 
X 
X 
X 
X 
X 
X 
X** 
X** 
X** 
X** 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X** 
X+ 
X** 
X** 
Study Termination 
 
 
 
 
 
 
 
 
 
X^ 
 
X** 
 
*Home pregnancy test permitted 
 
^ Only for subjects not participating in OLE (Open-Label Extension) 
 
**Only for subjects participating in OLE (Open-Label Extension) 
 
+ For participants in OLE (Open-Label Extension) and those not participating in OLE 
 
a. Pregnancy tests need to be done monthly in OLE (Open-Label Extension).  Participants will be given home 
pregnancy test kits to take home.
 
7 
ASSESSMENTS 
 
7.1 
Screening/Baseline Assessment 
 
Prior to enrollment, each participant will undergo a medical screen, be introduced to study procedures, 
X 
X 
X 
X 
X 
X 


The SATURN Study [CONFIDENTIAL – DO NOT REDISTRIBUTE] 
22 
 
 
and undergo informed consent. Screening will be conducted within 30 days of baseline assessment. If any 
of the screening labs were performed as part of standard of care within 4 weeks of the screening, these 
labs will be used for screening. 
 
If the patient qualifies and consents to participate, they will undergo baseline assessments. Baseline labs 
that were done within the previous 4 weeks will be accepted as baseline labs; if there are no labs for >4 
weeks, these will be repeated. If any of the following baseline procedures were performed and documented 
in the medical chart at part of standard of care within 2 months of the baseline visit, these will be accepted 
as the baseline assessment: RHC, PFTs, 6MWDT, 12-Lead ECG. 
 
All participants will start taking the study drug on the morning of Day 1, the day after the baseline 
assessment. All participants will follow up in person for assessments at Weeks 4, 12, and 24. 
Participants will also be contacted electronically and/or by telephone on Weeks 2, 8, 16, 20, 28. Participants 
will continue the study drug for 24 weeks with the final in person assessment at Week 24. A final follow- 
up electronically or by telephone will be performed at week 28 (4 weeks after treatment completion). If 
participants do not complete the 24 weeks of treatment for any reason, every effort will be made to conduct 
the Week 24 final assessment at the time of treatment termination and the participant will be followed 
until at least 4 weeks after stopping the study drug (longer if necessary to follow AEs).  If the participants 
are enrolled in the open-label extension, they will be contacted by telephone on Weeks 26 and 36.  A final 
in-person assessment will occur at Week 48. 
 
Biological samples: 
 
 Blood: 
• 6 ml blood for serum concentration of H01 and metabolites 
• 6 ml blood for serum HA level and biomarkers 
• 6 ml blood for CBC 
• 6 ml blood for CMP 
 Urine: 
• Pregnancy test for females of child-bearing potential (serum pregnancy test may be substituted 
for urine) 
 Exhaled breath condensate: 
• Concentration of HA levels, H01 and metabolites 
 
7.2 
Laboratories for Central Study-specific Testing 
 
Lab testing will be done at the trial site laboratory used in the provision of standard of care services will 
process routine bloodwork (as above). The laboratory manual and study operations manual will specify 
procedures for when tests in the study protocol are not completed as standard of care. The manual will 
also detail which tests may need to be processed for shipping to alternative laboratories at Stanford, two 
of which are referenced below. 


The SATURN Study [CONFIDENTIAL – DO NOT REDISTRIBUTE] 
23 
 
 
 
**HA Testing of Blood and/or EBC 
Lab of Dr. Paul Bollyky, Division of Infectious Diseases, Stanford University, 279 Campus Drive, 
Beckman Center B237, Stanford, CA 94305 
 
**H01 and metabolite Testing of Blood and/or EBC 
Lab of Dr. Paul Bollyky, Division of Infectious Diseases, Stanford University, 279 Campus Drive, 
Beckman Center B237, Stanford, CA 94305 
 
**Immune mediators (63-plex Luminex® human assay) 
Stanford Human Immune Monitoring Center (HIMC), Fairchild Science Bldg., 299 Campus Drive, 
Stanford, CA 94305 
 
7.3 
Clinical Improvement 
 
Clinical improvement in this study will utilize the RHC, 6MWD test, PFTs, and patient symptom score 
reports. 
 
RHC at rest and with exercise will be performed in accordance with standard procedures by a trained 
pulmonologist in a cardiac catheterization laboratory and standard sedation medications may be used. This 
procedure typically takes less than one hour. 
 
6MWD test and PFTs will be performed in the clinic at specified visits in accordance with standard 
guidelines and will be carried out by trained study staff. 
 
Quality of life questionnaires will be performed a selected time points and will include questions to 
measure physical activity, respiratory symptoms, pain, general health, mental and emotional wellbeing. 
8 
STUDY DRUG PROCEDURES 
 
8.1 
Treatment Assignment 
 
Up to 16 eligible participants will be randomly assigned to H01 or placebo in a 5:3 ratio using a computer- 
generated randomization scheme, stratified by PH type, developed by an unblinded biostatistician at 
Stanford University. The code used to generate the allocation, along with the seed used in the random 
number generation, will be stored on secure servers and maintained by the unblinded biostatistician. 
 
8.2 
Blinding 
 
This is a double-blind study design. Participants, study investigators, and clinicians will be blinded. All 
doses of study drugs and placebo will be prepackaged by a central study pharmacy. The central pharmacy 
will coordinate randomization with the independent biostatistician for randomization codes. The 
allocation codes and labeled product will be used by dedicated study personnel who will administer 


The SATURN Study [CONFIDENTIAL – DO NOT REDISTRIBUTE] 
24 
 
 
product to enrolled and randomized participants. An SOP will govern the blinding process. Any break in 
the blinding process will be reported to the DSMC and principal investigator. 
 
8.3 
Formulation of Test and Placebo Medications 
 
H01 will be supplied by a manufacturer in Europe that holds current good manufacturing practice (GMP) 
certification. Specifically, the tablet formulation approved in the European Union called Isochol 400 mg 
will be used and provided by the marketing authorization holder, Zentiva. U Kabelovny, 529/16, 102 00 
Praha-Dolní Měcholupy, Czechia. 
 
Under normal conditions, unopened H01 has a reported shelf-life by the manufacturer of 3 years. The drug 
product will be stored at a temperature under 25 °C in bottles, and bottles will be tightly closed in order 
to protect from moisture, in accordance with the storage instructions on the Iscohol 400mg label. 
 
The placebo tablets used in this trial are selected to match the general shape, size and color of H01 but are 
not identical. Storage and dispensing of medications H01 and placebo product will be performed at 
controlled room temperature, 59° to 77°F (15° to 25°C) and protected from light and moisture by study- 
designated pharmacy personnel. Study drug will be dispensed  to enrolled participants based on site-level 
standard operating procedures. Study drug will remain in the original bottles until the time of release of 
the product to patients for home administration. A site Drug Accountability Log will be maintained by 
site personnel. This log is subject to audit and will be signed off by the site investigator at the end of the 
trial.  A temperature log will be utilized by the IDS to ensure compliance with temperature requirements.
8.4 
Possible Reasons for Discontinuation of Treatment 
 
All reasons for discontinuation from study drug will be captured in study CRFs enabling for the ability to 
differentiate treatment discontinuation from study withdrawal. These include the following reasons: 
 
• Completed 24 weeks of treatment of the blinded study or 48 week of the open-label extension 
• Grade ≥3 Adverse Drug Reactions 
• Withdrawal of consent 
• Physician request 
 
Investigators and study staff are reminded of the importance of participant retention in the case of 
treatment discontinuation and should take steps to prevent missing data that will be critical to the 
interpretation of the study results. Investigators and study staff should remind participants of the 
importance of continued participation in laboratory and clinical monitoring. Participants who discontinue 
study drug should continue follow-up when possible. This concept will be reinforced in the Informed 
Consent Form (ICF). 
 
In the case of missing data for participant disposition for a randomized participant, a vital records search 
will be undertaken. 
 


The SATURN Study [CONFIDENTIAL – DO NOT REDISTRIBUTE] 
25 
 
 
 
9 
MONITORING AND REPORTING OF ADVERSE EVENTS 
 
9.1 
Adverse Events Definition 
 
An adverse event (AE) is any untoward or unfavorable medical occurrence in humans which occurs during 
the participant’s participation of a clinical study, whether or not considered drug related. Any change in 
clinical status, routine labs, physical examinations, etc. that is considered clinically significant by the study 
investigator are considered AEs. 
 
9.2 
Suspected Adverse Reaction Definition 
 
A Suspected Adverse Reaction is any adverse event for which there is a reasonable possibility that the 
investigational drug caused the AE. For the purposes of safety reporting, ‘reasonable possibility’ means 
there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug. 
 
9.3 
Serious Adverse Event or Serious Adverse Reaction Definition 
 
An AE or suspected adverse reaction or adverse reaction is considered serious if, in the view of either the 
PI or sponsor, it results in any of the following outcomes: 
 
• Death 
• Life-threatening AE: it is considered “life-threatening” if its occurrence, in the opinion of the 
investigator or sponsor, places the participant at immediate risk of death from the reaction as it 
occurred. It does not include an AE or SAR that, had it occurred in a more severe form, might have 
caused death. 
• Persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Congenital abnormality or birth defect 
• Necessary surgery or medical device intervention to prevent fatal or permanent adverse effects 
• Important medical event that may not result in one of the above outcomes, but may jeopardize the 
health of the study participant or require medical or surgical intervention to prevent one of the 
outcomes listed in the above definition of serious adverse event 
 
 
9.4 
Unexpected Adverse Event or Reaction Definition 
 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the 


The SATURN Study [CONFIDENTIAL – DO NOT REDISTRIBUTE] 
26 
 
 
Investigator Brochure or package insert or is not listed at the specificity, severity or rate of occurrence that 
has been observed. The below summary includes adverse reactions from product labels for H01 in Europe. 
 Cantabiline® 400 mg (France) 
Undesirable effects: Occasional cases of diarrhea and isolated reports of allergic skin reactions. 
 Cantabilin® 300 mg (Italy) 
Undesirable effects: Diarrhea, anaphylactic reactions, including urticaria, itching, dyspnea, Quincke's 
edema and hypotension that can evolve to anaphylactic shock. 
 Cholspasmin® forte 400 mg (Germany) 
Undesirable effects: With prolonged administration of higher doses, soft stool or diarrhea may occur; 
fullness, constipation and stomach pressures are also reported (<0.01%) hypersensitivity reactions may 
occur, which can manifest as skin changes (< 0.01%). 
 Isochol® 400 mg (Czech Republic)  
Undesirable effects: Rare frequency of headache and rash ( <0.001) 
 
9.5 
New Fact 
 
A new fact is defined as any new data that may lead to a reassessment of the risk-to-benefit ratio of the 
research or of the product being researched, changes in the use of this product, in the conduct of the 
research, or to the documents relating to the research, or data that may lead to the suspension, 
discontinuation or modification of the research protocol or similar research. 
 
9.6 
Identification of Adverse Events 
 
As all participants in this study will have pre-existing medical conditions, those pre-existing conditions 
will not be considered adverse events. New events that occur or worsening (through frequency or intensity) 
of pre-existing conditions will be considered as adverse events. 
 
Adverse events (including SAEs) may be discovered through any of these methods: 
1. 
Observing or interviewing the participant. 
2. 
Procedures / laboratories as performed as part of participating in the study. 
3. 
Receiving an unsolicited complaint from the participant. 
The investigator will provide the following information about an AE: 
• Date of onset and resolution 
• Severity, graded using the NIH Common Terminology Criteria for Adverse Events (CTCAE), 
Version 5.0 
• Action taken with study drug product 
• Changes in study drug dosing 
• Causal relationship to study drug 


The SATURN Study [CONFIDENTIAL – DO NOT REDISTRIBUTE] 
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• Outcome 
All reportable drug adverse events as defined above will be recorded on the appropriate AE/SAE CRF 
form starting after consent has been obtained until Day 196 (ie at least 30 days after the last dose of 
study drug). 
9.7 
Follow-up of Adverse Events 
 
If a participant experiences any clinical or laboratory abnormality attributed to the study drug, they will 
be monitored until the abnormality returns to baseline (as defined at enrollment) or stabilizes. This 
procedure is implemented in the study database and case report forms and includes both adverse events 
and serious adverse events. Participants can take medications for symptomatic relief (e.g. anti-emetics, 
anti-diarrhea, analgesics). 
 
9.8 
Guidelines for Assessing Severity of an Adverse Event 
 
Adverse events will be graded on a scale from 1 to 5 according to the NIH Common Terminology Criteria 
for Adverse Events (CTCAE), Version 5.0 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Referenc 
e_5x7.pdf). A summary is below. 
 
• Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL). 
• Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
• Grade 4 Life-threatening consequences; urgent intervention indicated. 
• Grade 5 Death related to AE. 
9.9 
Guidelines for Determining Causality 
 
Attribution of all grade 2 and higher AE’s as treatment related or not will be done in two ways. First, 
attribution will be done by the treating clinician at the time of clinical evaluation using the formal 
assignment detailed below. Later, attribution we be done again by investigators in aggregate data review 
and reporting. 
 
Attribution Standards: 
 
1. Unrelated: The AE is clearly not related to the investigational agent 
2. Unlikely: The AE is doubtfully related to the investigational agent 
3. Possible: The AE may be related to the investigational agent 
4. Probable: The AE is likely related to the investigational agent 


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5. Definite: The AE is clearly related to the investigational agent 
 
9.10 Serious Adverse Events 
 
Investigators will report to the Primary Investigator (PI) all serious adverse events within 24 hours of 
becoming aware of the event, regardless of relationship or expectedness. 
 
For serious adverse events, all requested information on the AE/SAE CRF will be provided. However, 
unavailable details of the event will not delay submission of the known information. As additional details 
become available, the AE/SAE CRF will be updated and submitted. 
 
9.11 Unexpected Non-serious Adverse Events 
 
An unexpected, non-serious adverse event that is of Grade 2 severity or higher and study related will be 
recorded and reported to the PI under the serious adverse event reporting procedure above (i.e., within 24 
hours). 
 
9.12 Reporting to Health Authority 
 
The Principal Investigator sponsor for the IND will report all AEs and SAEs to the FDA within the 
reporting time limits set forth by the FDA. 
 
9.12.1 Standard Reporting (IND Annual Report) 
 
This option applies if the AE is classified as one of the following: 
 Serious, expected, suspected adverse reactions 
 Serious and not a suspected adverse reaction 
 Pregnancies 
*Note that all adverse events (not just those requiring 24-hour reporting) will be reported in the Annual 
IND Report. 
 
9.12.2 Expedited Reporting 
 
The investigators must report in an IND safety report any suspected adverse reaction to study drug that is 
both serious and unexpected. In particular, any cases of anaphylaxis potentially due to the study drug must 
be reported. The time frame for submitting an IND safety report to FDA and all participating investigators 
is no later than 15 calendar days after the PI determines that the suspected adverse reaction or other 
information qualifies for reporting. 
 
Unexpected fatal or life-threatening suspected adverse reactions represent especially important safety 
information and, therefore, must be reported more rapidly to FDA. The requirement for reporting any 
unexpected fatal or life-threatening suspected adverse reaction to FDA is no later than 7 calendar days 
after the sponsor’s initial receipt of the information. 


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Investigators must submit IND and/or CTA safety reports as required by IRB. Documentation of the 
submission and receipt by the IRB must be retained for each IND safety report. 
 
9.13 Protocol Violations 
 
All protocol deviations will be recorded in a protocol deviation log by qualified study personnel. Based 
on IRB policies, protocol violations will be reported to the Institutional Review Board within 5 days of 
the protocol violation. As warranted, the PI will develop a corrective action plan to present to the IRB to 
address deviations and/or violations. 
 
9.14 Reasons for Early Termination 
 
Study drug administration must be discontinued if any of the following occurs: 
 
• Participant develops grade 3 adverse drug reaction. 
• Participant desires to discontinue participation in the study (withdrawal of consent) 
• Participant is unwilling or unable to comply with the protocol. 
• The investigator feels that is in the participant’s best interest to discontinue treatment with study 
drug. 
 
Participants who halt study drug due to an AE will continue to be followed until AE resolution or 
stabilization. 
 
9.14.1 Halting the Study 
 
The study will be halted if: 
• 
At any point in the study the Investigators feel that there are safety concerns in this study that put 
the participants at increased risk as compared to the original information on risk in the consenting 
process; enrollment will be paused and a safety review will be performed. The investigators in 
discussion with the FDA can choose to stop the study. 
OR 
 
• 
The independent Data and Safety Monitoring Committee for the study, after reviewing data on a 
rolling basis concludes that it is in the best interests of the participants to discontinue the study. 
Investigators and DSMC will consider the following to guidelines for adverse drug reactions (ARs) to 
guide decisions regarding study suspension. Given the severity of PH-ILD disease, the DSMC will need 
to assess the safety data to make final decisions and recommendations, including consultation with IRB 
and FDA as they deem important. 
 
Grade 2 serious ARs 
• If a total of 3 or more grade 2 ARs occur, enrollment will be paused and a safety review performed. 


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Grade 3 or 4 serious ARs 
 
• If 1 grade 3 or 4 serious AR occurs, enrollment will be paused and a safety review performed. 
 
Grade 5 (fatal) 
 
• Any incidence will lead to pausing enrollment and a safety review. 
 
A final decision to halt the study will be made by the investigators after consultation with the DSMC. 
Such a decision with its supporting documentation and possible future plans including possible protocol 
amendments for the study will be submitted to, and discussed with, the FDA. 
 
9.15 Data Safety Monitoring 
 
An independent Data and Safety Monitoring Committee (DSMC) will be established. The DSMC will 
consist of 3 individuals representing statistical and clinical expertise needed to perform the role of safety 
oversight and interpretation of data for this trial. Members will be selected to ensure no conflict of interest 
exists relative to study outcomes and will not be directly engaged in study conduct. 
 
The DSMC will monitor the trial, review safety data, and assess the performance of trial operations and 
will provide recommendations on whether the trial should continue as planned, be modified, or be stopped. 
Any action taken by the Board, and the reasons for the action, will be recorded. These documents will 
include any data summaries or analyses provided to the DSMC and will remain confidential until the study 
is concluded. The DSMC charter includes additional details on roles and responsibilities. 
10 STATISTICAL METHODS AND CONSIDERATIONS 
 
10.1 Analysis Population 
 
There will be two analysis populations for the trial: the intent-to-treat (ITT) and per-protocol (PP) 
populations. The following description provides how the populations will be derived and analyzed: 
 
• ITT population 
o Composed of all randomized participants 
o Analyzed according to their assigned treatment arm 
• PP population 
o Composed of all randomized participants who completed treatment and didn’t have any 
major protocol deviations 
o Analyzed according to their assigned treatment arm 
 
10.2 Descriptive Statistics 
 
Descriptive statistics will be reported for all key participant variables, including, but not limited to, 


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baseline clinical and demographic characteristics, use of medications, laboratory values, vital signs, 
clinical outcomes, adverse events, compliance, and study completion status. Proportions will be presented 
for categorical variables. Continuous variables will be presented using means, standard deviations, and 
number of observations if the data are normally distributed. If the data are not normally distributed, then 
continuous variables will be presented using medians and interquartile ranges. In all cases, between-group 
comparisons will be assessed using absolute standardized differences. 
 
10.3 Analysis of Primary Endpoints 
 
The primary endpoint is the change in PVR on RHC from baseline to the end of treatment period. No 
hypothesis testing will be performed in analyzing the primary endpoint. The primary endpoint will be 
analyzed in the ITT population. 
 
The PVR on RHC will be presented as means, standard deviations, number of observations and 95% 
confidence intervals for each randomization arm. Differences in PVR may be calculated between the 
treatment group, placebo group, and different types of PH (e.g. Group 1 versus Group 3) to assess 
treatment differences. The analysis will be performed after all participants in the ITT population have 
reached the end of treatment or have been withdrawn from the trial. 
10.4 Analysis of Secondary Endpoints 
 
All secondary endpoints will be analyzed in the ITT population. 
 
The proportion of participants experiencing adverse events (AE) events will be summarized by AE type 
and treatment arm. The proportion of participants experiencing an AE will be calculated as the number of 
participants who have experienced an AE divided by the number of participants in the ITT population. 
AEs will be summarized by each arm separately. AEs may be compared by arm using a Fisher’s exact 
test. 
 
The proportion of participants experiencing serious adverse events (SAE) events will be summarized by 
SAE type and treatment arm. The proportion of participants experiencing an SAE will be calculated as the 
number of participants who have experienced a SAE divided by the number of participants in the ITT 
population. SAEs will be summarized by each arm separately. SAEs may be compared by arm using a 
Fisher’s exact test. 
 
The baseline, follow-up, and change from baseline in mPAP, 6MWDT, EMPHAIS-10 score,  SGRQ score, 
serum HA concentration, and NT-proBNP will be summarized using means, standard deviations numbers 
of observations, and 95% confidence intervals for each randomization arm. Differences in these measures 
may be calculated between the treatment and placebo group overall and within different types of PH (e.g. 
Group 1 versus Group 3) to assess treatment differences. 
 
10.5 Analysis of Exploratory Endpoints 
 


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All exploratory endpoints will be analyzed in the ITT population and will be analyzed after all participants 
have completed treatment or have withdrawn from the trial. 
 
The baseline, follow-up, and change from baseline in inflammatory markers, pro-inflammatory cytokines, 
PFTs (including FEV1, FVC, TLC, and DLCO), and EBC HA concentration, and HA fragment size will 
be summarized using means, standard deviations numbers of observations, and 95% confidence intervals 
for each randomization arm. Differences in these measures may be calculated between the treatment group, 
placebo group, and different types of PH (e.g. Group 1 versus Group 3) to assess treatment differences. 
The pharmacokinetics and fragment size will be described. There will also be a sensitivity analysis to 
investigate whether drug product used (Isochol vs Cantabiline) led to differential primary endpoint 
outcomes, using a stratified analysis by drug product. 
 
10.6 Missing Data Handling 
 
While we expect minimal missing data, it is inevitable in clinical trials. We will thoroughly and 
transparently present the amount of missing data for each variable where missing data is present. Given 
the small sample size, we will use complete case analyses. 
10.7 Sample Size and Randomization 
 
A total of 16 participants with PH will be enrolled in the study. Participants will be randomized 5:3 to 
treatment:placebo. Randomization will be stratified by PH type. As no formal hypothesis testing will be 
performed on the primary endpoint, this sample size is not based on a statistical powering. However, data 
on hand regarding clinical improvement and HA changes in preclinical and clinical settings suggests we 
will be able to draw meaningful insights from a study of this size that informs future trials. 
 
11 DATA COLLECTION, RETENTION AND MONITORING 
 
11.1 Data Collection Instruments 
 
Data entry, database management, and data quality assurance will be led by a study coordinator at the 
study site. Source documentation will include site assessment forms, laboratory results, telephone surveys, 
and internet surveys. Where possible, electronic transfer of electronic source data to the study CRFs 
through a secure electronic data capture (EDC) system will be automated. Any paper-based forms that are 
used will be maintained in a secure locked facility at the study site and maintained by the site clinical 
research coordinator (CRC). An eCRF will ensure capture of information including subject identification, 
study identification, provision and date of informed consent form (ICF), visit dates, clinical results (safety 
and efficacy) as specified in the protocol, adverse events, concomitant medications, investigational 
medicine receipt/use/destruction, production administration, data of study completion, and reason for 
withdrawal if needed. The individual author of all source documents will be identifiable. Any adverse 
related reports will be signed off by the investigator. All study related documentation will employ the 
minimum of identifying information. 


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11.2 Data Management Procedures 
 
In compliance with ICH/GCP guidelines, the study site will maintain all source documentation, CRFs, 
and study-related documents. All participants will be assigned a study ID. All study tools will use only 
the subject’s study ID. Specimen containers and blood tubes for assignment to site laboratories or shipping 
to central laboratories will be labeled by the site CRC with the minimum amount of identifying information 
(e.g., participant identifier, study identifier, and date of collection). 
 
A secure trial master file (TMF) maintained by qualified study staff and will include all study-related 
documents including the protocol, investigator brochure, study operations manual, statistical analysis plan, 
laboratory manual, email communications, SOPs, evidence of validated processes for ECD systems. Trial 
site-specific files will also be maintained on the TMF including a delegation of authority log, site roster 
for study personnel, qualified person certification, local SOPs affecting study conduct, ICF, and IRB 
approvals. The trial master file system will include audit trails for document versions and archiving 
capabilities. 
 
11.3 Data Quality Control and Reporting 
 
The lead investigator is responsible for ensuring that a roster of active study personnel is maintained, a 
delegation of authority log assigns tasks to individual team members, and that access to the secure study 
EDC and TMF systems are controlled in alignment with the roster and log. 
 
In order to ensure data quality, quality audits will be performed. The timing of audits will be developed 
based on a risk-based approach, reflecting the nature of the study design, known profile of 
the drug being used, and patient population. Study monitors will follow an SOP. Elements of study 
monitoring will include: 
 
1. Implementation of patient consent processes 
2. Source data verification (SDV) (e.g., for questionnaires, hospital medical records, and 
biospecimen collections) 
3. Pharmacy monitoring (drug accountability processes, IMP storage, labeling and expiry dates, 
randomization and blinding) 
4. Laboratory monitoring (Adherence to Lab Manual and specimen handling requirements) 
5. Adverse event reporting (ensuring reporting from source documents to trial team, reporting to local 
authorities) 
 
The results of site audits will be shared with the clinical trial investigator(s) and IRB as appropriate. 
 
11.4 Archival of Data 
 
Electronic data including all study databases and supporting electronic documentation will be archived to 


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cloud-based servers on a daily basis. 
 
11.5 Availability and Retention of Investigational Records 
 
All electronic data will be kept in secured servers. All paper-based forms that are used will be maintained 
in a secure locked facility at the study site and maintained by the site CRC. Only the research team will 
have access to the data. 
 
11.6 Subject Confidentiality 
 
Participant medical and study information will be kept confidential. The following health information 
related to this study may be used or disclosed in connection with this research study, including, but not 
limited to, name and initials, address, email, phone number(s), date of birth, age, sex, race, ethnicity, 
medical record number, information related to COVID-19 disease, symptoms, physical exams, symptoms 
that might relate to medication side effects, vital signs including temperature and oxygen saturation levels, 
laboratory tests, pregnancy test, and medications received including study drug. 
 
All participants will be given a sequential study ID. The code for this ID with personal identifiers will be 
maintained in a locked research file accessible only to study personnel. Only research personnel will have 
access to the research records. The data will be keyed into a secure study website in a coded fashion by 
the study coordinator. Paper research charts will be kept in a locked file cabinet with limited access. 
Laboratory personnel will have access to study specimens. The data is transferred by computer via 
password protected electronic network. When transferring via electronic networks, a password protected 
encrypted computer will be used. 
12 ETHICAL CONSIDERATIONS 
 
12.1 IRB and HIPAA 
 
This study protocol, all procedures and informed consent forms (ICF), and any subsequent protocol 
amendments must be reviewed and approved by the Institutional Review Board (IRB). Prior to any study- 
related procedures, the investigator or designee will obtain from the participant a signed and dated written 
ICF consistent with FDA/ICH regulations and the HIPAA Privacy Rule. A HIPAA Privacy Rule 
Authorization language will be included in the ICF and must be IRB approved prior to study 
implementation. In addition, the document of Bill of Rights will be attached to the ICF so that the 
participants can read and understand the same. All versions will be maintained in the TMF. 
 
12.2 Potential Participant Risks 
 
H01: H01 is a natural active ingredient that is synthesized for pharmaceutical use. H01 is currently not 
FDA approved for use in the United States. However, H01 has been marketed and used as approved drug 
in Europe for >50 years (European Union reference date [EURD] 07/27/1965). Overall, H01 appears to 
be a safe and well-tolerated medication. The French product of H01 named Cantabiline will be used in 


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this trial. Cantabiline is authorized by the French Medicines Agency (Agence nationale de sécurité du 
médicament et des produits de santé (ANSM)) under CIP : 6 197 431 7. The recommended dose is 400 
mg with main meals. The main side effect listed in the product label is the gastrointestinal pathology of 
diarrhea, which is listed as common 0.1% to 10%. Potential anaphylactic or allergic reactions are also 
listed as possible side effects with an unknown rate. The label recommends to not use in cases of biliary 
obstruction or severe hepatic impairment. 
 
To minimize risks of potential severe allergic reactions, participants with a known allergy for H01 will be 
excluded. A standard operating procedure for managing allergic reactions, including anaphylaxis, will 
also be in place. These risks as well as guidance on the potential signs and symptom of a severe allergic 
reaction will be included in the participant consent. Additionally, if participants develop a grade 3 or 
higher allergic reaction thought to be due to the study drug, treatment with the study drug will be 
discontinued immediately. To minimize risks of gastrointestinal side effects, patients with acute biliary 
obstruction of severe hepatic impairment will be excluded from the study. Additionally, if participants 
develop diarrhea, we have developed guidelines based on diarrhea severity and participant preferences for 
1) treating symptoms, 2) avoiding dose increases, 3) reducing doses, or 4) discontinuing treatment. 
 
Right heart catherization: RHC can cause bruising of the skin or infection at the site where the catheter 
(sterile tube) is inserted into a vein, injury to blood vessels, excessive bleeding because of puncture or 
damage to the vein during catheter insertion, or partial collapse of a lung if a neck or chest vein is used to 
insert the catheter. Rare but serious risks include abnormal heart rhythm or electrical blockage of heart 
beats, perforation of the heart muscle with bleeding into the sack around the heart, blood clots, stroke, 
heart attack, or death. Medications for pain or sedation can cause allergic reaction, an unconscious state, and 
depressed breathing. During the RHC, you maybe asked to perform an exercise test.  With your feet on a 
supine ergometer you may exercise for 3 to 6 mins at a gentle pace.  You may feel short of breath during this 
portion of the study.  You can stop at any point.  
 
Pulmonary function tests and expired breath condensate: PFTs and EBC are usually safe for most people. 
However, PFTs may require participants to breathe in and out quickly so they may feel dizzy and may faint. 
 
Venipuncture & arterial blood gas: The risks of venipuncture and ABG include temporary discomfort, pain, 
and anxiety from the needle stick, bruising, and, rarely, infection. To minimize risk, all blood draws will 
follow hospital/clinical procedures and be drawn by experienced providers. There is minimal risk regarding 
the blood loss related to study tests. 
 
Privacy: There is a risk of loss of privacy around health information. To minimize this risk, information 
about participants will be handled with a goal of maintain confidentiality in compliance with privacy 
regulations (e.g. HIPPA and local government laws). Participant names and medical record numbers will 
be recorded for study management purposes. This information will not be included in the hard copy data 
case report forms or the electronic database used for data analysis and will be maintained in a locked file in 
a lockable office. It will not be disclosed to others. Study data will be identified by a unique study code for 
each participant. Hard copy study data will be maintained in a separate locked research file in a lockable 


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office. The electronic data set, which will be identified by the unique study codes, will be keyed into a 
computer that is password protected and encrypted. Access to study data will be limited to research personnel 
who have completed protocol-specific training. 
 
12.3 Potential Benefits 
 
Participation in this trial gives participants the potential benefits of a new treatment for PH that may be a 
disease-modifying agent. 
13 Abbreviations 
 
6MWDT = six minute walk distance test 
AE = adverse event 
ALT = alanine aminotransferase 
AST = aspartate aminotransferase 
BL = baseline 
BMI = body mass index 
BUN = blood urea nitrogen 
CBC = complete blood count 
CRC = clinical research coordinator 
CRP = C-reactive protein 
CTCAE = common terminology criteria for adverse events 
EBC = exhaled breath condensate 
ESR = erythrocyte sedimentation 
rate HA = hyaluronan, hyaluronic 
acid HED = human equivalent dose 
HFNC = high flow nasal cannula 
H01 = 4-Methylumbelliferone, Hymecromone 
ICF = Informed Consent Form 
INR = international normalized ratio 
ITT = intention to treat 
LDH = lactate dehydrogenase 
mPAP = mean pulmonary arterial pressure (mPAP) 


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NIPPV = non-invasive positive pressure ventilation 
PFT = pulmonary function test 
PK = pharmacokinetics 
PP = per protocol 
PT = prothrombin time 
PTT = partial thromboplastin time 
PVR = pulmonary vascular resistance 
RHC = right heart catheterization 
SC = subject contact 
TMF=trial master file 
V = visit 
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Arthritis & Rheumatology. 2018;70(10):1673–84. 


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33. Freitas JP, Filipe P, Emerit I, Meunier P, Manso CF, Guerra Rodrigo F. Hyaluronic acid in 
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