Investigation of H01 in Adults With Pulmonary Hypertension Including Interstitial Lung Disease (The SATURN Study).

Study Overview
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Brief Summary
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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
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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

Official Title
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Investigation of H01 in Adults With Pulmonary Hypertension Including Interstitial Lung Disease (The SATURN Study).

Conditions
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Pulmonary Hypertension

Intervention / Treatment
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* Drug: Hymecromone (H01)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Classified as WHO functional class II/III/IV despite treatment with maximally tolerated doses of 2 or more treatment modalities (exp. PDE5 inhibitors, guanylate cyclase stimulators, endothelin receptor antagonists, and prostanoids) Baseline 6MWT: greater than 100 meters and less than 550 meters Established diagnosis of Group 3 pulmonary hypertension as a result of interstitial lung disease OR established diagnosis of Group 1 pulmonary hypertension as a result of connective tissue disease, idiopathic, hereditary, drugs, or toxins. Right heart catheterization at randomization showing pre-capillary pulmonary hypertension (mPAP ≥ 25 mmHg and PVR > 400 dynes * sec * cm^ -5) and: 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 study requirements Be able to read, speak and understand English Exclusion Criteria: Participants with a diagnosis of PAH or PH for reasons due to any of the following: Group 2, 4, or 5 Group 1 due to HIV, veno-occlusive disease, porto-pulmonary hypertension, congenital heart disease Group 3 due to severe chronic obstructive pulmonary disease (COPD) or obstructive sleep apnea (OSA) Note: participants with overlapping syndromes will be evaluated on a case-by-case basis by the recruiting physician* Total Lung Capacity (TLC) less than 60% predicted FEV1/FVC less than 50% predicted or FEV1 less than 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 greater than 20 mmHg and/or left ventricular ejection fraction less than 40% 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 Participants must not have 3 or more of the following left ventricular disease / dysfunction risk factors: Body mass index (BMI) greater than 30kg/m2 History of essential hypertension requiring medication Diabetes mellitus 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 greater than 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 greater than 10L/min of oxygen supplementation by any mode of delivery at rest at baseline Body mass index greater than 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 less than 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 thereof Known allergy to any component of placebo (including wheat allergy, celiac disease, 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Treatment Oral Hymecromone (H01)<br>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. | Drug: Hymecromone (H01)<br>* 800 mg oral H01 two times a day (total dose: 1600 mg/day).<br>* Other names: Isochol;|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* Oral tablet placebo (inactive ingredients) two times a day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Pulmonary Vascular Resistance (PVR) | Change in pulmonary vascular resistance (PVR) measured by right heart catheterization (RHC). | Baseline to end of treatment (Week 24) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The safety and tolerability of H01 in adults with pulmonary hypertension using the NIH Common Terminology Criteria for Adverse Events (CTCAE) | 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. | Baseline to end of treatment (Week 24) | 
| Change in Mean Pulmonary Arterial Pressure (mPAP) | Change in mean pulmonary arterial pressure (mPAP) by RHC | Baseline to end of treatment (Week 24) | 
| 6 Minute Walk Distance Test (6 MWDT) | Change in 6 minute walk distance as measured by 6 MWDT | Baseline to end of treatment (Week 24) | 
| Quality of Life (QOL) score, EMPHASIS-10 score and St George Respiratory Questionnaire (SGRQ) score | Change in quality of life (QOL) score, EMPHASIS-19 score and St George Respiratory Questionnaire (SGRQ) score | Baseline to end of treatment (Week 24) | 
| Serum HA concentration | Change in serum HA concentration | Baseline to end of treatment (Week 24) | 
| N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) | Change in NT-proBNP | Baseline to end of treatment (Week 24) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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