A Study of RVT-1201 in Patients With Pulmonary Arterial Hypertension (ELEVATE 1)

Study Overview
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Brief Summary
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This is an exploratory Phase 2a, randomized, double-blind, placebo-controlled, parallel-group, multicenter study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of RVT-1201 in patients with pulmonary arterial hypertension (PAH).

Detailed Description
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This is an exploratory Phase 2a, randomized, double-blind, placebo-controlled, parallel-group, multicenter study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of RVT-1201 in patients with pulmonary arterial hypertension (PAH). Study participation for each patient will last approximately 3 months and will consist of a screening period (up to 28 days in duration), a baseline period (day 1, pre-dose), a 6-week treatment period, and a 2-week follow-up period. The study will enroll approximately 36 patients at approximately 20 centers across the United States and Canada.

Official Title
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A Phase 2a, Double-Blind, Placebo-Controlled Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Effects of RVT-1201 in Patients With Pulmonary Arterial Hypertension

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: RVT-1201
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Symptomatic PAH belonging to one of the following types: Idiopathic Heritable Drug- or toxin- induced Associated with one of the following: connective tissue disease or congenital heart disease World Health Organization (WHO) Functional Class (FC) II or III PAH diagnosed by right heart cardiac catheterization prior to Screening Receiving standard of care treatment for PAH with oral monotherapy or dual therapy for at least 12 weeks prior to Screening at a dose which has been stable for at least 8 weeks prior to Screening If on a diuretic, dose must be stable for at least 4 weeks prior to Screening, with no changes anticipated during study participation 6-Minute Walk Distance (6MWD) between 150 and 500 meters at Screening and Baseline visits Plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) level ≥ 300 pg/mL at Screening Ability and willingness to give written informed consent and to comply with the requirements of the study Key Exclusion Criteria: PAH associated with human immunodeficiency virus (HIV) infection, portal hypertension or schistosomiasis Other types of pulmonary hypertension (PH): Pulmonary hypertension due to left heart disease (WHO PH Group 2) Pulmonary hypertension due to lung diseases and/or hypoxia (WHO PH Group 3) Chronic thromboembolic pulmonary hypertension (WHO PH Group 4) Pulmonary hypertension with unclear multifactorial mechanisms (WHO PH Group 5) Hospitalization for pulmonary hypertension within 12 weeks of screening Cardiopulmonary rehabilitation program based on exercise (planned, or started ≤ 12 weeks prior to Screening) Prostanoid or prostacyclin receptor agonist therapy within 12 weeks of screening Evidence of left-sided heart disease If Pulmonary function tests were done prior to screening, Pulmonary function tests demonstrate obstructive or restrictive lung disease Use of telotristat (Xermelo®) within the last 6 months Use of any investigational drug within 30 days or five half-lives (whichever is longer) prior to Screening, or 90 days if an investigational drug for PAH Have uncontrolled atrial fibrillation (AFib) or other uncontrolled arrhythmias Body mass index (BMI) >45 kg/m2 Women of childbearing potential who are pregnant, planning to become pregnant, or lactating or female/male patients unwilling to use effective contraception

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
Interventional Model Description: Following screening assessments, PAH patients who meet all entrance criteria will be randomly assigned to receive one of the following treatments in a ratio of 2:1: Arm 1 (n=24) - RVT-1201 Treatment: RVT-1201 immediate-release tablets will be administered orally, at a dose of 600 mg twice daily (BID), for a total of 6 weeks in addition to the patient's current standard of care (SOC) medication(s) for PAH. Arm 2 (n=12) - Placebo Treatment: Matching placebo tablets will be administered orally, at a dose of 600 mg twice daily (BID), for a total of 6 weeks in addition to the patient's current SOC medication(s) for PAH. Participants will be followed in face-to-face visits with trial personnel every 2 weeks for 8 weeks (6 weeks of treatment plus a 2-week follow-up), with an additional phone call at Week 1, to assess drug effects and monitor safety during their treatments.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RVT-1201<br>RVT-1201 600 mg immediate-release tablet, administered orally twice daily with food for 6 weeks, in addition to the patient's current standard of care medication(s) for PAH (n=24 [Anticipated]) | Drug: RVT-1201<br>* RVT-1201 600 mg immediate-release tablet<br>* Other names: rodatristat ethyl;|
| Placebo Comparator: Placebo<br>Matching placebo tablet, administered orally twice daily with food for 6 weeks, in addition to the patient's current standard of care medication(s) for PAH (n=12 [Anticipated]) | Drug: Placebo<br>* Inactive pill manufactured to mimic RVT-1201 600 mg immediate-release tablet<br>* Other names: Placebo (for RVT-1201);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events (AEs) and discontinuations due to AEs | Incidence of treatment-emergent adverse events (TEAEs), drug-related adverse events (AEs), and discontinuations due to AEs | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of biomarkers of serotonin biosynthesis in plasma | Absolute concentrations and percent change from baseline in plasma 5-hydroxyindoleacetic acid (5-HIAA) and plasma 5-hydroxytryptamine (5-HT, also known as serotonin) concentrations | 8 weeks | 
| Concentration of biomarkers of serotonin biosynthesis in urine | Concentration of urine 5-hydroxyindoleacetic acid (5-HIAA) will be normalized against urine creatinine concentration to determine absolute ratio and percent change from baseline in urine 5-HIAA:creatinine ratio | 8 weeks | 
| Study drug (RVT-1201) and active metabolite (KAR5417) plasma concentrations | Measured RVT-1201 and KAR5417 plasma concentrations from sparse sampling | 6 weeks | 
| Area under the plasma concentration versus time curve (AUC) of KAR5417 (the active metabolite of RVT-1201) | Measured KAR5417 plasma concentrations from sparse sampling will be used to assess the pharmacokinetic (PK) parameter AUC of KAR5417 administered twice daily in patients with PAH, by means of population PK (PopPK) analysis | 6 weeks | 
| Relationship between KAR5417 exposure and percent change from baseline in plasma concentrations of the serotonin-related biomarkers | Evaluate the relationship between exposure (area under the plasma concentration versus time curve [AUC]) of KAR5417 (the active metabolite of RVT-1201) and percent change from baseline in plasma concentrations of the serotonin-related biomarkers (5-HIAA and 5-HT) | 6 weeks | 
| Relationship between KAR5417 exposure and percent change from baseline in urine concentrations of the serotonin-related biomarkers | Evaluate the relationship between exposure (area under the plasma concentration versus time curve [AUC]) of KAR5417 (the active metabolite of RVT-1201) and percent change from baseline in urine 5-HIAA:creatinine concentration ratio | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary arterial hypertension (PAH), Pulmonary hypertension (PH), RVT-1201, Rodatristat ethyl, Tryptophan hydroxylase (TPH), Serotonin reduction, ELEVATE 1, KAR5417