Dimethyl Fumarate (DMF) in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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A double-blinded, placebo-controlled study of Dimethyl fumarate (DMF) in 34 Systemic Sclerosis-Pulmonary Hypertension (SSc-PAH) patients. The study will determine safety and the primary outcome variability for DMF in treating SSc-PAH; the primary outcome of clinical efficacy in this pilot trial will be improvement in 6-minute walk distance (6MWD).

Detailed Description
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A double-blinded, placebo-controlled study of Dimethyl fumarate (DMF) in 34 Systemic Sclerosis-Pulmonary Hypertension (SSc-PAH) patients. The study medication will be added to stable background PAH medication(s). Subjects will be dosed for 24 weeks, will undergo examination every 8 weeks, and will be finally evaluated 12 weeks after completion of treatment. Dosage will begin at once daily oral doses of 120mg for the first 7 days and follow the up-titration schedule to a maintenance dose of 240mg twice a day (or highest tolerated dose of a minimum of 120mg twice a day by the start of Week 8) for the remainder of the study. Participation will be for a total of 40 weeks, including a 4-week screening period, 24 weeks of drug, and a safety follow-up 12 weeks after the last dose. The study will determine the safety and the primary outcome variability for DMF in treating SSc-PAH; the primary outcome of clinical efficacy in this pilot trial will be improvement in 6-minute walk distance (6MWD).

Official Title
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A Double-blinded, Placebo-controlled Pilot Study of Dimethyl Fumarate (DMF) in Pulmonary Arterial Hypertension (PAH) Associated With Systemic Sclerosis (SSc-PAH): The Effect of DMF on Clinical Disease and Biomarkers of Oxidative Stress.

Conditions
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Systemic Sclerosis, Pulmonary; Hypertension

Intervention / Treatment
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* Drug: Dimethyl Fumarate (DMF)
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed inform consent prior to any study-mandated procedures Adult patients 18-80 years of age World Health Organization Group 1 PAH associated with scleroderma (SSc-PAH) WHO functional Class II-III 6MWD 150 to 450 meters Right heart catheterization demonstrating mPAP≥ 25 mmHg and PCWP or left ventricular end diastolic pressure ≤15mm Hg and pulmonary vascular resistance ≥240 dynes/cm-5 (3 Wood units) within 12 weeks prior to study entry. ACR defined systemic sclerosis Exclusion Criteria: Pulmonary hypertension associated with PAH of any etiology other than scleroderma PH of any etiology other than WHO Group I PAH Pulmonary venous hypertension defined as PCWP or LVEDP >15 mHg Untreated sleep apnea with AHI >20 or SaO2 Nadir <87% Chronic thromboembolic disease Sarcoidosis Participation in a clinical investigational study within the previous 30 days Moderate to severe hepatic impairment (e.g., Child-Pugh Class B or C) Renal failure defined as: estimated creatinine clearance <30 m/min serum creatinine>2.5 mg/dl Serum aspartate aminotransferase (AST) and or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal Systolic blood pressure < 90mmHg Recently started (< 8 weeks prior to randomization) or planned cardiopulmonary rehabilitation program based on exercise Pregnant or lactating women Need for HAART therapy Planned treatment or treatment with another investigational drug within 1 month prior to start Moderate to severe interstitial lung disease, defined by FVC < 80% or evidence on HRCT of fibrosis or ground glass changes involving more than 30% of lung parenchyma

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dimethyl Fumarate (DMF)<br>Twice daily oral doses of Dimethyl Fumarate (DMF) 120mg for the first 7 days followed by the maintenance dose of Dimethyl Fumarate (DMF) 240mg twice a day. Subjects will be dosed for 24 weeks | Drug: Dimethyl Fumarate (DMF)<br>* Dimethyl Fumarate (DMF) is a prescription medicine used to treat relapsing multiple sclerosis.<br>* Other names: Tecfidera;|
| Placebo Comparator: Placebo<br>Twice daily oral doses of placebo for 12 weeks | Drug: Placebo Oral Tablet<br>* Sugar pill manufactured to mimic Dimethyl Fumarate (DMF)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 Minute Walk Distance (6MWD) | The primary outcome of clinical efficacy in this study is improvement in 6-minute walk distance (6MWD). Data depict the mean change (%) at end-of-study-treatment (Week 24) from baseline in both treatment groups, utilizing the Last Observation Carried Forward of withdrawn subjects. | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Worsening | The change in time to clinical worsening in DMF compared to placebo treated patients. | Baseline to Week 24 | 
| Borg Dyspnea Index (BDI) | The change in Borg Dyspnea Index (BDI) at 24 weeks from baseline in DMF compared to placebo treated patients | Baseline to Week 24 | 
| Serum Markers of Oxidative Stress | The change from baseline of serum markers of oxidative stress at 24 weeks, comparing DMF to placebo treated patients. | Baseline to Week 24 | 
| Proteomic Biomarkers | The change from baseline in proteomic biomarkers, including BNP, at 24 weeks, comparing DMF to placebo treated patients. | Baseline to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Systemic Sclerosis, Scleroderma, PAH, Pulmonary Hypertension