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

Phase 1

Terminated

• Conditions: Systemic Sclerosis; Pulmonary; Hypertension
• Interventions: Drug: Dimethyl Fumarate (DMF); Drug: Placebo Oral Tablet

• Registration Number: NCT02981082
• Lead Sponsor: Robert Lafyatis

Brief Summary

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

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).

Study Timeline

• Study First Submitted: 2016-11-30
• Study First Submitted QC: 2016-11-30
• Study Start: 2016-12
• Study First Posted: 2016-12-02
• Primary Completion: 2020-02-10
• Study Completion: 2020-02-10
• Results First Submitted: 2021-10-26
• Status Verified: 2022-03
• Results First Submitted QC: 2022-03-15
• Last Update Submitted: 2022-03-15
• Results First Posted: 2022-03-17
• Last Update Posted: 2022-03-17

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 6

Inclusion Criteria

1. Signed inform consent prior to any study-mandated procedures
2. Adult patients 18-80 years of age
3. World Health Organization Group 1 PAH associated with scleroderma (SSc-PAH)
4. WHO functional Class II-III
5. 6MWD 150 to 450 meters
6. 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.
7. ACR defined systemic sclerosis

Exclusion Criteria

1. 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

2. Participation in a clinical investigational study within the previous 30 days

3. Moderate to severe hepatic impairment (e.g., Child-Pugh Class B or C)

4. Renal failure defined as:

   • estimated creatinine clearance <30 m/min
   • serum creatinine>2.5 mg/dl

5. Serum aspartate aminotransferase (AST) and or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal

6. Systolic blood pressure < 90mmHg

7. Recently started (< 8 weeks prior to randomization) or planned cardiopulmonary rehabilitation program based on exercise

8. Pregnant or lactating women

9. Need for HAART therapy

10. Planned treatment or treatment with another investigational drug within 1 month prior to start

11. 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dimethyl Fumarate (DMF)	Dimethyl Fumarate (DMF)	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
Placebo	Placebo Oral Tablet	Twice daily oral doses of placebo for 12 weeks

Primary Outcome Measures

Name	Time	Method
6 Minute Walk Distance (6MWD)	Baseline to Week 24	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.

Secondary Outcome Measures

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

Trial Locations

Locations (4)

University of Pittsburgh; 🇺🇸 Pittsburgh, Pennsylvania, United States

National Jewish; 🇺🇸 Denver, Colorado, United States

John Hopkins; 🇺🇸 Baltimore, Maryland, United States

Boston University; 🇺🇸 Boston, Massachusetts, United States