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

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.

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).

Study Overview

• Status: Terminated
• Conditions: Systemic Sclerosis; Pulmonary; Hypertension
• Intervention / Treatment: Drug: Dimethyl Fumarate (DMF); Drug: Placebo Oral Tablet

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 Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • John Hopkins
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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	Drug: Dimethyl Fumarate (DMF); Dimethyl Fumarate (DMF) is a prescription medicine used to treat relapsing multiple sclerosis.; Other Names: Tecfidera
Placebo Comparator: Placebo; Twice daily oral doses of placebo for 12 weeks	Drug: Placebo Oral Tablet; Sugar pill manufactured to mimic Dimethyl Fumarate (DMF)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Robert Lafyatis
• Collaborators: Biogen
• Investigators: Principal Investigator: Robert A Lafyatis, MD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start: December 1, 2016
• Primary Completion (Actual): February 10, 2020
• Study Completion (Actual): February 10, 2020

Study Registration Dates

• First Submitted: November 30, 2016
• First Submitted That Met QC Criteria: November 30, 2016
• First Posted (Estimate): December 2, 2016

Study Record Updates

• Last Update Posted (Actual): March 17, 2022
• Last Update Submitted That Met QC Criteria: March 15, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Systemic Sclerosis, Scleroderma, PAH, Pulmonary Hypertension
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Respiratory Tract Diseases; Lung Diseases; Connective Tissue Diseases; Sclerosis; Hypertension; Scleroderma, Systemic; Scleroderma, Diffuse; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Dimethyl Fumarate
• Other Study ID Numbers: PRO16070614

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided