Study Description

Systemic sclerosis (SSc) is a complex, multifactorial autoimmune disease characterized by fibrosis and vasculopathy in skin and various internal organs such as the lungs, kidneys and heart disease with no specific treatment. Pulmonary arterial hypertension (PAH) is a common complication of SSc, and compared to other subgroups of PAH patients, responds poorly to currently approved vasodilators. Oxidative damage is a well-defined component of lung disease in SSc as well as in other organs and pathology studies have shown evidence of oxidative damage in SSc lungs. Dimethyl fumarate (DMF), recently been approved as a treatment for multiple sclerosis, triggers the general response to oxidative damage through Nrf2, resulting in the induction of multiple enzymes designed to counteract the oxidative process. Preclinical studies by the study team as well as other groups have shown that DMF inhibits PAH in murine models. In addition, multiple markers of oxidative stress are elevated in patients with SSc and SSc-PAH, suggesting that this is an important pathway mediating vascular damage in SSc-PAH. On the basis of these studies, the study team proposes a double-blinded, placebo-controlled study of DMF added to stable background, standard of care PAH therapy in SSc‐PAH patients, comparing the change in 6-minute walk distance (6MWD) at 24 weeks to baseline in DMF compared to placebo-treated patients.

To provide further information about target engagement and reinforce potential clinical efficacy, the study team will examine biomarkers of oxidative stress and of PAH. To assess the effect of DMF on markers of SSc-PAH, the team will compare changes from baseline to 24-weeks in levels of B-type natriuretic peptide, Endostatin, Endothelin- 1, Endoglin, Vascular Endothelial Growth Factor, von Willebrand Factor, and Vascular Cellular Adhesion Molecule 1, as well as peripheral blood mononuclear cell RNA expression biomarkers: IL13RA1, CCR1, JAK2 and MRC, comparing DMF to placebo-treated patients. The study team will examine the performance of each of these markers as potential pharmacodynamic biomarkers by comparing their levels longitudinally to changes in 6MWD. To assess the effect of DMF treatment on markers of oxidative stress, the study team will measure markers of lipid, DNA, and prostaglandin oxidation, comparing changes after treatment to baseline levels in DMF compared to placebo-treated patients.

ELIGIBILITY CRITERIA:

Ages Eligible for Study:           18 Years to 80 Years   (Adult, Older Adult)

Sexes Eligible for Study:          All

Accepts Healthy Volunteers:  No

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
  1. PAH of any etiology other than scleroderma
  2. PH of any etiology other than WHO Group I PAH
  3. Pulmonary venous hypertension defined as PCWP or LVEDP >15 mHg
  4. Untreated sleep apnea with AHI >20 or SaO2 Nadir <87%
  5. Chronic thromboembolic disease
  6. 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:
  1. estimated creatinine clearance <30 m/min
  2. 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

Study Design:

Allocation: Randomized

Intervention Model: Parallel Assignment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose: Treatment

Study Location(s):

National Jewish, Denver, Colorado, United States, 80206

John Hopkins, Baltimore, Maryland, United States, 21205

Boston University, Boston, Massachusetts, United States, 02118

University of Pittsburgh, Pittsburgh, Pennsylvania, United States, 15213

Study Website:

https://clinicaltrials.gov/ct2/show/NCT02981082?term=NCT02981082&rank=1