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.

Status

Terminated

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02981082

Enrollment

Registered

2016-12-02

Start date

2016-12-31

Completion date

2020-02-10

Last updated

2022-03-17

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pulmonary; Hypertension, Systemic Sclerosis

Keywords

Systemic Sclerosis, Scleroderma, PAH, Pulmonary Hypertension

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).

Interventions

DRUGDimethyl Fumarate (DMF)

Dimethyl Fumarate (DMF) is a prescription medicine used to treat relapsing multiple sclerosis.

DRUGPlacebo Oral Tablet

Sugar pill manufactured to mimic Dimethyl Fumarate (DMF)

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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
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.
Proteomic Biomarkers	Baseline to Week 24	The change from baseline in proteomic biomarkers, including BNP, at 24 weeks, comparing DMF to placebo treated patients.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Dimethyl Fumarate (DMF) Once daily oral doses of Dimethyl Fumarate (DMF) 120mg for the first 7 days, following a titration schedule reaching a minimum of 120mg DMF twice daily, maximum 240mg twice daily, by the start of week 8. Subjects will be dosed for 24 weeks. Dimethyl Fumarate (DMF): Dimethyl Fumarate (DMF) is a prescription medicine used to treat relapsing multiple sclerosis.	4
Placebo Twice daily oral doses of placebo for 12 weeks. Placebo Oral Tablet: Sugar pill manufactured to mimic Dimethyl Fumarate (DMF)	2
Total	6

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	0	1
Overall Study	Met stopping rule of low absolute lymphocyte count (<0.5L) at two visits	1	0
Overall Study	Withdrawal by Subject	2	0

Baseline characteristics

Characteristic	Total	Placebo	Dimethyl Fumarate (DMF)
6-minute walk distance (6MWD)	284.83 Mean 6MWD (meters)	243.5 Mean 6MWD (meters)	305.5 Mean 6MWD (meters)
Age, Continuous	69 years	72.5 years	66.4 years
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants	2 Participants	4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	5 Participants	1 Participants	4 Participants
Sex: Female, Male Female	6 Participants	2 Participants	4 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 4	0 / 2
other Total, other adverse events	4 / 4	2 / 2
serious Total, serious adverse events	0 / 4	1 / 2

Outcome results

Primary

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.