Clinical trial NCT02530996: Systemic Sclerosis (SSc) Vasculopathy: Improved Clinical Monitoring and Treatment
Official title: Systemic Sclerosis (SSc) Vasculopathy: Improved Clinical Monitoring and Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Rheumatologic Disease
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2015-08-21
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 95
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Twelve systemic sclerosis SSc patients were studied 5 hours after oral BH4 administration (10 mg/kg body weight) or placebo on separate days using controlled, counterbalanced, double-blind, crossover experimental design.
Primary purpose: BASIC_SCIENCE

Brief summary: Systemic sclerosis (SSc; scleroderma) is a multi-organ systemic disease characterized by activation of immune cells, which results in vascular dysfunction (vasculopathy) and subsequent scarring (fibrosis). SSc has a higher than expect prevalence in the US military. On a national level there are 5,766 SSc patients (ICD-9 710.1) presently cared for in the Veterans Health Administration (VHA). While there is no cure for SSc, studies of therapeutics that can help slow disease progression are valuable to our Veterans. This proposal addresses the solicitation for projects with attention to SSc requested by President Obama after reviewing potential contamination of water at Camp Lejeune. This proposal is a patient-centered outreach for our Veterans with SSc to inform and prevent catastrophic endstage vascular abnormalities, including digital ulcers, pulmonary arterial hypertension (PAH) and scleroderma renal crisis in SSc. The study proposes a novel application of a therapeutic for this disease. A better understanding of the initiating insult and natural progression of SSc vasculopathy is needed in order to develop therapeutics with a goal of curing/treating the underlying disease. This project has the potential to impact not only Veterans with SSc, but also those with vascular abnormalities including digital ulcers, PAH, and renal crisis. This proposal represents a potential major therapeutic advance for our Veterans with SSc.

Detailed description: Although SSc is heterogeneous in the extent of organ involvement and prognosis, it is accepted that all SSc cases have a progressive and usually devastating course. Since vasculopathy precedes fibrosis in this disease, a focus on understanding its natural history and preventative measures for vascular dysfunction has profound implications. This pilot work suggests that measurement of endothelial dysfunction with flow mediated dilatation (FMD) holds promise as novel method to assess disease progression as well as the therapeutic efficacy of the pharmacologic compound tetrahydrobiopterin (BH4) in SSc. The investigators believe that BH4, which targets the endothelium, has great promise to reduce SSc-related tissue hypoxia, end organ damage, and potentially may impact underlying disease progression. The first aim will adopt an integrative approach and validate a novel, non-invasive technique, FMD to define vasculopathy in SSc. The second aim and third aim (which is reported in this PRS report) will examine if BH4 is effective in ameliorating vascular dysfunction in patients with SSc and determine the role of oxidative stress in BH4-mediated improvements in vascular function in patients with SSc. The overarching goal of these aims is to improve vasculopathy detection and management in Veterans with SSc.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of systemic sclerosis (SSc, scleroderma) by ACR/EULAR 2013 criteria.

Exclusion Criteria:

* Age \< 18
* Pregnant or breast feeding
* Unwillingness to consent

Primary outcomes:
measure: Flow Mediated Dilatation (FMD)-Diameter of Artery
timeFrame: FMD was obtained on a single day at two different time points (after placebo and intervention) after a 5 day washout period.
measure: Flow Mediated Dilatation-shear Rate
timeFrame: FMD was obtained on a single day at two different time points (after placebo and intervention) after a 5 day wash out period.
measure: Flow Mediated Dilatation- Blood Velocity
timeFrame: FMD was obtained on a single day at two different time points (after placebo and intervention) after a 5 day wash out period.
measure: Flow Mediated Dilatation-blood Flow
timeFrame: FMD was obtained on a single day at two different time points (after placebo and intervention) after a 5 day wash out period.
Secondary outcomes:
measure: Oxidative Stress Measurement-MDA: Malondialdehyde
timeFrame: Oxidative stress measurements were obtained on a single day at two different time points (after placebo and intervention) after a 5-day wash out period.
measure: Oxidative Stress Measurement-catalase (CAT)
timeFrame: Oxidative stress measurements were obtained on a single day at two different time points (after placebo and intervention) after a 5-day wash out period.
measure: Oxidative Stress Measurement- Protein Carbonyl
timeFrame: Oxidative stress measurements were obtained on a single day at two different time points (after placebo and intervention) after a 5-day wash out period.
measure: Oxidative Stress Measurement- Ferric Reducing Ability of Plasma (FRAP)
timeFrame: Oxidative stress measurements were obtained on a single day at two different time points (after placebo and intervention) after a 5-day wash out period.
measure: Oxidative Stress Measurement- Superoxide Dismutase (SOD)
timeFrame: Oxidative stress measurements were obtained on a single day at two different time points (after placebo and intervention) after a 5-day wash out period.
measure: Oxidative Stress Measurement- Interleukin 6 (IL-6)
timeFrame: Oxidative stress measurements were obtained on a single day at two different time points (after placebo and intervention) after a 5-day wash out period.
measure: Oxidative Stress Measurement- Tumor Necrosis Factor Alpha (TNF-α,
timeFrame: Oxidative stress measurements were obtained on a single day at two different time points (after placebo and intervention) after a 5-day wash out period.
measure: Oxidative Stress Measurement- C-reactive Protein (CRP)
timeFrame: Oxidative stress measurements were obtained on a single day at two different time points (after placebo and intervention) after a 5-day wash out period.
Other outcomes:
Locations:
city: Salt Lake City
country: United States
facility: VA Salt Lake City Health Care System, Salt Lake City, UT
state: Utah
Study officials:
affiliation: VA Salt Lake City Health Care System, Salt Lake City, UT
name: Tracy M. Frech, MD MS
role: PRINCIPAL_INVESTIGATOR
References: