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NCT Number: NCT02530996

Systemic Sclerosis (SSc) Vasculopathy: Improved Clinical Monitoring and Treatment

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.

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Key information

Conditions

Rheumatologic Disease Collagen Diseases Connective Tissue Diseases Skin and Connective Tissue Diseases

Age range

18 year–95 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

VA Salt Lake City Health Care System, Salt Lake City, UT

Salt Lake City, Utah, 84148, United States

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

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

Exclusion criteria

  • Age < 18
  • Pregnant or breast feeding
  • Unwillingness to consent

Treatment and study plan

BH4

Drug

BH4 10 mg/kg/day given once to a total of 12 SSc patients

Other names: Kuvan

Vasculopathy assessment

Diagnostic Test

Non-invasive technique, flow mediated dilatation (FMD) to define vasculopathy in SSc.

Other names: Kuvan

Placebo

Drug

On the experimental days, patients reported to the laboratory after having consumed a standardized breakfast and oral BH4 (10mg/kg) or placebo five hours prior to their arrival. All measurements were taken at the same time of day to eliminate any diurnal effects. All participants abstained from alcohol, caffeine, and exercise for ≥12 hours prior to the study. Additionally, vasodilatory medications were discontinued 12 hours prior to study visit. In premenopausal women, measurements were performed during the early follicular phase of the menstrual cycle. All measurements were made under quiet, comfortable, ambient (~22°C) laboratory conditions.

Other names: Placebo from IDS

Primary outcomes

  1. Flow Mediated Dilatation (FMD)-Diameter of Artery

    Time frame: FMD was obtained on a single day at two different time points (after placebo and intervention) after a 5 day washout period.

    FMD diameter of artery (mm, higher better)

  2. Flow Mediated Dilatation-shear Rate

    Time frame: FMD was obtained on a single day at two different time points (after placebo and intervention) after a 5 day wash out period.

  3. Flow Mediated Dilatation- Blood Velocity

    Time frame: FMD was obtained on a single day at two different time points (after placebo and intervention) after a 5 day wash out period.

  4. Flow Mediated Dilatation-blood Flow

    Time frame: 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

  1. Oxidative Stress Measurement-MDA: Malondialdehyde

    Time frame: 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.

    MDA (lower better). Plasma malondialdehyde assessed by Oxis Research/Percipio Bioscience, Foster City, CA.

  2. Oxidative Stress Measurement-catalase (CAT)

    Time frame: 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.

    CAT (higher better) assessed by Cayman Chemical Company, Ann Arbor, MI.

  3. Oxidative Stress Measurement- Protein Carbonyl

    Time frame: 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.

    Protein carbonyl (lower better). Plasma protein carbonyl levels assessed by Northwest Life Science Specialties, LLC Vancouver, WA.

  4. Oxidative Stress Measurement- Ferric Reducing Ability of Plasma (FRAP)

    Time frame: 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.

    FRAP (higher better). FRAP assessed using the method described by Benzie and Strain.

  5. Oxidative Stress Measurement- Superoxide Dismutase (SOD)

    Time frame: 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.

    SOD (higher better). SOD assessed by Cayman Chemical Company, Ann Arbor, MI.

  6. Oxidative Stress Measurement- Interleukin 6 (IL-6)

    Time frame: 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.

    IL-6 (lower better), assessed by R&D Systems, Minneapolis, MN.

  7. Oxidative Stress Measurement- Tumor Necrosis Factor Alpha (TNF-α,

    Time frame: 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.

    TNF-α (lower better), assessed by R&D Systems, Minneapolis, MN.

  8. Oxidative Stress Measurement- C-reactive Protein (CRP)

    Time frame: 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.

    CRP (lower better). CRP assessed by R&D Systems, Minneapolis, MN.

Sponsors and collaborators

Lead sponsor

VA Office of Research and Development

Fed

Registry information

Acronym: Scleroderma

Important dates

Study start
2016
Primary completion
2016
Study completion
2019
First posted
Aug 21, 2015
Registry last updated
Apr 5, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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