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

Phase 1

Completed

• Conditions: Rheumatologic Disease
• Interventions: Drug: BH4; Diagnostic Test: Vasculopathy assessment; Drug: Placebo

• Registration Number: NCT02530996
• Lead Sponsor: VA Office of Research and Development

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.

Study Timeline

• Study First Submitted: 2015-07-29
• Study First Submitted QC: 2015-08-19
• Study First Posted: 2015-08-21
• Study Start: 2016-01-01
• Primary Completion: 2016-06-01
• Study Completion: 2019-12-31
• Results First Submitted: 2021-02-18
• Status Verified: 2021-04
• Results First Submitted QC: 2021-04-01
• Last Update Submitted: 2021-04-01
• Results First Posted: 2021-04-05
• Last Update Posted: 2021-04-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 12

Inclusion Criteria

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

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Exclusion Criteria

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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo before BH4	BH4	Six SSc received oral placebo 10 mg/kg and had flow mediated dilatation measured. After a five day washout they crossed over to oral BH4 10 mg/kg and had flow mediated dilatation measured. Blood samples were obtained from these SSc patients and assessed for oxidative stress.
Placebo before BH4	Vasculopathy assessment	Six SSc received oral placebo 10 mg/kg and had flow mediated dilatation measured. After a five day washout they crossed over to oral BH4 10 mg/kg and had flow mediated dilatation measured. Blood samples were obtained from these SSc patients and assessed for oxidative stress.
Placebo before BH4	Placebo	Six SSc received oral placebo 10 mg/kg and had flow mediated dilatation measured. After a five day washout they crossed over to oral BH4 10 mg/kg and had flow mediated dilatation measured. Blood samples were obtained from these SSc patients and assessed for oxidative stress.
BH4 before Placebo	BH4	Six SSc received oral BH4 10 mg/kg and had flow mediated dilatation measured. After a five day washout they crossed over to oral placebo 10 mg/kg and had flow mediated dilatation measured. Blood samples were obtained from these SSc patients and assessed for oxidative stress.
BH4 before Placebo	Vasculopathy assessment	Six SSc received oral BH4 10 mg/kg and had flow mediated dilatation measured. After a five day washout they crossed over to oral placebo 10 mg/kg and had flow mediated dilatation measured. Blood samples were obtained from these SSc patients and assessed for oxidative stress.
BH4 before Placebo	Placebo	Six SSc received oral BH4 10 mg/kg and had flow mediated dilatation measured. After a five day washout they crossed over to oral placebo 10 mg/kg and had flow mediated dilatation measured. Blood samples were obtained from these SSc patients and assessed for oxidative stress.

Primary Outcome Measures

Name	Time	Method
Flow Mediated Dilatation (FMD)-Diameter of Artery	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)
Flow Mediated Dilatation-shear Rate	FMD was obtained on a single day at two different time points (after placebo and intervention) after a 5 day wash out period.
Flow Mediated Dilatation- Blood Velocity	FMD was obtained on a single day at two different time points (after placebo and intervention) after a 5 day wash out period.
Flow Mediated Dilatation-blood Flow	FMD was obtained on a single day at two different time points (after placebo and intervention) after a 5 day wash out period.

Secondary Outcome Measures

Name	Time	Method
Oxidative Stress Measurement- Ferric Reducing Ability of Plasma (FRAP)	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.
Oxidative Stress Measurement- Superoxide Dismutase (SOD)	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.
Oxidative Stress Measurement- Interleukin 6 (IL-6)	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.
Oxidative Stress Measurement- Tumor Necrosis Factor Alpha (TNF-α,	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.
Oxidative Stress Measurement- C-reactive Protein (CRP)	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.
Oxidative Stress Measurement-MDA: Malondialdehyde	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.
Oxidative Stress Measurement-catalase (CAT)	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.
Oxidative Stress Measurement- Protein Carbonyl	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.

Trial Locations

Locations (1)

VA Salt Lake City Health Care System, Salt Lake City, UT; 🇺🇸 Salt Lake City, Utah, United States