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

Rheumatologic Disease Clinical Trial

— Scleroderma  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02530996
• Other study ID #: IMMA-006-14F
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: January 1, 2016
• Est. completion date: December 31, 2019

Study information

• Verified date: April 2021
• Source: VA Office of Research and Development
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: December 31, 2019
• Est. primary completion date: June 1, 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 95 Years

Eligibility

Inclusion Criteria:

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

Exclusion Criteria:

• Age < 18

• Pregnant or breast feeding

• Unwillingness to consent

Related Conditions & MeSH terms

• Rheumatologic Disease
• Scleroderma, Diffuse
• Scleroderma, Systemic

Intervention

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

Diagnostic Test:
• Vasculopathy assessment
Non-invasive technique, flow mediated dilatation (FMD) to define vasculopathy in SSc.

Drug:
• Placebo
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.

Locations

Country	Name	City	State
United States	VA Salt Lake City Health Care System, Salt Lake City, UT	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
VA Office of Research and Development

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Flow Mediated Dilatation (FMD)-Diameter of Artery	FMD diameter of artery (mm, higher better)	FMD was obtained on a single day at two different time points (after placebo and intervention) after a 5 day washout period.
Primary	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.
Primary	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.
Primary	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	Oxidative Stress Measurement-MDA: Malondialdehyde	MDA (lower better). Plasma malondialdehyde assessed by Oxis Research/Percipio Bioscience, Foster City, CA.	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.
Secondary	Oxidative Stress Measurement-catalase (CAT)	CAT (higher better) assessed by Cayman Chemical Company, Ann Arbor, MI.	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.
Secondary	Oxidative Stress Measurement- Protein Carbonyl	Protein carbonyl (lower better). Plasma protein carbonyl levels assessed by Northwest Life Science Specialties, LLC Vancouver, WA.	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.
Secondary	Oxidative Stress Measurement- Ferric Reducing Ability of Plasma (FRAP)	FRAP (higher better). FRAP assessed using the method described by Benzie and Strain.	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.
Secondary	Oxidative Stress Measurement- Superoxide Dismutase (SOD)	SOD (higher better). SOD assessed by Cayman Chemical Company, Ann Arbor, MI.	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.
Secondary	Oxidative Stress Measurement- Interleukin 6 (IL-6)	IL-6 (lower better), assessed by R&D Systems, Minneapolis, MN.	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.
Secondary	Oxidative Stress Measurement- Tumor Necrosis Factor Alpha (TNF-a,	TNF-a (lower better), assessed by R&D Systems, Minneapolis, MN.	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.
Secondary	Oxidative Stress Measurement- C-reactive Protein (CRP)	CRP (lower better). CRP assessed by R&D Systems, Minneapolis, MN.	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.