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

NCT02530996 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: IMMA-006-14F
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

Rheumatologic Disease

Outcome Measures

Primary Outcomes (4)

• 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.

• 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 Outcomes (8)

• 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.

• 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.

• 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.

• 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.

• 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.

Study Arms (2)

Placebo before BH4

EXPERIMENTAL

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.

Drug: BH4; Diagnostic Test: Vasculopathy assessment; Drug: Placebo

BH4 before Placebo

EXPERIMENTAL

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.

Drug: BH4; Diagnostic Test: Vasculopathy assessment; Drug: Placebo

Interventions

BH4 DRUG

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

Also known as: Kuvan

BH4 before Placebo; Placebo before BH4

Vasculopathy assessment DIAGNOSTIC_TEST

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

Also known as: Kuvan

BH4 before Placebo; Placebo before BH4

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.

Also known as: Placebo from IDS

BH4 before Placebo; Placebo before BH4

Eligibility Criteria

• Age: 18 Years - 95 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

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

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (1)

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

Salt Lake City, Utah, 84148, United States

Location

MeSH Terms

Conditions

Collagen Diseases

Interventions

sapropterin

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases

Limitations and Caveats

This trial was initially intended to include 32 patients with SSc with and without clinical complications of SSc randomly assigned oral BH4 or placebo for 5 consecutive days in a double-blind randomized crossover design. Due to budget constraints, we adapted the design to studying 12 patients, 5 hours after oral BH4 administration (10 mg/kg body weight) or placebo on separate days using controlled, counterbalanced, double-blind, crossover experimental design and a five day wash-out period.

Results Point of Contact

• Title: Dr. Tracy Frech
• Organization: Salt Lake VAMC and University of Utah

tracy.frech@hsc.utah.edu

801 213 2312

Study Officials

• Tracy M. Frech, MD MS

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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Drug was dispensed by the investigational drug services. A controlled, counter-balanced, double-blind, crossover experimental design with two conditions, BH4 and placebo, was employed. There was a washout period of at least 5 days before crossing over into the alternate condition. On
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: July 29, 2015
• First Posted: August 21, 2015
• Study Start: January 1, 2016
• Primary Completion: June 1, 2016
• Study Completion: December 31, 2019
• Last Updated: April 5, 2021
• Results First Posted: April 5, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)