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

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ClinicalTrials.gov Identifier: NCT02530996
Recruitment Status : Recruiting
First Posted : August 21, 2015
Last Update Posted : July 16, 2018
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment
Rheumatologic Disease Drug: BH4 Other: Vasculopathy assessment Drug: Placebo

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 will examine if BH4 is effective in ameliorating vascular dysfunction in patients with SSc. The third aim will 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 Type : Observational [Patient Registry]
Estimated Enrollment : 32 participants
Observational Model: Case-Only
Time Perspective: Prospective
Target Follow-Up Duration: 36 Months
Official Title: Systemic Sclerosis (SSc) Vasculopathy: Improved Clinical Monitoring and Treatment
Actual Study Start Date : May 1, 2015
Estimated Primary Completion Date : May 1, 2019
Estimated Study Completion Date : May 1, 2019

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
200
Telehealth outreach for Veterans and routine clinic visits
Other: Vasculopathy assessment
Non-invasive technique, flow mediated dilatation (FMD) to define vasculopathy in SSc.

Drug: Placebo
This will be given to a total of total of 32 SSc patients (16 complicated, 16 uncomplicated)

32
SSc receive BH4 intervention (blinded)
Drug: BH4
BH4 is between 5-20 mg/kg/day given to a total of 32 SSc patients (16 complicated, 16 uncomplicated)

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




Primary Outcome Measures :
  1. FMD variables: resting brachial artery diameter, resting forearm blood flow, reactive hyperemia, sheer rate. [ Time Frame: 3 years ]

    Validate a non-invasive vascular measurement technique (FMD) through evaluation of vasculopathy in patients with SSc and predict end-stage vasculopathy development (i.e., DU, PAH, and/or SRC), in patients with SSc without previous complications.

    Routine health assessments and patient reported outcomes (PRO) will be captured and FMD testing will be performed at baseline and at 6 mo intervals during clinic visits. The pilot data suggests FMD may predict patients at risk for DU. The goal is to use the predictive value of FMD to understand the development of SSc vasculopathy complications. The impact of this research will address the current challenge in clinical practice of monitoring and targeting SSc vasculopathy.



Secondary Outcome Measures :
  1. Vascular smooth muscle reactivity (endothelial independent dilation, EID) [ Time Frame: 3 years ]
    16 SSc patients with clinical complications (any or all DU, PAH, SRC) and 16 SSc patients without clinical complications (including SSc patients with a history of DU that have been without a DU for at least 1 month) will be recruited by Dr. Frech from VISN 19 (currently 43 active patients) and be randomly assigned oral BH4 or placebo for 5 consecutive days in a double-blind randomized crossover design. Patients will remain on existing standard of care treatments such as calcium channel blockers, endothelin antagonists, phosphodiesterase inhibitors and/or prostacyclin analogs.

  2. Tissue ischemia by Near Infrared Spectroscopy (NIRS): [ Time Frame: 3 years ]
    16 SSc patients with clinical complications (any or all DU, PAH, SRC) and 16 SSc patients without clinical complications (including SSc patients with a history of DU that have been without a DU for at least 1 month) will be recruited by Dr. Frech from VISN 19 (currently 43 active patients) and be randomly assigned oral BH4 or placebo for 5 consecutive days in a double-blind randomized crossover design. Patients will remain on existing standard of care treatments such as calcium channel blockers, endothelin antagonists, phosphodiesterase inhibitors and/or prostacyclin analogs.


Other Outcome Measures:
  1. Blood flow; Vmeanpi=(arterial diameter/2)squaredx60 [ Time Frame: 3 years ]
    As part as FMD measurement, blood flow will be determined. See Primary outcome description.

  2. Shear rate; (s 1)=8Vmean/arterial [ Time Frame: 3 years ]
    As part as FMD measurement, blood flow will be determined. See Primary outcome description.


Biospecimen Retention:   Samples With DNA
  1. Plasma BH4 and BH2 levels
  2. NO measurements.
  3. Two 3 mm punch skin biopsies and skin resistance artery collection.
  4. Spin trapping and electron paramagnetic resonance (EPR) spectroscopy in skin resistance arteries.
  5. Oxidant and antioxidant gene expression in skin arterioles and whole blood.
  6. Oxidative stress and antioxidant activity in whole blood and plasma.
  7. Spin trapping and EPR spectroscopy in whole blood.


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 95 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
SSc patients will be recruited by Dr. Frech from both the University of Utah SSc Clinic and VISN 19 to complete Specific Aim 1 then referred to VA for 40212 BH4 consent and randomization.
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02530996


Contacts
Contact: Martha Finco, MS (801) 585-6468 Martha.finco@va.gov

Locations
United States, Utah
VA Salt Lake City Health Care System, Salt Lake City, UT Recruiting
Salt Lake City, Utah, United States, 84148
Contact: Martha Finco, MS    801-585-6468    Martha.finco@va.gov   
Principal Investigator: Tracy M. Frech, MD MS         
Sponsors and Collaborators
VA Office of Research and Development
Investigators
Principal Investigator: Tracy M. Frech, MD MS VA Salt Lake City Health Care System, Salt Lake City, UT

Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT02530996     History of Changes
Other Study ID Numbers: IMMA-006-14F
First Posted: August 21, 2015    Key Record Dates
Last Update Posted: July 16, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Scleroderma, Systemic
Scleroderma, Diffuse
Vascular Diseases
Connective Tissue Diseases
Skin Diseases
Cardiovascular Diseases