Rheumatologic DiseasePhase 1/2SclerodermaNCT02530996
Systemic Sclerosis (SSc) Vasculopathy: Improved Clinical Monitoring and Treatment
A Phase 1/2 study testing BH4 and Vasculopathy assessment in people with Rheumatologic Disease, run by VA Office of Research and Development at 1 site in United States.
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. Read more about this study
- Who is it for?
- Ages 18 to 95 yearsHealthy volunteers can take part
- Conditions the study is for
- Rheumatologic Disease
- What is being tested?
- BH4 and Vasculopathy assessment
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Jan 2016to 31 Dec 2019
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 95 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Diagnosis of systemic sclerosis (SSc, scleroderma) by ACR/EULAR 2013 criteria.
Who cannot join
- Age < 18
- Pregnant or breast feeding
- Unwillingness to consent
Trial locations and contacts
1 site in 1 country.
United States1 site
VA Salt Lake City Health Care System, Salt Lake City, UT
Salt Lake City, Utah, 84148
About this study
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.
Read the 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.
- Conditions
- Rheumatologic Disease
- Being tested
- BH4, Vasculopathy assessment, Placebo
- Medical subject headings
- Collagen Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BH4Drug
Also called Kuvan
BH4 10 mg/kg/day given once to a total of 12 SSc patients
Vasculopathy assessmentDiagnostic test
Also called Kuvan
Non-invasive technique, flow mediated dilatation (FMD) to define vasculopathy in SSc.
PlaceboDrug
Also called Placebo from IDS
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: BH4; Diagnostic Test: Vasculopathy assessment; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Flow Mediated Dilatation (FMD)-Diameter of Artery
FMD diameter of artery (mm, higher better)
Measured: 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
Measured: 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
Measured: 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
Measured: 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
MDA (lower better). Plasma malondialdehyde assessed by Oxis Research/Percipio Bioscience, Foster City, CA.
Measured: 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)
CAT (higher better) assessed by Cayman Chemical Company, Ann Arbor, MI.
Measured: 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
Protein carbonyl (lower better). Plasma protein carbonyl levels assessed by Northwest Life Science Specialties, LLC Vancouver, WA.
Measured: 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)
FRAP (higher better). FRAP assessed using the method described by Benzie and Strain.
Measured: 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)
SOD (higher better). SOD assessed by Cayman Chemical Company, Ann Arbor, MI.
Measured: 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- Interleukin 6 (IL-6)
IL-6 (lower better), assessed by R\&D Systems, Minneapolis, MN.
Measured: 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- Tumor Necrosis Factor Alpha (TNF-α,
TNF-α (lower better), assessed by R\&D Systems, Minneapolis, MN.
Measured: 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- C-reactive Protein (CRP)
CRP (lower better). CRP assessed by R\&D Systems, Minneapolis, MN.
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Aug 2015 (estimated)
- Study start1 Jan 2016
- Primary completion1 Jun 2016
- Study completion31 Dec 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Rheumatologic DiseaseStudies of the same condition, open and under way.
- More trials run by VA Office of Research and DevelopmentThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- 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.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Responsible party
- Sponsor
- Investigators
- Tracy M. Frech, MD MS, Principal investigator, VA Salt Lake City Health Care System, Salt Lake City, UT
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02530996
- Sponsor's protocol ID
- IMMA-006-14F
- Acronym
- Scleroderma
- Status last verified
- Apr 2021
- First submitted
- 29 Jul 2015
- Last updated
- 5 Apr 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 5 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Systemic Sclerosis (SSc) Vasculopathy: Improved Clinical Monitoring and Treatment
- ClinicalTrials.gov ID
- NCT02530996
- Acronym / sponsor ID
- Scleroderma / IMMA-006-14F
- Conditions
- Rheumatologic Disease
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- VA Office of Research and DevelopmentUS federal agency
- Study start
- 1 Jan 2016 (actual)
- Primary completion
- 1 Jun 2016 (actual)
- Study completion
- 31 Dec 2019 (actual)
- First posted
- 21 Aug 2015 (estimated)
- Results
- Posted 5 Apr 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Placebo before BH4 | Experimental | Drug: BH4, Diagnostic Test: Vasculopathy assessment, Drug: PlaceboSix 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 | Experimental | Drug: BH4, Diagnostic Test: Vasculopathy assessment, Drug: PlaceboSix 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. |
Who may qualify
- Ages
- 18 to 95 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Diagnosis of systemic sclerosis (SSc, scleroderma) by ACR/EULAR 2013 criteria.
Key exclusion criteria (3 listed)
- Age < 18
- Pregnant or breast feeding
- Unwillingness to consent
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BH4Also: KuvanBH4 10 mg/kg/day given once to a total of 12 SSc patients | Drug | BH4 before Placebo, Placebo before BH4 |
| Vasculopathy assessmentAlso: KuvanNon-invasive technique, flow mediated dilatation (FMD) to define vasculopathy in SSc. | Diagnostic test | BH4 before Placebo, Placebo before BH4 |
| PlaceboAlso: Placebo from IDSOn 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. | Drug | BH4 before Placebo, Placebo before BH4 |
Primary outcome
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)
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.
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.
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.
8 secondary outcomes
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.
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.
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.
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.
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.
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.
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.
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Apr 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Tracy M. Frech, MD MS principal investigator
VA Salt Lake City Health Care System, Salt Lake City, UT
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing BH4 and Vasculopathy assessment in people with Rheumatologic Disease, run by VA Office of Research and Development at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 5 Apr 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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.). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Apr 2021.