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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
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| 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| BH4 | Drug | BH4 10 mg/kg/day given once to a total of 12 SSc patients |
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| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Tracy M. Frech, MD MS | VA Salt Lake City Health Care System, Salt Lake City, UT | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| VA Salt Lake City Health Care System, Salt Lake City, UT | Salt Lake City | Utah | 84148 | United States |
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While 32 participants were intended, this study was concluded after 12 participants due to budgetary restrictions.
156 patients were enrolled and screened in IRB 38705 during the funding period 01/01/2016 - 12/31/2020 in SSc clinic, but only 12 participated in a controlled, counter-balanced, double-blind, crossover experimental design with two conditions, BH4 and placebo IRB 40212 in the Utah Vascular Research Laboratory at the Salt Lake VAMC.
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| ID | Title | Description |
|---|---|---|
| FG000 | 6 SSc Patients Received BH4 Then Placebo | Prior to January 18, 2017, 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. |
| FG001 | 6 SSc Patients Received Placebo Then BH4 | Prior to January 18, 2017, 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
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| First Intervention |
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| Washout (5 Days) |
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| Second Intervention |
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| ID | Title | Description |
|---|---|---|
| BG000 | 12 SSc Patients Received BH4 and Placebo | 12 SSc received BH4 intervention (blinded) and placebo in a cross-over design. Patients were studied 5 hours after oral BH4 administration (10 mg/kg body mass) or placebo on separate days using controlled, counterbalanced, double-blind, crossover experimental design Vasculopathy assessment: Non-invasive technique, flow mediated dilatation (FMD) to define vasculopathy in SSc. |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Flow Mediated Dilatation (FMD)-Diameter of Artery | FMD diameter of artery (mm, higher better) | Posted | Mean | Standard Error | mm | FMD was obtained on a single day at two different time points (after placebo and intervention) after a 5 day washout period. |
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Adverse event data was collected over 6 month for 12 patients that received BH4 and placebo.
Patients were assessed on day of intervention and at their follow-up care visits for any untoward or unfavorable medical occurrence, including any abnormal physical exam or laboratory finding, symptom, or disease, temporally associated with the participant's participation in the research. Patients were queried for hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 12 SSc Participants Placebo | 12 SSc participants were studied 5 hours after oral placebo administration (10 mg/kg body mass) |
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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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Tracy Frech | Salt Lake VAMC and University of Utah | 801 213 2312 | tracy.frech@hsc.utah.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol: 38705 SSc Registry Trial | Dec 15, 2020 | Mar 16, 2021 | Prot_000.pdf |
| Prot | Yes | No | No | Study Protocol: 40212 (12 patients) | Mar 1, 2015 | Mar 30, 2021 | Prot_001.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 19, 2016 | Feb 18, 2021 | SAP_002.pdf |
| ICF | No | No | Yes | Informed Consent Form: 38705 (156 patients) | Aug 16, 2020 | Feb 12, 2021 | ICF_003.pdf |
| ICF | No | No | Yes | Informed Consent Form: 40212 (12 patients) | May 1, 2015 | Mar 30, 2021 | ICF_004.pdf |
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| ID | Term |
|---|---|
| D003095 | Collagen Diseases |
| ID | Term |
|---|---|
| D003240 | Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
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| ID | Term |
|---|---|
| C003402 | sapropterin |
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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.
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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
| Vasculopathy assessment | Diagnostic Test | Non-invasive technique, flow mediated dilatation (FMD) to define vasculopathy in SSc. |
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| 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. |
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| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| Oxidative Stress Measurement- Tumor Necrosis Factor Alpha (TNF-α, | TNF-α (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. |
| 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. |
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| Participants |
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| Age, Continuous | Median | Inter-Quartile Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| Primary | Flow Mediated Dilatation-shear Rate | Twelve patients with SSc had FMD parameters quantified after cuff at baseline, after placebo, and after BH4. FMD is expressed as a percent increase in diameter from baseline. | Posted | Mean | Standard Error | sec^-1 | FMD was obtained on a single day at two different time points (after placebo and intervention) after a 5 day wash out period. |
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| Primary | Flow Mediated Dilatation- Blood Velocity | Twelve patients with SSc had FMD parameters quantified after cuff at baseline, after placebo, and after BH4. FMD is expressed as a percent increase in diameter from baseline. | Posted | Mean | Standard Error | cm/sec | FMD was obtained on a single day at two different time points (after placebo and intervention) after a 5 day wash out period. |
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| Primary | Flow Mediated Dilatation-blood Flow | Posted | Mean | Standard Error | ml/min | FMD was obtained on a single day at two different time points (after placebo and intervention) after a 5 day wash out period. |
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| Secondary | Oxidative Stress Measurement-MDA: Malondialdehyde | MDA (lower better). Plasma malondialdehyde assessed by Oxis Research/Percipio Bioscience, Foster City, CA. | Posted | Mean | Standard Error | uM | 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. |
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| Secondary | Oxidative Stress Measurement-catalase (CAT) | CAT (higher better) assessed by Cayman Chemical Company, Ann Arbor, MI. | Posted | Mean | Standard Error | nM/min/mL | 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. |
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| Secondary | Oxidative Stress Measurement- Protein Carbonyl | Protein carbonyl (lower better). Plasma protein carbonyl levels assessed by Northwest Life Science Specialties, LLC Vancouver, WA. | Posted | Mean | Standard Error | nM/mg | 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. |
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| Secondary | Oxidative Stress Measurement- Ferric Reducing Ability of Plasma (FRAP) | FRAP (higher better). FRAP assessed using the method described by Benzie and Strain. | Posted | Mean | Standard Error | nM/L | 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. |
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| Secondary | Oxidative Stress Measurement- Superoxide Dismutase (SOD) | SOD (higher better). SOD assessed by Cayman Chemical Company, Ann Arbor, MI. | Posted | Mean | Standard Error | U/mL | 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. |
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| Secondary | Oxidative Stress Measurement- Interleukin 6 (IL-6) | IL-6 (lower better), assessed by R&D Systems, Minneapolis, MN. | Posted | Mean | Standard Error | pg/mL | 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. |
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| Secondary | Oxidative Stress Measurement- Tumor Necrosis Factor Alpha (TNF-α, | TNF-α (lower better), assessed by R&D Systems, Minneapolis, MN. | Posted | Mean | Standard Error | pg/mL | 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. |
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| Secondary | Oxidative Stress Measurement- C-reactive Protein (CRP) | CRP (lower better). CRP assessed by R&D Systems, Minneapolis, MN. | Posted | Mean | Standard Error | mg/L | 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. |
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| 0 |
| 12 |
| 0 |
| 12 |
| 0 |
| 12 |
| EG001 | 12 SSc Participants BH4 | 12 SSc participants were studied 5 hours after oral BH4 administration (10 mg/kg body mass) | 0 | 12 | 0 | 12 | 0 | 12 |
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