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

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02530996

Acronym

Scleroderma

Enrollment

Registered

2015-08-21

Start date

2016-01-01

Completion date

2019-12-31

Last updated

2021-04-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Rheumatologic Disease

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.

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.

Interventions

DRUGBH4

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

DIAGNOSTIC_TESTVasculopathy assessment

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

DRUGPlacebo

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 design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

BASIC_SCIENCE

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

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

Intervention 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.

Eligibility

Sex/Gender

ALL

Age

18 Years to 95 Years

Healthy volunteers

Yes

Inclusion criteria

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

Exclusion criteria

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

Design outcomes

Primary

Measure	Time frame	Description
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.	—
Flow Mediated Dilatation (FMD)-Diameter of Artery	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	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.	—

Secondary

Measure	Time frame	Description
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.	FRAP (higher better). FRAP assessed using the method described by Benzie and Strain.
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.	SOD (higher better). SOD assessed by Cayman Chemical Company, Ann Arbor, MI.
Oxidative Stress Measurement- C-reactive Protein (CRP)	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.	CRP (lower better). CRP assessed by R&D Systems, Minneapolis, MN.
Oxidative Stress Measurement- Tumor Necrosis Factor Alpha (TNF-α,	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.	TNF-α (lower better), assessed by R&D Systems, Minneapolis, MN.
Oxidative Stress Measurement- Interleukin 6 (IL-6)	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.	IL-6 (lower better), assessed by R&D Systems, Minneapolis, MN.
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.	MDA (lower better). Plasma malondialdehyde assessed by Oxis Research/Percipio Bioscience, Foster City, CA.
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.	CAT (higher better) assessed by Cayman Chemical Company, Ann Arbor, MI.
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.	Protein carbonyl (lower better). Plasma protein carbonyl levels assessed by Northwest Life Science Specialties, LLC Vancouver, WA.

Countries

United States

Participant flow

Recruitment details

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.

Pre-assignment details

While 32 participants were intended, this study was concluded after 12 participants due to budgetary restrictions.

Participants by arm

Arm	Count
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.	12
Total	12

Arm

Count

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.

Total

Baseline characteristics

Characteristic	12 SSc Patients Received BH4 and Placebo
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	0 Participants
Age, Categorical Between 18 and 65 years	12 Participants
Age, Continuous	62 years
Race/Ethnicity, Customized Hispanic or Latino	1 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	11 Participants
Race/Ethnicity, Customized Unknown	0 Participants
Region of Enrollment United States	12 Participants
Sex: Female, Male Female	9 Participants
Sex: Female, Male Male	3 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 12	0 / 12
other Total, other adverse events	0 / 12	0 / 12
serious Total, serious adverse events	0 / 12	0 / 12

Outcome results

Primary

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.

Arm	Measure	Value (MEAN)	Dispersion
12 SSc Participants With Placebo	Flow Mediated Dilatation-blood Flow	32 ml/min	Standard Error 7
12 Participants With BH4	Flow Mediated Dilatation-blood Flow	30 ml/min	Standard Error 3

Primary

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.

Population: 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.

Arm	Measure	Value (MEAN)	Dispersion
12 SSc Participants With Placebo	Flow Mediated Dilatation- Blood Velocity	4.4 cm/sec	Standard Error 0.6
12 Participants With BH4	Flow Mediated Dilatation- Blood Velocity	4.5 cm/sec	Standard Error 0.4

Primary

Flow Mediated Dilatation (FMD)-Diameter of Artery

FMD diameter of artery (mm, higher better)

Time frame: FMD was obtained on a single day at two different time points (after placebo and intervention) after a 5 day washout period.

Arm	Measure	Value (MEAN)	Dispersion
12 SSc Participants With Placebo	Flow Mediated Dilatation (FMD)-Diameter of Artery	3.79 mm	Standard Error 0.2
12 Participants With BH4	Flow Mediated Dilatation (FMD)-Diameter of Artery	3.78 mm	Standard Error 0.21

Primary

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.

Population: 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.

Arm	Measure	Value (MEAN)	Dispersion
12 SSc Participants With Placebo	Flow Mediated Dilatation-shear Rate	95 sec^-1	Standard Error 12
12 Participants With BH4	Flow Mediated Dilatation-shear Rate	100 sec^-1	Standard Error 13

Comparison: Statistics were performed using SPSS software (IBM, Chicago, IL). Paired t-tests were used to identify significant changes in measured variables between placebo and BH4. Unpaired t-tests were used to identify significant changes in measured variables between ordered groups. Based on data published in PMID: 25511849 power calculations for this study of SSc patients were made.p-value: <0.05t-test, 2 sided

Secondary