Scleroderma
Conditions
Keywords
early diffuse scleroderma, Raynaud
Brief summary
The purpose of this study is to learn about the effect atorvastatin on blood vessel function and Raynaud symptoms in patients with early diffuse systemic sclerosis. Systemic sclerosis is a disease characterized by blood vessel injury, immune system activation and fibrosis. Blood vessel injury is thought to be important early in the disease. Blood vessel complications of systemic sclerosis include Raynaud phenomena, finger and toe ulcers, and pulmonary hypertension. While atorvastatin reduces cholesterol, it is recognized to have many effects beyond cholesterol reduction. These include improvement of blood vessel function and reduction of fibrosis. We hypothesize that treatment with atorvastatin over 16 weeks will improve blood vessel function and Raynaud symptom in patients with early diffuse systemic sclerosis. We hope that by targeting therapy early in the disease we may delay blood vessel changes and improve Raynaud symptoms.
Detailed description
Systemic sclerosis (SSc) is a multisystem autoimmune illness characterized by vasculopathy, immune system activation and fibrosis of the skin and internal organs. SSc affects approximately 240 people per million in the US, but is a disease for which there is no FDA approved medication. Current hypothesis of pathogenesis suggest that a vascular injury with endothelial dysfunction may be an inciting event contributing to immunologic activation and fibrosis in the pathogenesis of the disease. More than 90% of individuals with SSc have vascular complications including Raynaud phenomenon, digital ulcers or gangrene and pulmonary hypertension; with microvascular abnormalities felt to contribute to Raynaud and digital ulcerations. Statin medications are well-recognized to have pleiotropic effects which may modify all three aspects of SSc pathogenesis. Early diagnosis and treatment of microvascular endothelial dysfunction and Raynaud phenomeonan may have the greatest effect in early disease. Thus, we hypothesize that treatment with atorvastatin in a well-defined cohort of early diffuse systemic sclerosis will produce beneficial results. Participants will be patients with early diffuse systemic sclerosis and Raynaud phenomenon who have no history of cardiovascular disease or diabetes. A total of 30 patients will be enrolled and followed for 16 weeks. Half the patients will be randomized to atorvastatin and half to placebo. Patients will be allowed to continue underlying immunosuppressive and Raynaud therapy at stable doses during the trial. Since this is a pilot study, future larger controlled trials will be necessary to clearly demonstrate drug effectiveness. Investigators are hoping that this study will give us signals to guide a future multicenter clinical trial.
Interventions
DRUGatorvastatin
Atorvastatin is an oral cholesterol-lowering medication commonly referred to as statin therapy.
DRUGPlacebo
oral drug of similar appearance to atorvastatin
Sponsors
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Robyn T. Domsic, MD, MPH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. early diffuse scleroderma (\< 3 years from the first scleroderma-related symptom) 2. Raynaud phenomenon 3. no use of lipid-lowering medication within 60 days
Exclusion criteria
1. pregnancy 2. renal or kidney dysfunction (creatinine \< 2.0 mg/dL or creatinine clearance \< 60 c/min) 3. diabetes mellitus 4. known cardiovascular disease or a prior history of stroke 5. history of liver disease 6. new or changed dose of calcium channel blockers (CCB) and angiotensin receptor blockers (ARBs) in the last 4 weeks 7. known allergy or adverse reaction to the atorvastatin or another statin drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Improving Their EndoPAT Reactive Hyperemia Index (RHI) at the End-of-study (16 Weeks) | Change in RHI from baseline to 16 weeks expressed as the percentage of patients who improve (respond). | EndoPAT is a proprietary device that assesses digital (microvascular) endothelial function during reactive hyperemia. A probe is placed on both index fingers. After 5 minutes of baseline observation, one arm is occluded for 5 minutes, while the other is not and serves as control. Output is the reactive hyperemia index (RHI), calculated as the post-to-pre occlusion signal ratio in the occluded side, normalized to the control side and further corrected for baseline vascular tone per Itamar Medical. There are no units. RHI ≤ 1.67 is abnormal and indicates endothelial dysfunction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Raynaud Condition Score (RCS) at 16 Weeks (End-of-study) From Baseline | change in RCS from baseline to week 16 | The Raynaud Condition Score is a patient-reported outcome of a single question regarding Raynaud severity. It is a visual analog scale with a results range of 0-100. A score of 0 us is no symptoms, and 100 severe symptoms. It is recommended by OMERACT for assessment of Raynaud phenomenon. |
| The Median Change in the Raynaud Phenomenon Visual Analog Scale (RP-VAS) Score at 16 Weeks (End-of-study) Compared to Baseline in the Atorvastatin and Placebo Groups. | baseline to 16 weeks | The RP-VAS scale measure ranges from 0-100, with 0 being no symptoms and 100 severe symptoms. Reported is the median and interquartile range of change between baseline and week 16 (end-of-study). |
| % of Patients Who Improved Their Brachial Flow-mediation Dilation (%FMD) at 16 Weeks | baseline to 16 weeks | %FMD = change in brachial artery flow-mediation dilation between pre and post-ischemia. Baseline (pre-ischemia) is the reference to which percentage change is calculated. Result is expressed as the % of patients who had an improvement in their %FMD at 16 weeks compared to baseline. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited at a single Scleroderma Center between March 2015 and August 2017.
Participants by arm
| Arm | Count |
|---|---|
| Atorvastatin 40 mg Daily Atorvastatin 40 mg daily x 16 weeks | 10 |
| Placebo Placebo daily x 16 weeks | 14 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Patient started prohibited medication | 0 | 1 |
Baseline characteristics
| Characteristic | Atorvastatin 40 mg Daily | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 50.0 years STANDARD_DEVIATION 13.9 | 55.7 years STANDARD_DEVIATION 5.3 | 53.3 years STANDARD_DEVIATION 10.7 |
| Brachial % flow mediated dilation (%FMD) | 11.3 % | 10.3 % | 10.3 % |
| Family history of early cardiovascular disease | 1 Participants | 1 Participants | 2 Participants |
| History of hyperlipidemia | 4 participants | 2 participants | 6 participants |
| History of hypertension | 1 Participants | 7 Participants | 8 Participants |
| Mean EndoPAT reactive hyperemia index (RHI) | 1.36 units STANDARD_DEVIATION 0.36 | 1.85 units STANDARD_DEVIATION 1.2 | 1.46 units STANDARD_DEVIATION 0.96 |
| mean modified Rodnan skin score | 18.9 points STANDARD_DEVIATION 9.6 | 22.8 points STANDARD_DEVIATION 8.9 | 21.3 points STANDARD_DEVIATION 9.2 |
| Obesity | 2 Participants | 6 Participants | 8 Participants |
| Race/Ethnicity, Customized African-American | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White, non-hispanic | 8 Participants | 13 Participants | 21 Participants |
| Raynaud condition score (median, IQR) | 5.0 units on a scale | 2.0 units on a scale | 2.5 units on a scale |
| Raynaud symptom severity assessed by visual analog scale | 4.0 units on a scale | 1.5 units on a scale | 2.3 units on a scale |
| Sex: Female, Male Female | 9 Participants | 10 Participants | 19 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 14 |
| other Total, other adverse events | 0 / 10 | 0 / 14 |
| serious Total, serious adverse events | 0 / 10 | 1 / 14 |
Outcome results
Primary
Proportion of Patients Improving Their EndoPAT Reactive Hyperemia Index (RHI) at the End-of-study (16 Weeks)
EndoPAT is a proprietary device that assesses digital (microvascular) endothelial function during reactive hyperemia. A probe is placed on both index fingers. After 5 minutes of baseline observation, one arm is occluded for 5 minutes, while the other is not and serves as control. Output is the reactive hyperemia index (RHI), calculated as the post-to-pre occlusion signal ratio in the occluded side, normalized to the control side and further corrected for baseline vascular tone per Itamar Medical. There are no units. RHI ≤ 1.67 is abnormal and indicates endothelial dysfunction.
Time frame: Change in RHI from baseline to 16 weeks expressed as the percentage of patients who improve (respond).
Population: The patient who did not complete the study had his data analyzed using last observation carried forward. Improvement was defined as an increase in the RHI from baseline to 16 weeks. Non-responders were defined as no change or worsening (decrease) in the RHI at 16 weeks. Results are expressed as a percentage
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Drug | Proportion of Patients Improving Their EndoPAT Reactive Hyperemia Index (RHI) at the End-of-study (16 Weeks) | 6 Participants |
| Placebo Control | Proportion of Patients Improving Their EndoPAT Reactive Hyperemia Index (RHI) at the End-of-study (16 Weeks) | 4 Participants |
Secondary
Change in the Raynaud Condition Score (RCS) at 16 Weeks (End-of-study) From Baseline
The Raynaud Condition Score is a patient-reported outcome of a single question regarding Raynaud severity. It is a visual analog scale with a results range of 0-100. A score of 0 us is no symptoms, and 100 severe symptoms. It is recommended by OMERACT for assessment of Raynaud phenomenon.
Time frame: change in RCS from baseline to week 16
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Drug | Change in the Raynaud Condition Score (RCS) at 16 Weeks (End-of-study) From Baseline | -2.0 score on a scale |
| Placebo Control | Change in the Raynaud Condition Score (RCS) at 16 Weeks (End-of-study) From Baseline | 0 score on a scale |
Secondary
% of Patients Who Improved Their Brachial Flow-mediation Dilation (%FMD) at 16 Weeks
%FMD = change in brachial artery flow-mediation dilation between pre and post-ischemia. Baseline (pre-ischemia) is the reference to which percentage change is calculated. Result is expressed as the % of patients who had an improvement in their %FMD at 16 weeks compared to baseline.
Time frame: baseline to 16 weeks
Population: For the patient with a SAE, data was treated as last observation carried forward
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Drug | % of Patients Who Improved Their Brachial Flow-mediation Dilation (%FMD) at 16 Weeks | 5 Participants |
| Placebo Control | % of Patients Who Improved Their Brachial Flow-mediation Dilation (%FMD) at 16 Weeks | 5 Participants |
Secondary
The Median Change in the Raynaud Phenomenon Visual Analog Scale (RP-VAS) Score at 16 Weeks (End-of-study) Compared to Baseline in the Atorvastatin and Placebo Groups.
The RP-VAS scale measure ranges from 0-100, with 0 being no symptoms and 100 severe symptoms. Reported is the median and interquartile range of change between baseline and week 16 (end-of-study).
Time frame: baseline to 16 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Drug | The Median Change in the Raynaud Phenomenon Visual Analog Scale (RP-VAS) Score at 16 Weeks (End-of-study) Compared to Baseline in the Atorvastatin and Placebo Groups. | 0.5 score on a scale |
| Placebo Control | The Median Change in the Raynaud Phenomenon Visual Analog Scale (RP-VAS) Score at 16 Weeks (End-of-study) Compared to Baseline in the Atorvastatin and Placebo Groups. | 0.0 score on a scale |