Atorvastatin for Microvascular Endothelial Function and Raynaud in Early Diffuse Scleroderma

Study Overview
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Brief Summary
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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
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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.

Official Title
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The Effect of Atorvastatin on Microvascular Endothelial Function and Raynaud in Early Diffuse Systemic Sclerosis

Conditions
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Scleroderma

Intervention / Treatment
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* Drug: atorvastatin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: early diffuse scleroderma (< 3 years from the first scleroderma-related symptom) Raynaud phenomenon no use of lipid-lowering medication within 60 days Exclusion Criteria: pregnancy renal or kidney dysfunction (creatinine < 2.0 mg/dL or creatinine clearance < 60 c/min) diabetes mellitus known cardiovascular disease or a prior history of stroke history of liver disease new or changed dose of calcium channel blockers (CCB) and angiotensin receptor blockers (ARBs) in the last 4 weeks known allergy or adverse reaction to the atorvastatin or another statin drug

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Drug<br>atorvastatin 40 mg once daily for sixteen weeks | Drug: atorvastatin<br>* Atorvastatin is an oral cholesterol-lowering medication commonly referred to as statin therapy.<br>* Other names: Lipitor;|
| Placebo Comparator: Placebo control<br>receive a placebo of similar appearance once daily for sixteen weeks | Drug: Placebo<br>* oral drug of similar appearance to atorvastatin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Change in RHI from baseline to 16 weeks expressed as the percentage of patients who improve (respond). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | change in RCS from baseline to week 16 | 
| 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). | baseline to 16 weeks | 
| % 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. | baseline to 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Raynaud, early diffuse scleroderma