TAMER: Atorvastatin for Microvascular Endothelial Function and Raynaud in Early Diffuse Scleroderma

• Sponsor: Robyn T. Domsic, MD, MPH (Other)
• Overall Status: Completed
• CT.gov ID: NCT02370784
• Collaborator: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (NIH)
• Enrollment: 24
• Location: 1
• Arms: 2
• Duration (Months): 58.4
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Scleroderma	Drug: atorvastatin; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Effect of Atorvastatin on Microvascular Endothelial Function and Raynaud in Early Diffuse Systemic Sclerosis
• Study Start Date: Feb 1, 2015
• Actual Primary Completion Date: Dec 15, 2018
• Actual Study Completion Date: Dec 15, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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).

3. % 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15261

Sponsors and Collaborators

• Robyn T. Domsic, MD, MPH
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 13, 2015

More Information

Publications

None provided.

• Responsible Party: Robyn T. Domsic, MD, MPH, MD, MPH, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT02370784
• Other Study ID Numbers: PRO14010170; 1R21AR066305-01A1
• First Posted: Feb 25, 2015
• Last Update Posted: Aug 12, 2020
• Last Verified: Aug 1, 2020

• Keywords provided by Robyn T. Domsic, MD, MPH, MD, MPH, University of Pittsburgh: early diffuse scleroderma; Raynaud
• Additional relevant MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse; Atorvastatin

Study Results

Participant Flow

Recruitment Details	Patients were recruited at a single Scleroderma Center between March 2015 and August 2017.

Arm/Group Title	Atorvastatin 40 mg Daily	Placebo Control
Arm/Group Description	Length of intervention: 16 weeks atorvastatin: Atorvastatin is an oral cholesterol-lowering medication commonly referred to as statin therapy.	Placebo: oral drug of similar appearance to atorvastatin
Period Title: Overall Study
STARTED	10	14
COMPLETED	10	13
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Atorvastatin 40 mg Daily	Placebo	Total
Arm/Group Description	Atorvastatin 40 mg daily x 16 weeks	Placebo daily x 16 weeks	Total of all reporting groups
Overall Participants	10	14	24
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.0 (13.9)	55.7 (5.3)	53.3 (10.7)
Sex: Female, Male (Count of Participants)
Female	9 90%	10 71.4%	19 79.2%
Male	1 10%	4 28.6%	5 20.8%
Race/Ethnicity, Customized (Count of Participants)
White, non-hispanic	8 80%	13 92.9%	21 87.5%
African-American	1 10%	1 7.1%	2 8.3%
Asian	1 10%	0 0%	1 4.2%
History of hyperlipidemia (participants) [Number]
Number [participants]	4 40%	2 14.3%	6 25%
History of hypertension (Count of Participants)
Count of Participants [Participants]	1 10%	7 50%	8 33.3%
Obesity (Count of Participants)
Count of Participants [Participants]	2 20%	6 42.9%	8 33.3%
Family history of early cardiovascular disease (Count of Participants)
Count of Participants [Participants]	1 10%	1 7.1%	2 8.3%
mean modified Rodnan skin score (points) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [points]	18.9 (9.6)	22.8 (8.9)	21.3 (9.2)
Mean EndoPAT reactive hyperemia index (RHI) (units) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units]	1.36 (0.36)	1.85 (1.20)	1.46 (0.96)
Raynaud condition score (median, IQR) (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	5.0	2.0	2.5
Raynaud symptom severity assessed by visual analog scale (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	4.0	1.5	2.3
Brachial % flow mediated dilation (%FMD) (%) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [%]	11.3	10.3	10.3

Outcome Measures

1. Primary Outcome

Title	Proportion of Patients Improving Their EndoPAT Reactive Hyperemia Index (RHI) at the End-of-study (16 Weeks)
Description	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).

Outcome Measure Data

Analysis Population Description

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/Group Title	Active Drug	Placebo Control
Arm/Group Description	atorvastatin 40 mg once daily for sixteen weeks atorvastatin: Atorvastatin is an oral cholesterol-lowering medication commonly referred to as statin therapy.	receive a placebo of similar appearance once daily for sixteen weeks Placebo: oral drug of similar appearance to atorvastatin
Measure Participants	10	14
Count of Participants [Participants]	6 60%	4 28.6%

2. Secondary Outcome

Title	Change in the Raynaud Condition Score (RCS) at 16 Weeks (End-of-study) From Baseline
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Drug	Placebo Control
Arm/Group Description	atorvastatin 40 mg once daily for sixteen weeks atorvastatin: Atorvastatin is an oral cholesterol-lowering medication commonly referred to as statin therapy.	receive a placebo of similar appearance once daily for sixteen weeks Placebo: oral drug of similar appearance to atorvastatin
Measure Participants	10	14
Median (Inter-Quartile Range) [score on a scale]	-2.0	0

3. Secondary Outcome

Title	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.
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Drug	Placebo Control
Arm/Group Description	atorvastatin 40 mg once daily for sixteen weeks atorvastatin: Atorvastatin is an oral cholesterol-lowering medication commonly referred to as statin therapy.	receive a placebo of similar appearance once daily for sixteen weeks Placebo: oral drug of similar appearance to atorvastatin
Measure Participants	10	14
Median (Inter-Quartile Range) [score on a scale]	0.5	0.0

4. Secondary Outcome

Title	% of Patients Who Improved Their Brachial Flow-mediation Dilation (%FMD) at 16 Weeks
Description	%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

Outcome Measure Data

Analysis Population Description

For the patient with a SAE, data was treated as last observation carried forward

Arm/Group Title	Atorvastatin 40 mg Daily	Placebo
Arm/Group Description	Atorvastatin 40 mg daily x 16 weeks	Placebo daily x 16 weeks
Measure Participants	10	14
Count of Participants [Participants]	5 50%	5 35.7%

Adverse Events

Time Frame	16 weeks plus 30 days after the end of intervention
Arm/Group Title	Atorvastatin 40 mg Daily		Placebo Control
Arm/Group Description	Length of intervention: 16 weeks atorvastatin: Atorvastatin is an oral cholesterol-lowering medication commonly referred to as statin therapy.		Placebo: oral drug of similar appearance to atorvastatin
All Cause Mortality
	Atorvastatin 40 mg Daily		Placebo Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/14 (0%)
Serious Adverse Events
	Atorvastatin 40 mg Daily		Placebo Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		1/14 (7.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Esophageal cancer	0/10 (0%)	0	1/14 (7.1%)	1
Other (Not Including Serious) Adverse Events
	Atorvastatin 40 mg Daily		Placebo Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/14 (0%)

Limitations/Caveats

This was a single-centered trial, and underpowered, as only 24 were enrolled with an initial goal of 30. The groups were unbalanced for both the primary and secondary endpoint at baseline despite randomization.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.