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Rapamycin vs Methotrexate in Diffuse SSc

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00241189
Recruitment Status : Completed
First Posted : October 18, 2005
Last Update Posted : April 11, 2016
Information provided by (Responsible Party):
Philip Clements, University of California, Los Angeles

Brief Summary:
This is a study to determine the safety of the immunosuppressive rapamycin in patients with systemic sclerosis with diffuse cutaneous scleroderma. The effects (both good and bad) are being compared to another group of systemic sclerosis patients receiving methotrexate

Condition or disease Intervention/treatment Phase
Systemic Sclerosis Drug: rapamycin Drug: methotrexate Phase 1 Phase 2

Detailed Description:

Systemic sclerosis (SSc) is a disorder characterized by overproduction and deposition of collagen in the skin and visceral organs, abnormalities of the microcirculation, and autoimmunity. Patients who develop extensive skin thickening (diffuse cutaneous scleroderma) usually do so within the first 5 years. In add tion they are at significant risk of early death, severe involvement of heart (10%), lung (15%) and kidney (15-20%) and loss of functional capacity (moderate to severe disability in about 50% within the first few years). there is as yet no proven cure or treatment which prevents heart, lung or kidney damage, prevents disability or improves survival.

In a previsou study, we treated 10 SSc patients with diffuse cutaneous scleroerma with cyclosporin A (CsA), an agent which suppresses the immune response by reducing production of the pro-inflammatory cytokine, interleukin-2 (IL-2). Significant improvement in skin thickening was noted in 6 of the 10 SSc patients. Unfortuantely, significant reduction in kidney function and/or new onset high blood pressure occurred in 8 of the 10. This frequency and degree of adverse events ina population already at risk of kidney failure and high blood pressure is unacceptable.

More recently an immunosuppressive agent with little kidney toxicity, rapamycin, has been found to block the effects of the same pro-inflammatory cytokine as cyclosporin (IL-2) in transplant patients as part of its immunosuppressive action. Since improvement in skin thickening was seen in our patients who received CsA, we postulate that blocking the effects of IL-2 by rapamycin will also result in improvement in skin thickening in SSc patients with extensive skin thickening. There is growing evidence (from our work and the work of others) that softening thick skin in diffuse SSc is associated with improvement in hand function, joint mobility, arthritis signs, overall functional ability, and survival.

The effectiveness of another immunosuppressive, methotrexate, has been compared to placebo (a dummy) in two SSc studies that had a combined total of 100 patients with estensive skin thickening. In both studies there was a trend to greater softening of the thick scleroderma skin. In one study a greater sense of general well being was also noted in the methotrexate group and in the other study the physician global assessment improved to a greater extent in the methotrexate group. Because there is a suggestion of benefit from methotrexate, the present trial evaluating rapamycin is being compared to methotrexte. During a 48 week period rapamycin and methotrexate will be taken as randomly assigned (9 patients in each arm for a total of 18 patients). Over 48 weeks, the status of these patients' scleroderma will be assessed by simple but validated techniques, including simple palpation of the skin to assess skin thickness; lung function texts, electrocardiogram and chest x-ray to assess heart and lungp; blood pressure and serum creatinine to assess kidney; 3 questionnaires (completed by patients) to assess function, quality of life and shortness of breath; and CBC, chemistries and rapamycin levels to assess safety. Statistical analysis of the courses of the two treatment groups will help us determine whether rapamycin has excessive toxicity and whether there are suggestions of efficacy of rapamycin.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 17 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
Official Title: A 48-week, Double-blind, Randomized, Parallel Phase I/II Study of Oral Rapamycin Versus Methotrexate in Systemic Sclerosis (Scleroderma)
Study Start Date : August 2002
Actual Primary Completion Date : June 2006
Actual Study Completion Date : June 2006

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Scleroderma

Arm Intervention/treatment
Experimental: Rapamycin
Patients take oral rapamycin 6 mg daily (and dose adjusted to keep a serum trough level of 5-15 ng/ml) for one year
Drug: rapamycin
Other Name: rapimmune

Active Comparator: Methotrexate
Methotrexate 20 mg taken orally weekly for one year
Drug: methotrexate

Primary Outcome Measures :
  1. Adverse events
  2. Modified Rodnan Skin thickness score

Secondary Outcome Measures :
  1. Forced vital capacity
  2. Diffusing capacity (DLCO)
  3. Health Assessment Questionnaire-Disability Index
  4. Mahler Dyspnea Index
  5. Medical Outcomes Questionnaire SF-36
  6. Patient global (VAS)
  7. Physician global (VAS)
  8. % responders in skin score (=>35% decrease from baseline)
  9. % responders in HAQ-DI(=>0.22 units decrease from baseline)
  10. % responders in FVC (=>10% decrease from baseline)
  11. Serum rapamycin levels

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Satisfy American College of Rheumatology classification criteria for systemic sclerosis
  • Have skin thickening proximal to the elbows and/or knees (diffuse scleroderma)
  • Cutaneous involvement for less than 5 years from the onset of the first non-Raynaud's manifestation

Exclusion Criteria:

  • Severe intractable malabsorption
  • Chronic debilitation from any underlying disease
  • Off putative disease modifying therapies for one month prior to entry

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00241189

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United States, California
Philip Clements, MD
Los Angeles, California, United States, 90095-1670
Sponsors and Collaborators
University of California, Los Angeles
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Principal Investigator: Philip J Clements, MD, MPH University of California, Los Angeles
Publications of Results:
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Responsible Party: Philip Clements, MD, MPH, University of California, Los Angeles Identifier: NCT00241189    
Other Study ID Numbers: UCLA IRB Number: 01-10-045
First Posted: October 18, 2005    Key Record Dates
Last Update Posted: April 11, 2016
Last Verified: April 2016
Keywords provided by Philip Clements, University of California, Los Angeles:
Systemic sclerosis
Additional relevant MeSH terms:
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Scleroderma, Systemic
Scleroderma, Diffuse
Pathologic Processes
Connective Tissue Diseases
Skin Diseases
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents