Rapamycin vs Methotrexate in Diffuse SSc

NCT ID: NCT00241189

Last Updated: 2016-04-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 17 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2002-08-31
• Study Completion Date: 2006-06-30

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

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.

Conditions

Systemic Sclerosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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

Group Type: EXPERIMENTAL

rapamycin

Intervention Type: DRUG

Methotrexate

Methotrexate 20 mg taken orally weekly for one year

Group Type: ACTIVE_COMPARATOR

methotrexate

Intervention Type: DRUG

Interventions

rapamycin

Intervention Type: DRUG

methotrexate

Intervention Type: DRUG

Other Intervention Names

rapimmune

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of California, Los Angeles

OTHER

Sponsor Role: lead

Responsible Party

Philip Clements

MD, MPH

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Philip J Clements, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

University of California, Los Angeles

Locations

Philip Clements, MD

Los Angeles, California, United States

Countries

United States

References

Su TI, Khanna D, Furst DE, Danovitch G, Burger C, Maranian P, Clements PJ. Rapamycin versus methotrexate in early diffuse systemic sclerosis: results from a randomized, single-blind pilot study. Arthritis Rheum. 2009 Dec;60(12):3821-30. doi: 10.1002/art.24986.

Reference Type: RESULT

PMID: 19950289 (View on PubMed)

Other Identifiers

UCLA IRB Number: 01-10-045

Identifier Type: -

Identifier Source: org_study_id