Rapamycin vs Methotrexate in Diffuse SSc

Systemic Sclerosis Clinical Trial

Official title:

A 48-week, Double-blind, Randomized, Parallel Phase I/II Study of Oral Rapamycin Versus Methotrexate in Systemic Sclerosis (Scleroderma)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00241189
• Other study ID #: UCLA IRB Number: 01-10-045
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: October 14, 2005
• Last updated: April 8, 2016
• Start date: August 2002
• Est. completion date: June 2006

Study information

• Verified date: April 2016
• Source: University of California, Los Angeles
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17
• Est. completion date: June 2006
• Est. primary completion date: June 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Scleroderma, Diffuse
• Scleroderma, Systemic
• Sclerosis
• Systemic Sclerosis

Intervention

Drug:
• rapamycin

• methotrexate

Locations

Country	Name	City	State
United States	Philip Clements, MD	Los Angeles	California

Sponsors (1)

Lead Sponsor	Collaborator
University of California, Los Angeles

Country where clinical trial is conducted

United States, 

References & Publications (1)

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.2 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse events
Primary	Modified Rodnan Skin thickness score
Secondary	Forced vital capacity
Secondary	Diffusing capacity (DLCO)
Secondary	Health Assessment Questionnaire-Disability Index
Secondary	Mahler Dyspnea Index
Secondary	Medical Outcomes Questionnaire SF-36
Secondary	Patient global (VAS)
Secondary	Physician global (VAS)
Secondary	% responders in skin score (=>35% decrease from baseline)
Secondary	% responders in HAQ-DI(=>0.22 units decrease from baseline)
Secondary	% responders in FVC (=>10% decrease from baseline)
Secondary	Serum rapamycin levels