High Dose Cyclophosphamide for Treatment of Scleroderma

NCT00501995 | Completed Phase 3 Results

• 1 other identifier: 00-11-17-02
• Study Type: interventional
• Target: 6
• Locations: 0 countries
• Sites: N/A

Brief Summary

Systemic Sclerosis (Scleroderma) varies greatly in clinical manifestations, mode of presentation, and course. The natural history of this chronic autoimmune disease ranges from benign to fatal. Patients are classified into limited and diffuse scleroderma defined by the degree of skin involvement. Patients with limited disease (e.g. the C.R.E.S.T. syndrome) generally have mild disease and normal survival. However, patients with diffuse cutaneous scleroderma often have severe multi-system disease that is not only devastating emotionally and physically but is associated with a 60-70% five year survival and a 40-50% 10 year survival. No therapies have proven effective in the treatment of scleroderma. Strategy to treat scleroderma have included attempts to prevent fibrosis with drugs that interfere with collagen metabolism, attempts to modify the disease process by immunosuppression and attempts to alter the disease by vasoactive drugs. High dose of corticosteroids and other immunosuppressive drugs (e.g. chlorambucil, 5-fluorouracil, methotrexate, cyclophosphamide, cyclosporine) used at conventional doses have not proven curative, but have shown some benefit for inflammatory features of the disease (e.g. arthritis, myositis, fibrosing alveolitis). Both allogeneic and autologous bone marrow transplantation (BMT) have shown to modify and in some instances reverse a variety of animal models of autoimmune disease. This has prompted many investigators to propose the use of peripheral blood stem cell transplantation (PBSCT) for the treatment of autoimmune disease including scleroderma. Unfortunately, this approach risks infusing untreated autoreactive lymphocyte clones after the immunoablative preparative regimen. We have previously demonstrated that high-dose cyclophosphamide without BMT can induce durable and complete remissions in another autoimmune disease, severe aplastic anemia. Recent data with high dose cyclophosphamide show that it can induce complete remissions in other autoimmune hematologic disorders. The objective of this study is to determine whether high dose cyclophosphamide can induce a durable remission in scleroderma patients with life-threatening disease, and to determine toxicity of high dose cyclophosphamide in high risk scleroderma patients.

Conditions

Scleroderma

Keywords

High Dose Cyclophosphamide; Systemic Sclerosis; Scleroderma; immunoablation

Outcome Measures

Primary Outcomes (1)

• Improvement in the Modified Rodnan Skin Score.

  The modified Rodnan skin score is the accepted clinical measure of scleroderma skin activity. The investigator will assess the thickening of the skin using the modified Rodnan skin score through simple palpation on 17 different body areas: fingers, hands, forearms, arms, feet, legs, and thighs (bilaterally) and face, chest, and abdomen (singly). Skin thickness is assessed on a scale of 0-3; 0 representing normal skin and 3 being severe thickening. The sum of the individual scores can range from 0-51; 0 (normal) to 51 (severe thickening in all 17 areas) A 25% improvement in the modified Rodnan Skin score will be considered significant at any time point in the study. Modified Rodnan Skin Score was evaluated at months 0,1,3,6,12 and 24 months.

  0 to 24 months

Secondary Outcomes (1)

• Change in the HAQ-DI, PGA, FVC and DLCO

  0-24 months

Study Arms (1)

IV Cyclophosphamide (50 mg/kg)

EXPERIMENTAL

This is an open-labeled single arm study of Cyclophosphamide (50 mg/kg) administered intravenously over 1 hour daily for four consecutive days (200 mg/kg total) through a Hickman catheter .

Drug: IV Cyclophosphamide

Interventions

IV Cyclophosphamide DRUG

Cyclophosphamide (50 mg/kg) intravenously daily for 4 consecutive days (total 200 mg/kg) followed by granulocyte colony-stimulating factor (5 µg/kg/day)

Also known as: Cytoxan, Neosar

IV Cyclophosphamide (50 mg/kg)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Meet established criteria for a diagnosis of diffuse cutaneous scleroderma and have evidence of moderately severe organ damage and clinical evidence of active disease.
• Patients with diffuse scleroderma who have evidence of active fibrosing alveolitis manifested by either a greater than 10% decline in the forced vital capacity or the diffusing capacity from the defined normal values or from baseline measurements.
• Patients with severe deforming localized scleroderma (generalized morphea, liner morphea, keloid or bullous scleroderma) that threatens their capacity to function normally in society.

You may not qualify if:

• Age less than 18 years and over 70 years
• Any risk of pregnancy
• Cardiac ejection fraction of \< 45%
• Serum creatinine \> 3.0
• Patients who are pre-terminal or moribund
• Bilirubin \> 2.0, transaminases \> 2x normal
• Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), (5/30/01) \< 50% predicted

Sponsors & Collaborators

• Johns Hopkins University: lead

Related Publications (1)

• Tehlirian CV, Hummers LK, White B, Brodsky RA, Wigley FM. High-dose cyclophosphamide without stem cell rescue in scleroderma. Ann Rheum Dis. 2008 Jun;67(6):775-81. doi: 10.1136/ard.2007.077446. Epub 2007 Nov 1.

  PMID: 17974598 RESULT

MeSH Terms

Conditions

Scleroderma, Diffuse; Scleroderma, Systemic

Interventions

Cyclophosphamide

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: Gwen Leatherman,R.N.,M.S.
• Organization: Johns Hopkins University

gleathe@jhmi.edu

410-550-8582

Study Officials

• Fredrick M Wigley, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: July 13, 2007
• First Posted: July 17, 2007
• Study Start: February 1, 2001
• Primary Completion: July 1, 2008
• Study Completion: May 1, 2010
• Last Updated: June 14, 2017
• Results First Posted: July 2, 2014

Record last verified: 2017-05