High Dose Cyclophosphamide for Treatment of Scleroderma

Scleroderma Clinical Trial

Official title:

High Dose Cyclophosphamide for Treatment of Systemic Sclerosis (Scleroderma)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00501995
• Other study ID #: 00-11-17-02
• Status: Completed
• Phase: Phase 3
• First received: July 13, 2007
• Last updated: October 21, 2015
• Start date: February 2001
• Est. completion date: May 2010

Study information

• Verified date: October 2015
• Source: Johns Hopkins University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

Description:

Study design

The study was an open-label, single-site trial of a single exposure to high-dose cyclophosphamide without stem cell rescue. Each patient was followed up by the same doctor to eliminate interobserver skin score variation. Baseline measurements included comprehensive laboratory studies that included complete blood count with differential, comprehensive metabolic panel, urine analysis with culture, quantitative immunoglobulins, antibodies to hepatitis B core and surface antigens and antibodies to hepatitis C, human immunodeficiency, herpes, varicella, Epstein-Barr viruses; rapid plasma reagin test, chest x-ray or high-resolution computed tomography (HRCT) scan of the lungs, pulmonary function testing, electrocardiogram, and echo or MUGA scan.

The primary clinical efficacy end point was the modified Rodnan skin score (mRSS).24 A 25% sustained improvement in the mRSS at any point in the follow-up was considered clinically important and a successful outcome.25 Secondary outcome measures included the Health Assessment Questionnaire-Disability Index (HAQ-DI) and physician global assessment (PGA) determined by a visual analogue scale on a scale from 0 to 100. Values for the percentage predicted lung volumes were referenced from NHANES/Hanikson et al26 and for DLCO from Knudson et al.27 The disease duration was defined as the time from the first non-Raynaud's symptom related to scleroderma to study entry.

Treatment protocol

Cyclophosphamide (50 mg/kg) was administered intravenously over 1 hour daily for four consecutive days (200 mg/kg total) through a Hickman catheter. The dose of cyclophosphamide was based on the ideal body weight as determined by the Metropolitan Life tables.28 29 If the patient's actual weight was less than the ideal body weight, the actual body weight was used to calculate the cyclophosphamide dose. Intravenous mesna (10 mg/kg) was given 30 minutes before cyclophosphamide and then 3, 6 and 8 hours after cyclophosphamide was administered for prophylaxis against haemorrhagic cystitis. Intravenous ondansetron (32 mg) was administered 1 hour before each dose of cyclophosphamide. Six days after the last dose of cyclophosphamide, all patients received granulocyte colony-stimulating factor (5 µg/kg/day) until the neutrophil count was 1×109/l for two consecutive days. Prophylactic antibiotic support, consisting of fluconazole (400 mg/day), norfloxacin (400 mg/day), and valaciclovir (500 mg twice a day, if antibodies to herpes simplex were present), was given beginning the day after the last dose of cyclophosphamide and continuing until the neutrophil count exceeded 0.5×109/l. Dapsone (100 mg three times a week for 6 months) or trimethoprim-sulfamethoxazole (80/400 mg three times a week for 6 months) was administered for Pneumocystis carinii prophylaxis. Packed red blood cell (leucocyte-poor) transfusions were administered to maintain a haematocrit level >25%. Platelet transfusions were given for bleeding or to maintain a platelet count >10×109/l, or both. All blood products were irradiated (>2000 rad) to prevent graft versus host disease.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6
• Est. completion date: May 2010
• Est. primary completion date: July 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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

• FVC, FEV1 (5/30/01) < 50% predicted

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Scleroderma
• Scleroderma, Diffuse
• Scleroderma, Localized
• Scleroderma, Systemic

Intervention

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

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Johns Hopkins University

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The Primary Endpoint Will be an 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	No
Secondary	Secondary Endpoint Was Changes in the Total Severity Score (Composite) and Measures of Severity in Each Specific Organ (Organ Specific Measures).	The total severity score is comprised of results from the Health Assessment Questionnaire-Disability Index (HAQ-DI) a 48 item questionnaire assessing ability to perform activities of daily living, use of assistive devises and a 6 item analog scale of pain severity from 0 cm (no pain) to 14.3 cm (very severe pain). The physician global assessment (PGA) which is a visual analogue scale from 0 to 100 on which the physician rates the patient's disease severity based on their observations. The score also included the Forced Vital Capacity (FVC) which is a measure of lung capacity and Diffusing Capacity (DLCO) which measures the ability of the lung to absorb oxygen accross the membrances in the alveoli. The FVC and DLCO are measured through pulmonary function testing. The predicted lung volumes were referenced from NHANES/Hanikson et al and for DLCO predicteds were from Knudson. Pre and post study intervention scores were compared.	0-24 months	No