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High Dose Cyclophosphamide for Treatment of Scleroderma

Primary Purpose

Scleroderma

Status
Completed
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
IV Cyclophosphamide
Sponsored by
Johns Hopkins University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Scleroderma focused on measuring High Dose Cyclophosphamide, Systemic Sclerosis, Scleroderma, immunoablation

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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
  • Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), (5/30/01) < 50% predicted

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    IV Cyclophosphamide (50 mg/kg)

    Arm Description

    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 .

    Outcomes

    Primary Outcome Measures

    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.

    Secondary Outcome Measures

    Change in the HAQ-DI, PGA, FVC and DLCO
    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 lower the HAQ-DI score the less the disability. 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. A score of 0 is no disease activity and 100 is the worst possible disease activity. The Forced Vital Capacity (FVC) measure of lung capacity and Diffusing Capacity (DLCO) measures of oxygen exchange in the alveoli ( pulmonary function testing). The predicted lung volumes were referenced from NHANES/Hanikson et al and for DLCO predicts were from Knudson. Pre and post study percent predicted values were compared.

    Full Information

    First Posted
    July 13, 2007
    Last Updated
    May 15, 2017
    Sponsor
    Johns Hopkins University
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00501995
    Brief Title
    High Dose Cyclophosphamide for Treatment of Scleroderma
    Official Title
    High Dose Cyclophosphamide for Treatment of Systemic Sclerosis (Scleroderma)
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    May 2017
    Overall Recruitment Status
    Completed
    Study Start Date
    February 2001 (undefined)
    Primary Completion Date
    July 2008 (Actual)
    Study Completion Date
    May 2010 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Johns Hopkins University

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    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.
    Detailed 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 multigated acquisition (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 diffusing capacity of the lungs for carbon monoxide (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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Scleroderma
    Keywords
    High Dose Cyclophosphamide, Systemic Sclerosis, Scleroderma, immunoablation

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    6 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    IV Cyclophosphamide (50 mg/kg)
    Arm Type
    Experimental
    Arm Description
    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 .
    Intervention Type
    Drug
    Intervention Name(s)
    IV Cyclophosphamide
    Other Intervention Name(s)
    Cytoxan, Neosar
    Intervention Description
    Cyclophosphamide (50 mg/kg) intravenously daily for 4 consecutive days (total 200 mg/kg) followed by granulocyte colony-stimulating factor (5 µg/kg/day)
    Primary Outcome Measure Information:
    Title
    Improvement in the Modified Rodnan Skin Score.
    Description
    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.
    Time Frame
    0 to 24 months
    Secondary Outcome Measure Information:
    Title
    Change in the HAQ-DI, PGA, FVC and DLCO
    Description
    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 lower the HAQ-DI score the less the disability. 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. A score of 0 is no disease activity and 100 is the worst possible disease activity. The Forced Vital Capacity (FVC) measure of lung capacity and Diffusing Capacity (DLCO) measures of oxygen exchange in the alveoli ( pulmonary function testing). The predicted lung volumes were referenced from NHANES/Hanikson et al and for DLCO predicts were from Knudson. Pre and post study percent predicted values were compared.
    Time Frame
    0-24 months

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    70 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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 Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), (5/30/01) < 50% predicted
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Fredrick M Wigley, MD
    Organizational Affiliation
    Johns Hopkins University
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    17974598
    Citation
    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.
    Results Reference
    result

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    High Dose Cyclophosphamide for Treatment of Scleroderma

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