Ignite Creation Date:
2024-05-05 @ 6:33 PM
Last Modification Date:
2024-10-26 @ 9:34 AM
Study NCT ID:
NCT00501995
Status:
COMPLETED
Last Update Posted:
2017-06-14
First Post:
2007-07-13
Brief Title:
High Dose Cyclophosphamide for Treatment of Scleroderma
Sponsor:
Johns Hopkins University
Organization:
Johns Hopkins University
Study Overview
Official Title:
High Dose Cyclophosphamide for Treatment of Systemic Sclerosis Scleroderma
Status:
COMPLETED
Status Verified Date:
2017-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 eg the CREST 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 eg 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 eg 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
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 mRSS24 A 25 sustained improvement in the mRSS at any point in the follow-up was considered clinically important and a successful outcome25 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 NHANESHanikson et al26 and for diffusing capacity of the lungs for carbon monoxide DLCO from Knudson et al27 The disease duration was defined as the time from the first non-Raynauds symptom related to scleroderma to study entry
Treatment protocol
Cyclophosphamide 50 mgkg was administered intravenously over 1 hour daily for four consecutive days 200 mgkg total through a Hickman catheter The dose of cyclophosphamide was based on the ideal body weight as determined by the Metropolitan Life tables28 29 If the patients actual weight was less than the ideal body weight the actual body weight was used to calculate the cyclophosphamide dose Intravenous mesna 10 mgkg 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 µgkgday until the neutrophil count was 1109l for two consecutive days Prophylactic antibiotic support consisting of fluconazole 400 mgday norfloxacin 400 mgday 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 05109l Dapsone 100 mg three times a week for 6 months or trimethoprim-sulfamethoxazole 80400 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 10109l or both All blood products were irradiated 2000 rad to prevent graft versus host disease
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 mRSS24 A 25 sustained improvement in the mRSS at any point in the follow-up was considered clinically important and a successful outcome25 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 NHANESHanikson et al26 and for diffusing capacity of the lungs for carbon monoxide DLCO from Knudson et al27 The disease duration was defined as the time from the first non-Raynauds symptom related to scleroderma to study entry
Treatment protocol
Cyclophosphamide 50 mgkg was administered intravenously over 1 hour daily for four consecutive days 200 mgkg total through a Hickman catheter The dose of cyclophosphamide was based on the ideal body weight as determined by the Metropolitan Life tables28 29 If the patients actual weight was less than the ideal body weight the actual body weight was used to calculate the cyclophosphamide dose Intravenous mesna 10 mgkg 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 µgkgday until the neutrophil count was 1109l for two consecutive days Prophylactic antibiotic support consisting of fluconazole 400 mgday norfloxacin 400 mgday 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 05109l Dapsone 100 mg three times a week for 6 months or trimethoprim-sulfamethoxazole 80400 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 10109l or both All blood products were irradiated 2000 rad to prevent graft versus host disease
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None