Use of Infliximab for the Treatment of Pemphigus Vulgaris

Study Overview
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Brief Summary
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Pemphigus vulgaris (PV) is a rare skin disorder that causes blistering of the skin and mucous membranes. Infliximab is a man-made antibody used to treat certain types of immune system disorders, including rheumatoid arthritis and Crohn's disease. This study will determine if infliximab given in combination with prednisone is a safe and effective treatment for adults with PV.

Detailed Description
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PV involves blistering of the outer layer of skin and mucous membranes, causing a separation of epidermal cells. The disease occurs when the immune system produces antibodies to specific proteins in the skin and mucous membranes; the cause for production of these autoantibodies is unknown. Infliximab is a genetically engineered monoclonal antibody directed against tumor necrosis factor (TNF)-alpha, a chemical messenger that activates an immune response. Infliximab has been used to treat other autoimmune disorders, including rheumatoid arthritis, ankylosing spondylitis, and Crohn's disease. This study will evaluate the safety and efficacy of infliximab given in combination with prednisone for the treatment of adults with PV. This study will last 26 weeks. At study entry, all patients will be taking a stable dose of prednisone (or an equivalent corticosteroid) of 20 to 120 mg/day for at least 2 weeks prior to study entry. Patients will be randomly assigned to one of two arms: experimental or placebo comparator. The experimental treatment arm will receive infusions of infliximab, and the control arm will receive placebo. Infusions will be given at study entry and Weeks 2, 6, and 14. Before the start of each infusion, a physical exam, vital signs measurement, medical and medication history, review of a disease activity log, a skin evaluation, and blood collection will occur. During each infusion and for 1 hour postinfusion, patients' vital signs will be monitored for any adverse events. Patients will need a responsible adult to take them home after they are discharged from the treatment facility; this person should remain with the patient overnight in case any problems arise from the treatment. The patient will be contacted by phone that night and the next morning after infusion and will be asked about any adverse effects they may have experienced. Those patients that experience adverse effects may be asked to return to the treatment facility for examination. Prednisone doses may be tapered by 15 percent every 2 weeks during the study at the investigator's discretion. There will be a total of 9 study visits until Week 26: screening, study entry, Week 2, and every 4 weeks thereafter. Each study visit will include a physical exam, vital signs measurement, medical and medication history, a review of the disease activity log and adverse events experienced since the last visit, skin assessments, and blood collection; patients will also be asked to complete a tuberculosis (TB) questionnaire. Patients will be asked to complete quality of life questionnaires at study entry and Weeks 10, 18, and 26. Skin biopsies of unaffected skin will be done at study entry and Weeks 10, 18, and 26; if patients have PV-associated lesions, additional skin biopsies of affected skin will be done at study entry and Week 18.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Infliximab in Subjects With Pemphigus Vulgaris Receiving Prednisone

Conditions
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Pemphigus

Intervention / Treatment
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* Drug: Infliximab
* Other: Placebo Comparator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Positive direct immunofluorescence of patient's skin showing IgG or complement C3 protein on cell surface with histopathology of lesional skin biopsies consistent with diagnosis of pemphigus vulgaris Failure to completely respond to standard steroid therapy (equivalent to prednisone 1 to 2 mg/kg/day followed by tapering) Systemic corticosteroid therapy of at least 20 mg prednisone daily and no more than 120 mg/day Inability to reduce systemic corticosteroid dosage below 20 mg/day for at least 8 weeks Stable dosage of prednisone for at least 2 weeks prior to study entry Oral/mucosal disease or skin disease. Detailed information about this criterion can be found in the protocol Willing to comply with the study protocol Willing to use acceptable means of contraception for the duration of the study and for 6 months after the end of the study Exclusion Criteria: Positive tuberculosis (TB) test within 1 month prior to first administration of study drug History of latent or active TB prior to screening Signs or symptoms suggestive of TB disease by medical history or physical examination within 3 months prior to first administration of study drug Posterior/anterior/lateral chest radiograph within 3 months prior to screening showing evidence of cancer, infection, or abnormalities (apical scarring) suggestive of previous TB Serious infection, hospitalization for an infection, or treatment with intravenous (IV) antibiotics for an infection within 2 months prior to screening. Patients who have had less serious infections are eligible for this study at the discretion of the investigator. History or presence of opportunistic infections within 6 months prior to screening History of receiving human/murine recombinant products Known allergy to murine products or other chimeric proteins Human immunodeficiency virus (HIV) infected Chronic hepatitis B or hepatitis C virus infection History of hepatitis C virus infection Cancer within the 5 years prior to study entry. Patients with completely resected non-melanoma skin cancers are not excluded. History or presence of congestive heart failure History or presence of seizure or demyelinating disorder History of latent or active granulomatous infection, including TB, histoplasmosis, or coccidioidomycosis Received a Bacillus Calmette-Guerin (BCG) vaccine within 12 months of screening History of lymphoproliferative disease, including lymphoma or signs and symptoms of possible lymphoproliferative disease, such as lymphadenopathy of unusual size or location or enlarged spleen Current signs or symptoms of severe progressive or uncontrolled kidney, liver, blood, gastrointestinal, endocrine, lung, heart, neurologic, or cerebral disease Have had chronic or recurrent infectious disease including, but not limited to, chronic kidney infection, chronic chest infection, sinusitis, recurrent urinary tract infection, infected skin wound, or ulcer Previous treatment with infliximab, other monoclonal antibodies, or antibody fragments Previous treatment with etanercept or other anti-tumor necrosis factor (TNF) agents in the 3 months prior to screening Treatment with methotrexate, azathioprine, mycophenolate mofetil, plasmapheresis, IV immunoglobulin, pulse systemic corticosteroids, or other systemic immunosuppressive agents within the 4 weeks prior to study entry History of alcohol or drug abuse within the 3 years prior to study entry History of noncompliance to medical regimens History of a systemic inflammatory disease other than pemphigus vulgaris History of a medical condition that would interfere with participation or increase the risk to the participant Unable or unwilling to undergo blood draws because of poor tolerability or lack of easy access Use of any investigational drug within 30 days prior to screening OR within 5 half-lives of the investigational agent, whichever is longer Participation in another investigative clinical trial Presence of transplanted solid organ. Participants who have received a corneal transplant more than 3 months prior to screening are not excluded. Require certain medications Other conditions or circumstances that could interfere with participant's adherence to the study requirements Pregnancy, breastfeeding, or plans to become pregnant

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Infliximab<br>Participants are randomized to receive intravenous infusions of infliximab (5mg/kg reconstituted in 10 mL of Sterile Water for Injection, USP ) at Weeks 0, 2, 6, and 14 over a time period of no less than two hours in a masked (blinded) fashion. Refer to section titled, Detailed Description for additional treatment information. | Drug: Infliximab<br>* Chimeric IgG monoclonal antibody that binds to TNF-alpha, generally used to treat Crohn's disease, given in a dosage of 5 mg/kg<br>* Other names: Remicade®;|
| Placebo Comparator: Placebo Comparator<br>Participants are randomized to receive intravenous infusions of placebo (5 mg/kg comprised of a white lyophilized powder reconstituted in 10 mL of Sterile Water for Injection, USP) at Weeks 0, 2, 6, and 14 over a time period of no less than two hours in a masked (blinded) fashion. Refer to section titled, Detailed Description for additional treatment information. | Other: Placebo Comparator<br>* Placebo administered in place of infliximab for control group<br>* Other names: Control Arm;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participant Response to Treatment at Week 18 | Participants classified as responders at Week 18 had: 1. Achieved a prednisone dosage <= 25% of the initial starting dose or <= 10 mg/day (whichever is greater), and 2. Had no new blisters within the previous 4 weeks. | Baseline to Week 18 | 
| Treatment-Related Adverse Events >= Grade 3 On or Before Week 18 | Grades were based on the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 3.0. An adverse event (AE) was considered treatment-related if it was classified as unlikely, possibly, probably, or definitely related to study treatment. Participants who experienced at least one treatment-related, grade 3 or higher AE were counted only once. AEs of skin including rash, skin ulceration, and chelitis as defined by the NCI-CTCAE V3.0 System Organ Class of Skin and Subcutaneous Tissues Disorders were excluded. | Baseline to Week 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participant Response to Treatment at Week 18 | Participants classified as responders at Week 18 had: 1. Achieved a prednisone dosage <= 25% of the initial starting dose or <=10 mg/day (whichever is greater), and 2. Had no new blisters within the previous 4 weeks. | Baseline to Week 18 | 
| Participant Modified Response Status at Week 18 | Modified responder status was defined as participants achieving a prednisone dosage <=25% of the initial starting dose or <=10 mg/day (whichever is greater) at Week 18 regardless of status on new blister formation during the previous 4 weeks. | Baseline to Week 18 | 
| Participant Time to Cessation of New Blisters | Time to cessation of new blisters was defined as the time from a participant's first treatment infusion date to the first date where that date and all subsequent dates had no new blisters. Participant diaries were used to assess new blister formation. To achieve cessation, participants had to be free of new blisters at least 3 weeks prior to their last assessment. In order to analyze missing or incomplete data, the data was censored at the date where a participant had no more data or on the date where 50% of the participant's data was missing past that point. | Baseline to Week 26 | 
| Time to 80% Lesion Healing | Time to 80% healing of existing erosions/ulcerations at time of enrollment was assessed using the SAGE II computerized burn-mapping system. The date of 80% healing of existing erosions/ulcerations at time of enrollment was defined as follows: the first date at which the percent of total body surface area (BSA) involved is at least 80% less than the percent of total BSA calculated at the time of enrollment, where the baseline percent of total BSA must be greater than zero percent. If a participant had missing post-baseline assessments, their data was censored at their last non-missing assessment date. | Baseline to Week 26 | 
| Total Prednisone Dosage Required for Participants to Achieve Cessation of New Blisters | Each participant's prednisone dose was summed from the time of enrollment until the date of cessation of new blisters. Actual prednisone use per day was computed as the average over all days in the week. | Baseline to Week 26 | 
| Total Prednisone Dosage Required for Participants to Achieve 80% Healing of Existing Erosions | Each participant's prednisone dose was summed from the time of enrollment until the date of 80% healing of existing erosions. Actual prednisone use per day was computed as the average over all days in the week. | Baseline to Week 26 | 
| Participant Health Related Quality of Life (Medical Outcome Study Short Form 36) Score Changes From Baseline to Week 18 | The Medical Outcome Study Short Form 36 (MOS SF-36) measures health -related quality of life across multiple disease states. It has 36 questions with 8 subscale scores and 2 summary scores: PCS=physical functioning, role-physical, bodily pain, and general health; MCS=vitality, social functioning, role-emotional, and mental health. Scoring is done for both subscores and summary scores. For both, 0=worst score (or quality of life) and 100=best score. Change from baseline is computed as the value at Week 18 minus the baseline value. A positive value in change from Baseline indicates an improvement and a negative value worsening. | Baseline to Week 18 | 
| Participant Dermatology-Related Quality of Life Changes From Baseline to Week 18 | The Dermatology Life Quality Index (DLQI) is a 10-question questionnaire with a weighted value to each question. The DLQI score was calculated by summing the score of each question, resulting in a maximum score of 30 and a minimum score of 0. The higher the score, the greater quality of life is impaired. Change from baseline values (defined as the visit value - baseline value) were calculated. A negative change indicates better quality of life; a positive change indicates poorer quality of life. | Baseline to Week 18 | 
| Participant Duration of Clinical Response | The primary efficacy endpoint of response to treatment at Week 18 was reassessed at study weeks 22 and 26 for participants who were responders at Week 18. Participants classified as responders had: 1. Achieved a prednisone dosage <= 25% of the initial starting dose or <= 10 mg/day (whichever is greater), and 2. had no new blisters within the previous 4 weeks. | Baseline to Week 26 | 
| Participants Who Experienced Severe Infusion Reactions | Participants who experienced severe infusion reactions of Grade 3 or greater based on the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 3.0 were assessed. | Baseline to Week 26 | 
| Participants Who Experienced Severe Infectious Complications | Serious and life-threatening infections of Grade 3 or greater based on the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 3.0 were assessed. | Baseline to Week 26 | 
| Adverse Events Resulting in Treatment Discontinuation | Adverse events experienced by participants resulting in study treatment discontinuation and assessed by the investigators as at least possibly related to treatment (i.e., possibly, probably, definitely) were assessed. | Baseline to Week 26 | 
| Participant Pemphigus Vulgaris Disease Activity Score | The Pemphigus Vulgaris Disease Activity (PVDA) score was used to grade a participant's disease activity using the SAGE II computerized burn mapping system, which calculated the total body surface area (BSA) involved. Scores were based on the number of new lesions and blisters present, old lesion history and BSA involved. Scores range from 0 to 3 (none to severe disease activity). A new disease activity score of 3 or an old lesion score of 3 indicates active disease. New disease activity scores of 3 for a 1-month duration or an old lesion score of 3 for 2 consecutive months was cause for removal from the study treatment | Baseline to Week 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Skin Diseases, Autoimmune Diseases