Use of Infliximab for the Treatment of Pemphigus Vulgaris

Phase 2

Completed

Conditions: Pemphigus

Interventions: Drug: Infliximab
Other: Placebo Comparator

Registration Number: NCT00283712

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 20

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Infliximab	Infliximab	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.
Placebo Comparator	Placebo Comparator	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.

Primary Outcome Measures

Name	Time	Method
Participant Response to Treatment at Week 18	Baseline to 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.
Treatment-Related Adverse Events >= Grade 3 On or Before Week 18	Baseline to 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.

Secondary Outcome Measures

Name	Time	Method
Participant Response to Treatment at Week 18	Baseline to 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.
Participant Modified Response Status at Week 18	Baseline to 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.
Participant Time to Cessation of New Blisters	Baseline to Week 26	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.
Time to 80% Lesion Healing	Baseline to Week 26	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.
Total Prednisone Dosage Required for Participants to Achieve Cessation of New Blisters	Baseline to Week 26	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.
Total Prednisone Dosage Required for Participants to Achieve 80% Healing of Existing Erosions	Baseline to Week 26	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.
Participant Health Related Quality of Life (Medical Outcome Study Short Form 36) Score Changes From Baseline to Week 18	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.
Participant Dermatology-Related Quality of Life Changes From Baseline to Week 18	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.
Participant Duration of Clinical Response	Baseline to Week 26	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.
Participants Who Experienced Severe Infusion Reactions	Baseline to Week 26	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.
Participants Who Experienced Severe Infectious Complications	Baseline to Week 26	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.
Adverse Events Resulting in Treatment Discontinuation	Baseline to Week 26	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.
Participant Pemphigus Vulgaris Disease Activity Score	Baseline to Week 26	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

Trial Locations

Locations (4): University of Pennsylvania
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Philadelphia, Pennsylvania, United States
University of Iowa Hospitals and Clinics
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Iowa City, Iowa, United States
Norris Cancer Center, University of Southern California
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Los Angeles, California, United States
Duke University Medical Center
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Durham, North Carolina, United States