Clinical Trial: Use of Infliximab for the Treatment of Pemphigus Vulgaris

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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

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 Summary:

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

Current Primary Outcome:

  • Participant Response to Treatment at Week 18 [ Time Frame: 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 [ Time Frame: 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.


Original Primary Outcome:

  • Proportion of participants who experience treatment-related adverse events of Grade 3 or higher at Week 18
  • response to treatment at Week 18, comparing study arms


Current Secondary Outcome:

  • Participant Response to Treatment at Week 18 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame:&nb

    Original Secondary Outcome:

    • Severe infusion reactions
    • Severe infectious complications
    • Adverse events resulting in discontinuation and assessed by the investigators as at least possibly related to treatment
    • Disease activity, defined as a new disease activity score of 3 or an old lesion score of 3
    • modified responder status, defined as achieving prednisone dosage less than or equal to 25% of the initial starting dose or a dosage of less than 10 mg prednisone/day (whichever is greater) at Week 18, regardless of new blister formation
    • Time to cessation of new blisters
    • Time to 80% healing of erosions or ulcerations existing at the time of enrollment
    • total prednisone dosage required to achieve cessation of new blisters and to achieve 80% healing of existing erosions
    • quality of life (SF-36) changes from baseline through Week 26
    • dermatology-related quality of life changes from baseline through Week 26
    • change in serum anti-DSG1 antibody levels from baseline through Week 26
    • change in serum anti-DSG3 antibody levels from baseline through Week 26
    • change in serum TNF-alpha and IL-6 levels from baseline through Week 26
    • change in skin expression of TNF-alpha and IL-6 mRNA from baseline through Week 26
    • change in number and proportion of immature B cells in circulation from baseline through Week 26
    • duration of primary clinical efficacy endpoint from Week 18 through Week 26 as measured by disease activity score and prednisone dosage
    • evaluation at baseline and Week 26 for development of human anti-chimera antibodies (HACA)


    Information By: National Institute of Allergy and Infectious Diseases (NIAID)

    Dates:
    Date Received: January 26, 2006
    Date Started: March 2006
    Date Completion:
    Last Updated: October 15, 2014
    Last Verified: October 2014