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

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver), Placebo Control, Parallel Assignment, Safety/Efficacy Study

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. The 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% 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.

Intervention(s) in this Clinical Trial

• Drug: Infliximab
  • Chimeric IgG monoclonal antibody that binds to TNF-alpha, generally used to treat Crohn's disease, given in a dosage of 5 mg/kg at Study entry and Weeks 2, 6, and 14
• Drug: Prednisone
  • Systemic corticosteroid at therapeutic levels. Dosage may be tapered by approximately 15% every 2 weeks if no new lesions are observed as determined by clinical assessment of the investigator.
• Other: Placebo
  • Placebo given in place of infliximab for control group

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Treatment
  • Intravenous infusions of infliximab at study entry and Weeks 2, 6, and 14 and prednisone or other systemic corticosteroids throughout study
• Placebo Comparator: Control
  • Intravenous infusions of placebo at Study entry and Weeks 2, 6, and 14 and prednisone or other systemic corticosteroids throughout study

Primary Measures

• Proportion of participants who experience treatment-related adverse events of Grade 3 or higher
  • Time Frame: At Week 18
    Safety Issue?: Yes
• Achieved a prednisone dosage of 25% or less of initial starting dosage or 10 mg/day or less (whichever is greater)
  • Time Frame: At Week 18
    Safety Issue?: No
• Had no new blisters within the previous 4 weeks
  • Time Frame: At Week 18
    Safety Issue?: No

Secondary Measures

• Severe infusion reactions
  • Time Frame: Throughout study
    Safety Issue?: Yes
• Severe infectious complications
  • Time Frame: Throughout study
    Safety Issue?: Yes
• Adverse events resulting in discontinuation and assessed by the investigators as at least possibly related to treatment
  • Time Frame: Throughout study
    Safety Issue?: Yes
• Disease activity, defined as a new disease activity score of 3 or an old lesion score of 3
  • Time Frame: Throughout study
    Safety Issue?: Yes
• Achieved a prednisone dosage of 25% or less of initial starting dosage or 10 mg/day or less (whichever is greater)
  • Time Frame: At Week 18
    Safety Issue?: No
• Time to cessation of new blisters
  • Time Frame: Throughout study
    Safety Issue?: No
• Time to 80% healing of erosions or ulcerations existing at the time of enrollment
  • Time Frame: Throughout study
    Safety Issue?: No
• Total prednisone dosage required to achieve cessation of new blisters and achieve 80% healing of existing erosions
  • Time Frame: Throughout study
    Safety Issue?: No
• Quality of life (SF-36) changes
  • Time Frame: Throughout study
    Safety Issue?: No
• Dermatology-related quality of life changes
  • Time Frame: Throughout study
    Safety Issue?: No
• Change in serum anti-DSG1 antibody levels
  • Time Frame: Throughout study
    Safety Issue?: No
• Change in serum anti-DSG3 antibody levels
  • Time Frame: Throughout study
    Safety Issue?: No
• Change in serum TNF-alpha and IL-6 levels
  • Time Frame: Throughout study
    Safety Issue?: No
• Change in skin expression of TNF-alpha and IL-6 mRNA
  • Time Frame: Throughout study
    Safety Issue?: No
• Change in number and proportion of immature B cells in circulation
  • Time Frame: Throughout study
    Safety Issue?: No
• Duration of primary clinical efficacy endpoint as measured by disease activity score and prednisone dosage
  • Time Frame: From Week 18 through Week 26
    Safety Issue?: No
• Development of human antichimera antibodies (HACA)
  • Time Frame: At study entry and Week 26
    Safety Issue?: No

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 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
• HIV infected
• Chronic hepatitis B or 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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

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

Overall Clinical Trial Officials and Contacts

Russell P. Hall, MD Study Chair Division of Dermatology, Duke University Medical Center  

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00283712

Study ID Number: DAIT APV01

ClinicalTrials.gov Identifier: NCT00283712

Health Authority: United States: Food and Drug Administration