Use of Infliximab for the Treatment of Pemphigus Vulgaris

Condition(s) targeted: Pemphigus

Intervention: Infliximab (Drug); Prednisone (Drug); Placebo (Other)

Phase: Phase 2

Status: Recruiting

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
Russell P. Hall, MD, Study Chair, Affiliation: Division of Dermatology, Duke University Medical Center
E. William St. Clair, MD, Study Chair, Affiliation: Division of Rheumatology and Immunology, Duke University Medical Center
Garnett Kelsoe, DSci, Principal Investigator, Affiliation: Department of Immunology, Duke University
Victoria Werth, MD, Principal Investigator, Affiliation: Department of Dermatology, University of Pennsylvania School of Medicine
Janet Fairley, MD, Principal Investigator, Affiliation: Department of Dermatology, University of Iowa
David Woodley, MD, Principal Investigator, Affiliation: Department of Dermatology, Norris Cancer Center, University of Southern California

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.

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

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

Primary outcome:

Proportion of participants who experience treatment-related adverse events of Grade 3 or higher

Achieved a prednisone dosage of 25% or less of initial starting dosage or 10 mg/day or less (whichever is greater)

Had no new blisters within the previous 4 weeks

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

Achieved a prednisone dosage of 25% or less of initial starting dosage or 10 mg/day or less (whichever is greater)

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 achieve 80% healing of existing erosions

Quality of life (SF-36) changes

Dermatology-related quality of life changes

Change in serum anti-DSG1 antibody levels

Change in serum anti-DSG3 antibody levels

Change in serum TNF-alpha and IL-6 levels

Change in skin expression of TNF-alpha and IL-6 mRNA

Change in number and proportion of immature B cells in circulation

Duration of primary clinical efficacy endpoint as measured by disease activity score and prednisone dosage

Development of human antichimera antibodies (HACA)

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. 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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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

Norris Cancer Center, University of Southern California, Los Angeles, California 90033, United States; Recruiting
David T. Woodley, MD, Phone: 323-865-0983, Email: dwoodley@usc.edu

University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, United States; Recruiting
Debra Brandt, RN, Phone: 319-353-6439, Email: debra-brandt@uiowa.edu.
Janet Fairley, MD, Principal Investigator

Duke University Medical Center, Durham, North Carolina 27710, United States; Recruiting
Russell P. Hall, MD, Phone: 919-684-3110, Email: hall0009@mc.duke.du
E. William St. Clair, MD, Phone: 919-684-4499, Email: stcla003@mc.duke.edu

University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States; Recruiting
Victoria Werth, MD, Phone: 315-662-2399, Email: werth@mail.med.upenn.edu

Related publications:

Anhalt GJ, Diaz LA. Pemphigus vulgaris--a model for cutaneous autoimmunity. J Am Acad Dermatol. 2004 Jul;51(1 Suppl):S20-1. Review. No abstract available.

Drosou A, Kirsner RS, Welsh E, Sullivan TP, Kerdel FA. Use of infliximab, an anti-tumor necrosis alpha antibody, for inflammatory dermatoses. J Cutan Med Surg. 2003 Sep-Oct;7(5):382-6. Epub 2003 Sep 24.

Jacobi A, Shuler G, Hertl M. Rapid control of therapy-refractory pemphigus vulgaris by treatment with the tumour necrosis factor-alpha inhibitor infliximab. Br J Dermatol. 2005 Aug;153(2):448-9. No abstract available.

Pardo J, Mercader P, Mahiques L, Sanchez-Carazo JL, Oliver V, Fortea JM. Infliximab in the management of severe pemphigus vulgaris. Br J Dermatol. 2005 Jul;153(1):222-3. No abstract available.

Starting date: March 2006
Last updated: September 26, 2008