Use of Infliximab for the Treatment of Pemphigus Vulgaris - Full Text View

Sponsor:	National Institute of Allergy and Infectious Diseases (NIAID)
Collaborator:	Autoimmunity Centers of Excellence
Information provided by:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00283712

Purpose

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.

Condition	Intervention	Phase
Pemphigus	Drug: Infliximab Drug: Prednisone Other: Placebo	Phase II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver), Placebo Control, Parallel Assignment, Safety/Efficacy Study
Official Title:	A Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Infliximab in Subjects With Pemphigus Vulgaris Receiving Prednisone

Resource links provided by NLM:

MedlinePlus related topics: Pemphigus Skin Conditions

Drug Information available for: Prednisone Infliximab

U.S. FDA Resources

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:

Proportion of participants who experience treatment-related adverse events of Grade 3 or higher [ Time Frame: At Week 18 ] [ Designated as 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 ] [ Designated as safety issue: No ]
Had no new blisters within the previous 4 weeks [ Time Frame: At Week 18 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Severe infusion reactions [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
Severe infectious complications [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
Adverse events resulting in discontinuation and assessed by the investigators as at least possibly related to treatment [ Time Frame: Throughout study ] [ Designated as 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 ] [ Designated as 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 ] [ Designated as safety issue: No ]
Time to cessation of new blisters [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Time to 80% healing of erosions or ulcerations existing at the time of enrollment [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Total prednisone dosage required to achieve cessation of new blisters and achieve 80% healing of existing erosions [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Quality of life (SF-36) changes [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Dermatology-related quality of life changes [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Change in serum anti-DSG1 antibody levels [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Change in serum anti-DSG3 antibody levels [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Change in serum TNF-alpha and IL-6 levels [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Change in skin expression of TNF-alpha and IL-6 mRNA [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Change in number and proportion of immature B cells in circulation [ Time Frame: Throughout study ] [ Designated as 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 ] [ Designated as safety issue: No ]
Development of human antichimera antibodies (HACA) [ Time Frame: At study entry and Week 26 ] [ Designated as safety issue: No ]

Estimated Enrollment:	20
Study Start Date:	March 2006
Estimated Primary Completion Date:	February 2009 (Final data collection date for primary outcome measure)

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

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00283712

Locations

United States, California
Norris Cancer Center, University of Southern California	Recruiting
Los Angeles, California, United States, 90033
Contact: David T. Woodley, MD 323-865-0983 dwoodley@usc.edu
United States, Iowa
University of Iowa Hospitals and Clinics	Recruiting
Iowa City, Iowa, United States, 52242
Contact: Debra Brandt, RN 319-353-6439 debra-brandt@uiowa.edu.
Principal Investigator: Janet Fairley, MD
United States, North Carolina
Duke University Medical Center	Recruiting
Durham, North Carolina, United States, 27710
Contact: Russell P. Hall, MD 919-684-3110 hall0009@mc.duke.du
Contact: E. William St. Clair, MD 919-684-4499 stcla003@mc.duke.edu
United States, Pennsylvania
University of Pennsylvania	Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Victoria Werth, MD 315-662-2399 werth@mail.med.upenn.edu

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Autoimmunity Centers of Excellence

Investigators

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

More Information

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.

Responsible Party:	DAIT/NIAID ( Associate Director, Clinical Research Program )
Study ID Numbers:	DAIT APV01
Study First Received:	January 26, 2006
Last Updated:	September 26, 2008
ClinicalTrials.gov Identifier:	NCT00283712 History of Changes
Health Authority:	United States: Food and Drug Administration

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

Skin Diseases
Autoimmune Diseases

Additional relevant MeSH terms:

Anti-Inflammatory Agents
Prednisone
Autoimmune Diseases
Skin Diseases, Vesiculobullous
Skin Diseases
Immune System Diseases
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Infliximab
Physiological Effects of Drugs

Gastrointestinal Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Glucocorticoids
Hormones
Pharmacologic Actions
Pemphigus
Therapeutic Uses
Antirheumatic Agents
Dermatologic Agents

ClinicalTrials.gov processed this record on February 08, 2010