Efficacy and Safety of Rituximab Combined With Omalizumab in Patients With Bullous Pemphigoid

An Open-Label Study to Evaluate the Efficacy and Safety of Rituximab Combined With Omalizumab in Patients With Bullous Pemphigoid

To evaluate the efficacy of rituximab combined with omalizumab in achieving sustained complete remission, evaluated by Bullous Pemphigoid Disease Area Index (BPDAI) in patients with bullous pemphigoid (BP) at Week 24 in patients with active moderate-to-severe BP refractory to rituximab therapy alone.

Study Overview

• Status: Withdrawn
• Conditions: Bullous Pemphigoid
• Intervention / Treatment: Drug: Rituximab combined with Omalizumab

Detailed Description

This is an open-label, noncontrolled, single center prospective study to evaluate the efficacy and safety of rituximab combined with omalizumab in patients with active moderate-to-severe BP refractory to rituximab treatment alone. Patients must have a confirmed diagnosis of BP and evidence of refractory disease after initiation of rituximab treatment at least 8 weeks prior.

Refractory disease will be defined as a failure of therapy (development of new non-transient lesions or continued extension of old lesions, or failure of established lesions to begin to heal or continued pruritus) or evidence of a relapse/flare (Appearance of ≥3 new lesions/month (blisters, eczematous lesions, or urticarial plaques) or at least one large (>10 cm diameter) eczematous lesion or urticarial plaques that do not heal within 1 week, or extension of established lesions or daily pruritus in patient who have achieved disease control) based on the outcome measures defined for BP from an international panel of experts.41

This study will be conducted at the University of California, Davis Department of Dermatology's investigational site.

The study will consist of 3 periods: a screening period, 24-week treatment period, and a 28-week follow-up period. During the treatment period, patient visits will be monthly. After the primary endpoint at Week 24, follow up assessments will be scheduled every 3 months.

Rituximab 1000 mg will be administered by IV infusion 6 months after the patient's initial cycle of rituximab (received in the screening period). In order to reduce the frequency and severity of infusion-related reactions, all patients will be pre-medicated per the infusion center's therapy beacon protocol. Omalizumab (300 mg) will be administered subcutaneously every 2 weeks starting on Day 1.

All patients will be provided topical clobetasol 0.05% ointment or equivalent strength potency topical corticosteroid. Topical steroid application will be used 40 grams twice daily as needed for itch.

Patients can be discontinued from study treatment at any time during the study. Patients who withdraw from the treatment period will return to the clinic for an early withdrawal visit. After the withdrawal visit, the patient will be asked to enter the follow up period of the study.

From Week 1 through Week 52, patients who do not experience 50% improvement in their BPDAI at week 16 are eligible to receive rescue therapy with prednisone, another immunosuppressive medication (e.g. cellcept), IV Ig, or another treatment or procedure as per the investigator's best medical judgment. Patients who receive rescue therapy will be withdrawn from the study.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95816
      • University of California, Davis, Department of Dermatology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 86 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must be 18-90 years of age
• All individuals must have the ability to provide inform consent
• Patients diagnosed with bullous pemphigoid by biopsy, serum ELISA, direct immunofluorescence, indirect immunofluorescence
• Presence of moderate-to-severe active disease refractory to at least one cycle of rituximab therapy

Exclusion Criteria:

• Diagnosis of mucous membrane pemphigoid or evidence of other non-BP autoimmune blistering disease
• Individuals with allergic reaction or adverse reaction to humanized or murine monoclonal antibodies, or known hypersensitivity to any component of rituximab or omalizumab
• Evidence of acute infection or history of a chronic infection including viral hepatitis, recurrent HSV, AIDS, etc
• Women who are pregnant or actively nursing
• Evidence of any new or uncontrolled concomitant disease that, in the investigator's judgment, would preclude patient participation, including but not limited to cardiovascular, pulmonary, nervous system, renal, hepatic, endocrine, malignant, or gastrointestinal disorders
• Treatment with a live or attenuated vaccine within 28 days prior to first rituximab infusion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rituximab combined with Omalizumab; All patients will receive daily doxycycline, nicotinamide, and high-potency topical steroids. Additionally, all patients will receive rituximab combined with omalizumab.	Drug: Rituximab combined with Omalizumab; Rituximab 1000 mg will be administered by IV infusion 6 months after the patient's initial cycle of rituximab (received in the screening period).Omalizumab (300 mg) will be administered subcutaneously every 2 weeks starting on Day 1 until week 24 (primary endpoint) and again until week 52 (secondary endpoint).; Other Names: Xolair

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Remission	Complete remission is defined as achieving wound healing with no new active lesions (i.e. Bullous Pemphigoid Disease Area Index (BPDAI) score of 0) for at least 2 consecutive weeks during the 24-week treatment period. BPDAI scores can range from 0 to 360, with lower scores indicating less disease activity and better outcomes.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Remission	Proportion of patients achieving a sustained complete remission with rituximab combined with omalizumab at week 52	52 weeks
Number of Disease Flares	Total number of disease flares during the treatment period, as defined by appearance of three or more new lesions a month or at least one large (>10 cm diameter) eczematous lesion or urticarial plaques that do not heal within 1 week or by the extension of established lesions.	52 weeks
Time to Remission	Time to sustained complete remission	52 weeks
Time to Flares	Time to disease flare	52 weeks
Duration of Remission	Duration of sustained complete remission	52 weeks
Clinical Impression	Clinician impression of change in patients' BP symptoms, as measured by the Clinician Global Impression of Change (CGIC) score during the treatment period. The CGIC is a seven point scale to rate the severity of a patient's illness at the time of the assessment, with higher scores indicating better outcomes.	52 weeks
Patient Impression	Patients' impression of change in BP symptoms, as measured by the Patient Global Impression of Change (PGIC) score during the treatment period. The CGIC is a seven point scale to rate the severity of a patient's illness at the time of the assessment, with higher scores indicating better outcomes.	52 weeks
Improvement in Itch	Change in patients' scores in improvement of Itch Numeric Rating Scale (NRS) during the treatment period. The NRS is on a scale of 0 to 10 with 0 representing "no itch" and better outcomes.	52 weeks
Health-Related Quality of Life	Change in health-related quality of life, as measured by the Dermatology Life Quality Index (DLQI) score from baseline to Week 24. The DLQI is a ten item questionnaire with a sum total of 30 points. The higher the score, the more quality of life is impaired, indicating worse outcomes.	52 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events That Are Related to Treatment	To evaluate the safety of rituximab combined with omalizumab by monitoring adverse events related to treatment, such as number of abnormal laboratory values.	52 weeks
Gene Expression	To evaluate gene expression profiling of skin biopsies taken (1) before omalizumab therapy and (2) after omalizumab therapy.	52 weeks
Cumulative Corticosteroid Application	To evaluate total cumulative dose of topical corticosteroid applied during treatment and follow up periods	52 weeks

Collaborators and Investigators

• Sponsor: University of California, Davis
• Investigators: Principal Investigator: Emanual Maverakis, MD, UC Davis

Publications and helpful links

General Publications

• Ujiie H, Nishie W, Shimizu H. Pathogenesis of bullous pemphigoid. Dermatol Clin. 2011 Jul;29(3):439-46, ix. doi: 10.1016/j.det.2011.03.008.
• Maglie R, Hertl M. Pharmacological advances in pemphigoid. Curr Opin Pharmacol. 2019 Jun;46:34-43. doi: 10.1016/j.coph.2018.12.007. Epub 2019 Feb 13.

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2017
• Primary Completion (Estimated): May 25, 2023
• Study Completion (Estimated): November 25, 2023

Study Registration Dates

• First Submitted: October 12, 2019
• First Submitted That Met QC Criteria: October 15, 2019
• First Posted (Actual): October 16, 2019

Study Record Updates

• Last Update Posted (Actual): July 3, 2024
• Last Update Submitted That Met QC Criteria: July 1, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Rituximab; Omalizumab; Bullous Pemphigoid
• Additional Relevant MeSH Terms: Skin Diseases; Immune System Diseases; Autoimmune Diseases; Skin Diseases, Vesiculobullous; Pemphigoid, Bullous; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Anti-Asthmatic Agents; Respiratory System Agents; Anti-Allergic Agents; Rituximab; Omalizumab
• Other Study ID Numbers: 1510820

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No