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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Bullous Pemphigoid

Intervention / Treatment
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* Drug: Rituximab combined with Omalizumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab combined with Omalizumab<br>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<br>* 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).<br>* Other names: Xolair;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Omalizumab, Rituximab, Bullous Pemphigoid