IVIG With Rituximab vs Rituximab as First Line Treatment of Pemphigus

Study Overview
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Brief Summary
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Pemphigus is a rare acquired autoimmune disease in which immunoglobulin G (IgG) antibodies target desmosomal proteins to produce intraepithelial, and mucocutaneous blisters. It is potentially fatal and the average mortality of pemphigus vulgaris (PV) was 75% before the introduction of corticosteroids in the early 1950s. Traditionally, treatment of pemphigus included high dose systemic corticosteroids with or without adjuvant immunosuppressants. However; the prolonged use of high dose steroids carries significant side effects. A recent randomized trial has proved the efficacy of Rituximab, a monoclonal anti-CD20 antibody against B-lymphocytes, as an efficacious therapy for pemphigus. Early use of rituximab was associated with better clinical outcomes, hence combination treatment of rituximab and intravenous immunoglobulins (IVIG) has shown to be effective for refractory pemphigus cases and can potentially induce long-term complete remission and lower risks infectious complications. In this study, investigators will evaluate the efficacy and safety of early use of rituximab with or without IVIG in patients with moderate to severe pemphigus using protocols that were similar to those previously published, investigators will also aim to measure the impact of health care economics and in doing so, assess the cost and benefits of both treatment arms.

Detailed Description
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Pemphigus is a rare acquired autoimmune disease in which immunoglobulin G (IgG) antibodies target desmosomal proteins to produce intraepithelial, and mucocutaneous blisters. It is potentially fatal and the average mortality of pemphigus vulgaris (PV) was 75% before the introduction of corticosteroids in the early 1950s. Traditionally, treatment of pemphigus included high dose systemic corticosteroids with or without adjuvant immunosuppressants. However; the prolonged use of high dose steroids carries significant side effects. A recent randomized trial has proved the efficacy of Rituximab, a monoclonal anti-CD20 antibody against B-lymphocytes, as an efficacious therapy for pemphigus. Furthermore, early use of rituximab was associated with associated with better clinical outcomes. Moreover, combination treatment of rituximab and intravenous immunoglobulins (IVIG) has shown to be effective for refractory pemphigus cases and can potentially induce long-term complete remission and lower risks infectious complications. Cost effectiveness is an important issue and while combination of IVIG and rituximab has been advocated, the cost of such treatment is substantial and whether it poses any benefit over rituximab alone, or with other more conventional immunosuppressive agents, has not been established. Both treatment approaches have been previously published in high impact journals. In this study, investigators aim to evaluate the efficacy and safety of early use of rituximab with or without IVIG in patients with moderate to severe pemphigus using protocols that were similar to those previously published. Apart from complete remission and adverse effects, investigators will also aim to measure the impact of health care economics and in doing so, assess the cost and benefits of both treatment arms.

Official Title
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The Use of IVIG in Combination With Rituximab VS Rituximab as the First Line Treatment of Pemphigus

Conditions
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Pemphigus

Intervention / Treatment
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* Drug: Rituximab
* Other: IVIg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent obtained from patient Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult) Newly or recently diagnosed (less than 18 months) diagnosed pemphigus vulgaris or pemphigus foliaceus based on clinical features; histological features of acantholysis via skin or mucosal biopsy; and intercellular staining pattern of indirect immunofluorescence or serological detection of DSG 1 or DSG 3 by enzyme-linked immunosorbent assay (ELISA) Moderate to severe active disease, as defined by overall PDAI >= 15 or skin involvement BSA>= 5%. 9 [Annex 1] Receiving standard-of-care oral prednisolone up to 1.5 mg/kg/day Women who are sexually active and not postmenopausal, agreement to remain abstinent or use 2 effective methods of contraception. Ability to comply with study protocol as deemed by investigator's assessment Exclusion criteria: Age <18 or >75 Pregnant women or nursing mother Already diagnosed pemphigus patients diagnosed > 18 months Non-consenting patients, or patient who cannot be followed up regularly Patient with history of serious allergy or anaphylactic reaction to monoclonal antibody treatment Severe heart failure (NYHA Class III or IV) Unstable angina or myocardiac infarction within last 3 months or post-infarction heart failure Anaemia (haemoglobin <10g/dL), Neutropenia (<1000/mm3), Lymphopenia (<900/mm3), thrombocytopenia (<100,000/mm3) Renal insufficiency eGFR <60 Liver insufficiency of ALT/ALT > 2 times normal limit range Positive test results for hepatitis C (HCV) serology at screening *Patients who are HepBs Ag positive, or HepBs Ag negative and anti-HepBc Ab - positive: Patients who are HepBs Ag positive - will be started on entecavir 0.5mg daily, and will be referred to a gastroenterologist for further follow up. Patients who are HepBs Ag negative, and HBc Ab positive, with detectable HepB DNA levels - will be started on entecavir 0.5mg daily, and will be referred to a gastroenterologist for further follow up. Patients who are HepBs Ag negative, HBc Ab positive, with no detectable HepB DNA levels - will be started on entecavir 0.5mg daily, and will be continued on entecavir for at least 18 months after completion of last dose of rituximab. Blood test positive for HIV Signs of active infection on CXR Positive interferon gamma release assay Quantiferon or T.Spot TB test: must be treated with at least 4 weeks post initiation of isoniazid or other TB therapy Inherited or acquired severe immunodeficiency History of malignancy Patient with active severe infection (excluding fungal infections of the nail), which has required antibiotic treatment within 2 week prior to study enrolment Infection requiring hospitalisation or intravenous antibiotic treatment within the last 8 weeks prior to enrolment Past history of osteomyelitis, or fasciitis, septic arthritis within the last one year Patients with drug induced pemphigus. A thorough medication history will be taken to rule out drug induced pemphigus including D-penicillamine, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and cephalosporins Evidence of any new or uncontrolled concomitant disease that in the investigators' judgement would preclude the patients participation Patients with history of allergy or adverse events to IVIG or rituximab treatment10 Treatment with intravenous immunoglobulins, plasmaphoresis within the last 8 weeks prior to randomization Previous treatment with rituximab or any monoclonal antibody inducing profound lymphopenia Treatment with live or attenuated vaccine within the last 28 days prior to randomization

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rituximab only<br>Rituximab infusion 375mg/m2 body surface area (BSA) weekly for 4 weeks from baseline (week 0, 1, 2, 3) Rituximab infusion 375mg/m2 BSA weekly for 4 weeks at week 24 (week 24, 25, 26, 27) Rituximab infusion 375mg/m2 BSA weekly for 2 weeks at week 52 (week 52, 53) Rituximab infusion 375mg/m2 BSA weekly for 4 weeks at week 76 (week 76, 77) A total of 12 doses of rituximab will be given in 55 weeks | Drug: Rituximab<br>* Rituximab would be given intravenously. IV Rituximab is prediluted at a dose of 500mg in 500ml of 0.9% normal saline (i.e. 1:1 dilution, 1 mg/ml) Initial infusion rate starts at a rate of 50mg/hr (50ml/hr) If no hypersensitivity/anaphylaxis reaction occurs, increase infusion rate in 50mg/hr (50 ml/hr) increments every 30 minutes Maximum infusion rate is 400 mg/hr (400 ml/hr) Subsequent infusion: start at rate of 100mg/hr (100 ml/hr), increase 100mg/hr (100 ml/hr) increments every 30 minutes Monitor temperature, BP HR, respiratory rate and SpO2 every 30 minutes<br>* Other names: MabThera;|
| Experimental: Rituximab and IVIG<br>Rituximab (375 mg/m2 BSA) once a week for 4 weeks (week 1, 2, 3); Week 4: Rituximab + IVIG 2g per kg Week 5, 6, 7: Above treatment repeated for 2nd cycle, infusion of rituximab (375 mg/m2 BSA) once a week for 4 weeks (week 5, 6, 7); Week 8: Rituximab + IVIG 2g/kg In months 3, 4, 5, 6, patients received a single infusion of rituximab (375 mg/m2 BSA) plus infusion of 2g/kg IVIG Thus in 6-month period patients received a total of 12 infusions of rituximab and 7 infusions of IVIG If a patient was clinically free of disease at end of 6 months, additional infusions of IVIG will be given at week 30, 38, 48, 60 and 76 A total of 12 doses of rituximab and 12 cycles of IVIG will be given | Drug: Rituximab<br>* Rituximab would be given intravenously. IV Rituximab is prediluted at a dose of 500mg in 500ml of 0.9% normal saline (i.e. 1:1 dilution, 1 mg/ml) Initial infusion rate starts at a rate of 50mg/hr (50ml/hr) If no hypersensitivity/anaphylaxis reaction occurs, increase infusion rate in 50mg/hr (50 ml/hr) increments every 30 minutes Maximum infusion rate is 400 mg/hr (400 ml/hr) Subsequent infusion: start at rate of 100mg/hr (100 ml/hr), increase 100mg/hr (100 ml/hr) increments every 30 minutes Monitor temperature, BP HR, respiratory rate and SpO2 every 30 minutes<br>* Other names: MabThera;Other: IVIg<br>* IVIg would be given in combination with Rituximab intravenously. Infusion plan of IVIg: 0 min: 50ml/hour 15 min: 75ml/hour 30 min: 100ml/hour 45 min: 125ml/hour 60 min: 150ml/hour 75 min & beyond: 180ml/hour<br>* Other names: Privigen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| relapse-free complete remission | Percentage of participants who achieve relapse-free complete remission | From baseline up to 208 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to protocol defined disease flare | Time to protocol defined disease flare | From baseline up to 208 weeks | 
| Duration of complete remission | Duration of complete remission, evaluated by the PDAI activity score | From baseline up to 208 weeks | 
| Number of protocol defined disease flares | Number of protocol defined disease flares | From baseline up to 208 weeks | 
| Time to initial complete remission | Time to initial complete remission, evaluated by the PDAI activity score | From baseline up to 208 weeks | 
| Change in health-related quality of life: Dermatology Life Quality Index (DLQI) Score | Change in health-related quality of life as measured by the Dermatology Life Quality Index (DLQI) Score. The DLQI is calculated by summing the score of each question resulting in maximum of 30 and a minimum of 0. The higher the score, the more quality of life is impaired. | Baseline, Week 4, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192 | 
| Occurrence of severe treatment adverse events | Safety endpoints: Occurrence of treatment adverse events, serious adverse events (grade 3 or 4) based on common terminology criteria for adverse events (CTCAE). Death from any cause. Adverse events leading to discontinuation, vital signs, and laboratory tests | Baseline, week 4, 12, 24, 36, 48, 60, 72, 96, 120, 144, 168, 192 | 
| Blood DSG 1 and 3 levels | Blood DSG 1 and 3 levels | Baseline week 0, week 4, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192 | 
| Blood lymphocyte level (CBC) | Blood lymphocyte level (CBC) | Baseline week 0, week 4, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192 | 
| Blood CD19/20 mean B cell counts percentage | Blood CD19/20 mean B cell counts percentage | Week 0, week 4, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192 | 
| Number of rescue therapy given | Number of rescue therapy given | Baseline up to Week 208 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pemphigus, intravenous immunoglobulins, rituximab