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IVIG With Rituximab vs Rituximab as First Line Treatment of Pemphigus

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04400994
Recruitment Status : Recruiting
First Posted : May 26, 2020
Last Update Posted : June 22, 2020
Sponsor:
Information provided by (Responsible Party):
Dr. Mandy Chan, The University of Hong Kong

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Pemphigus Drug: Rituximab Other: IVIg Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Use of IVIG in Combination With Rituximab VS Rituximab as the First Line Treatment of Pemphigus
Actual Study Start Date : June 20, 2020
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Pemphigus
Drug Information available for: Rituximab

Arm Intervention/treatment
Active Comparator: Rituximab only
  • 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 4 weeks at week 52 (week 52, 53, 54, 55)
  • A total of 12 doses of rituximab will be given in 55 weeks
Drug: Rituximab

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
Other Name: MabThera

Experimental: Rituximab and IVIG
  • 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

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
Other Name: MabThera

Other: IVIg

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

Other Name: Privigen




Primary Outcome Measures :
  1. relapse-free complete remission [ Time Frame: From baseline up to 208 weeks ]
    Percentage of participants who achieve relapse-free complete remission


Secondary Outcome Measures :
  1. Time to protocol defined disease flare [ Time Frame: From baseline up to 104 weeks ]
    Time to protocol defined disease flare

  2. Duration of complete remission [ Time Frame: From baseline up to 104 weeks ]
    Duration of complete remission, evaluated by the PDAI activity score

  3. Number of protocol defined disease flares [ Time Frame: From baseline up to 104 weeks ]
    Number of protocol defined disease flares

  4. Time to initial complete remission [ Time Frame: From baseline up to 104 weeks ]
    Time to initial complete remission, evaluated by the PDAI activity score

  5. Change in health-related quality of life: Dermatology Life Quality Index (DLQI) Score [ Time Frame: Baseline, Week 12, 24, 36, 48, 60, 72, 84, 96, 104 ]

    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.


  6. Occurrence of severe treatment adverse events [ Time Frame: Baseline, week 4, 12, 24, 36, 48, 60, 72, 96, 120, 144, 168, 192 ]
    Occurrence of severe treatment adverse events (grade 3 or 4) based on based on common terminology criteria for adverse events (CTCAE), or death from any cause Blood DSG 1 and 3 levels

  7. Blood CD19/20 mean B cell counts percentage [ Time Frame: Baseline, week 4, 24, 36, 48, 60, 72, 96, 120, 144, 168, 180, 192 ]
    Blood CD19/20 mean B cell counts percentage

  8. Number of rescue therapy given [ Time Frame: From baseline up to 208 weeks ]
    Number of rescue therapy given



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent obtained from patient
  • Ages Eligible for Study: 18 years to 70 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 >70
  • 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 B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) or hepatitis C (HCV) serology at screening
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04400994


Contacts
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Contact: Wai Man Mandy Chan, MBBS +852 22554244 chanwmm@hku.hk
Contact: Tze Lei Judy Sham, MCoun +852 22556489 js83213@hku.hk

Locations
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Hong Kong
Department of Medicine Recruiting
Central, Hong Kong
Contact: Mandy Chan, MBBS    +852 22554244    chanwmm@hku.hk   
Contact: Judy Sham, MCoun    +852 22556489    js83213@hku.hk   
Sponsors and Collaborators
The University of Hong Kong
Investigators
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Principal Investigator: Wai Man Mandy Chan The University of Hong Kong
  Study Documents (Full-Text)

Documents provided by Dr. Mandy Chan, The University of Hong Kong:
Informed Consent Form  [PDF] December 2, 2019

Publications:
Joly P, Maho-Vaillant M, Prost-Squarcioni C, Hebert V, Houivet E, Calbo S, Caillot F, Golinski ML, Labeille B, Picard-Dahan C, Paul C, Richard MA, Bouaziz JD, Duvert-Lehembre S, Bernard P, Caux F, Alexandre M, Ingen-Housz-Oro S, Vabres P, Delaporte E, Quereux G, Dupuy A, Debarbieux S, Avenel-Audran M, D'Incan M, Bedane C, Bénéton N, Jullien D, Dupin N, Misery L, Machet L, Beylot-Barry M, Dereure O, Sassolas B, Vermeulin T, Benichou J, Musette P; French study group on autoimmune bullous skin diseases. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial. Lancet. 2017 May 20;389(10083):2031-2040. doi: 10.1016/S0140-6736(17)30070-3. Epub 2017 Mar 22.
US Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Common terminology criteria for Adverse Events (CTCAE), version 5.0: Nov 27, 2017.
Murrell DF, Peña S, Joly P, Marinovic B, Hashimoto T, Diaz LA, Sinha AA, Payne AS, Daneshpazhooh M, Eming R, Jonkman MF, Mimouni D, Borradori L, Kim SC, Yamagami J, Lehman JS, Saleh MA, Culton DA, Czernik A, Zone JJ, Fivenson D, Ujiie H, Wozniak K, Akman-Karakaş A, Bernard P, Korman NJ, Caux F, Drenovska K, Prost-Squarcioni C, Vassileva S, Feldman RJ, Cardones AR, Bauer J, Ioannides D, Jedlickova H, Palisson F, Patsatsi A, Uzun S, Yayli S, Zillikens D, Amagai M, Hertl M, Schmidt E, Aoki V, Grando SA, Shimizu H, Baum S, Cianchini G, Feliciani C, Iranzo P, Mascaró JM Jr, Kowalewski C, Hall R, Groves R, Harman KE, Marinkovich MP, Maverakis E, Werth VP. Diagnosis and management of pemphigus: Recommendations of an international panel of experts. J Am Acad Dermatol. 2020 Mar;82(3):575-585.e1. doi: 10.1016/j.jaad.2018.02.021. Epub 2018 Feb 10.

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Responsible Party: Dr. Mandy Chan, Clinical Assistant Professor of Practice, The University of Hong Kong
ClinicalTrials.gov Identifier: NCT04400994    
Other Study ID Numbers: UW19-671
First Posted: May 26, 2020    Key Record Dates
Last Update Posted: June 22, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Dr. Mandy Chan, The University of Hong Kong:
Pemphigus
intravenous immunoglobulins
rituximab
Additional relevant MeSH terms:
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Pemphigus
Skin Diseases, Vesiculobullous
Skin Diseases
Autoimmune Diseases
Immune System Diseases
Rituximab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents