<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04400994</url>
  </required_header>
  <id_info>
    <org_study_id>UW19-671</org_study_id>
    <nct_id>NCT04400994</nct_id>
  </id_info>
  <brief_title>IVIG With Rituximab vs Rituximab as First Line Treatment of Pemphigus</brief_title>
  <official_title>The Use of IVIG in Combination With Rituximab VS Rituximab as the First Line Treatment of Pemphigus</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The University of Hong Kong</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The University of Hong Kong</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Pemphigus is a rare acquired autoimmune disease in which immunoglobulin G (IgG) antibodies&#xD;
      target desmosomal proteins to produce intraepithelial, and mucocutaneous blisters. It is&#xD;
      potentially fatal and the average mortality of pemphigus vulgaris (PV) was 75% before the&#xD;
      introduction of corticosteroids in the early 1950s.&#xD;
&#xD;
      Traditionally, treatment of pemphigus included high dose systemic corticosteroids with or&#xD;
      without adjuvant immunosuppressants. However; the prolonged use of high dose steroids carries&#xD;
      significant side effects. A recent randomized trial has proved the efficacy of Rituximab, a&#xD;
      monoclonal anti-CD20 antibody against B-lymphocytes, as an efficacious therapy for pemphigus.&#xD;
      Early use of rituximab was associated with better clinical outcomes, hence combination&#xD;
      treatment of rituximab and intravenous immunoglobulins (IVIG) has shown to be effective for&#xD;
      refractory pemphigus cases and can potentially induce long-term complete remission and lower&#xD;
      risks infectious complications.&#xD;
&#xD;
      In this study, investigators will evaluate the efficacy and safety of early use of rituximab&#xD;
      with or without IVIG in patients with moderate to severe pemphigus using protocols that were&#xD;
      similar to those previously published, investigators will also aim to measure the impact of&#xD;
      health care economics and in doing so, assess the cost and benefits of both treatment arms.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Pemphigus is a rare acquired autoimmune disease in which immunoglobulin G (IgG) antibodies&#xD;
      target desmosomal proteins to produce intraepithelial, and mucocutaneous blisters. It is&#xD;
      potentially fatal and the average mortality of pemphigus vulgaris (PV) was 75% before the&#xD;
      introduction of corticosteroids in the early 1950s.&#xD;
&#xD;
      Traditionally, treatment of pemphigus included high dose systemic corticosteroids with or&#xD;
      without adjuvant immunosuppressants. However; the prolonged use of high dose steroids carries&#xD;
      significant side effects. A recent randomized trial has proved the efficacy of Rituximab, a&#xD;
      monoclonal anti-CD20 antibody against B-lymphocytes, as an efficacious therapy for pemphigus.&#xD;
      Furthermore, early use of rituximab was associated with associated with better clinical&#xD;
      outcomes. Moreover, combination treatment of rituximab and intravenous immunoglobulins (IVIG)&#xD;
      has shown to be effective for refractory pemphigus cases and can potentially induce long-term&#xD;
      complete remission and lower risks infectious complications.&#xD;
&#xD;
      Cost effectiveness is an important issue and while combination of IVIG and rituximab has been&#xD;
      advocated, the cost of such treatment is substantial and whether it poses any benefit over&#xD;
      rituximab alone, or with other more conventional immunosuppressive agents, has not been&#xD;
      established. Both treatment approaches have been previously published in high impact&#xD;
      journals.&#xD;
&#xD;
      In this study, investigators aim to evaluate the efficacy and safety of early use of&#xD;
      rituximab with or without IVIG in patients with moderate to severe pemphigus using protocols&#xD;
      that were similar to those previously published. Apart from complete remission and adverse&#xD;
      effects, investigators will also aim to measure the impact of health care economics and in&#xD;
      doing so, assess the cost and benefits of both treatment arms.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">June 20, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>relapse-free complete remission</measure>
    <time_frame>From baseline up to 208 weeks</time_frame>
    <description>Percentage of participants who achieve relapse-free complete remission</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to protocol defined disease flare</measure>
    <time_frame>From baseline up to 208 weeks</time_frame>
    <description>Time to protocol defined disease flare</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of complete remission</measure>
    <time_frame>From baseline up to 208 weeks</time_frame>
    <description>Duration of complete remission, evaluated by the PDAI activity score</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of protocol defined disease flares</measure>
    <time_frame>From baseline up to 208 weeks</time_frame>
    <description>Number of protocol defined disease flares</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to initial complete remission</measure>
    <time_frame>From baseline up to 208 weeks</time_frame>
    <description>Time to initial complete remission, evaluated by the PDAI activity score</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in health-related quality of life: Dermatology Life Quality Index (DLQI) Score</measure>
    <time_frame>Baseline, Week 4, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192</time_frame>
    <description>Change in health-related quality of life as measured by the Dermatology Life Quality Index (DLQI) Score.&#xD;
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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Occurrence of severe treatment adverse events</measure>
    <time_frame>Baseline, week 4, 12, 24, 36, 48, 60, 72, 96, 120, 144, 168, 192</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood DSG 1 and 3 levels</measure>
    <time_frame>Baseline week 0, week 4, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192</time_frame>
    <description>Blood DSG 1 and 3 levels</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood lymphocyte level (CBC)</measure>
    <time_frame>Baseline week 0, week 4, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192</time_frame>
    <description>Blood lymphocyte level (CBC)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood CD19/20 mean B cell counts percentage</measure>
    <time_frame>Week 0, week 4, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192</time_frame>
    <description>Blood CD19/20 mean B cell counts percentage</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of rescue therapy given</measure>
    <time_frame>Baseline up to Week 208</time_frame>
    <description>Number of rescue therapy given</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Pemphigus</condition>
  <arm_group>
    <arm_group_label>Rituximab only</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Rituximab infusion 375mg/m2 body surface area (BSA) weekly for 4 weeks from baseline (week 0, 1, 2, 3)&#xD;
Rituximab infusion 375mg/m2 BSA weekly for 4 weeks at week 24 (week 24, 25, 26, 27)&#xD;
Rituximab infusion 375mg/m2 BSA weekly for 2 weeks at week 52 (week 52, 53)&#xD;
Rituximab infusion 375mg/m2 BSA weekly for 4 weeks at week 76 (week 76, 77)&#xD;
A total of 12 doses of rituximab will be given in 55 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Rituximab and IVIG</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Rituximab (375 mg/m2 BSA) once a week for 4 weeks (week 1, 2, 3);&#xD;
Week 4: Rituximab + IVIG 2g per kg&#xD;
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);&#xD;
Week 8: Rituximab + IVIG 2g/kg&#xD;
In months 3, 4, 5, 6, patients received a single infusion of rituximab (375 mg/m2 BSA) plus infusion of 2g/kg IVIG&#xD;
Thus in 6-month period patients received a total of 12 infusions of rituximab and 7 infusions of IVIG&#xD;
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&#xD;
A total of 12 doses of rituximab and 12 cycles of IVIG will be given</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Rituximab would be given intravenously.&#xD;
IV Rituximab is prediluted at a dose of 500mg in 500ml of 0.9% normal saline (i.e. 1:1 dilution, 1 mg/ml)&#xD;
Initial infusion rate starts at a rate of 50mg/hr (50ml/hr)&#xD;
If no hypersensitivity/anaphylaxis reaction occurs, increase infusion rate in 50mg/hr (50 ml/hr) increments every 30 minutes&#xD;
Maximum infusion rate is 400 mg/hr (400 ml/hr)&#xD;
Subsequent infusion: start at rate of 100mg/hr (100 ml/hr), increase 100mg/hr (100 ml/hr) increments every 30 minutes&#xD;
Monitor temperature, BP HR, respiratory rate and SpO2 every 30 minutes</description>
    <arm_group_label>Rituximab and IVIG</arm_group_label>
    <arm_group_label>Rituximab only</arm_group_label>
    <other_name>MabThera</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>IVIg</intervention_name>
    <description>IVIg would be given in combination with Rituximab intravenously. Infusion plan of IVIg:&#xD;
0 min: 50ml/hour 15 min: 75ml/hour 30 min: 100ml/hour 45 min: 125ml/hour 60 min: 150ml/hour 75 min &amp; beyond: 180ml/hour</description>
    <arm_group_label>Rituximab and IVIG</arm_group_label>
    <other_name>Privigen</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Written informed consent obtained from patient&#xD;
&#xD;
          -  Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)&#xD;
&#xD;
          -  Newly or recently diagnosed (less than 18 months) diagnosed pemphigus vulgaris or&#xD;
             pemphigus foliaceus based on clinical features; histological features of acantholysis&#xD;
             via skin or mucosal biopsy; and intercellular staining pattern of indirect&#xD;
             immunofluorescence or serological detection of DSG 1 or DSG 3 by enzyme-linked&#xD;
             immunosorbent assay (ELISA)&#xD;
&#xD;
          -  Moderate to severe active disease, as defined by overall PDAI &gt;= 15 or skin&#xD;
             involvement BSA&gt;= 5%. 9 [Annex 1]&#xD;
&#xD;
          -  Receiving standard-of-care oral prednisolone up to 1.5 mg/kg/day&#xD;
&#xD;
          -  Women who are sexually active and not postmenopausal, agreement to remain abstinent or&#xD;
             use 2 effective methods of contraception.&#xD;
&#xD;
          -  Ability to comply with study protocol as deemed by investigator's assessment&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  Age &lt;18 or &gt;70&#xD;
&#xD;
          -  Pregnant women or nursing mother&#xD;
&#xD;
          -  Already diagnosed pemphigus patients diagnosed &gt; 18 months&#xD;
&#xD;
          -  Non-consenting patients, or patient who cannot be followed up regularly&#xD;
&#xD;
          -  Patient with history of serious allergy or anaphylactic reaction to monoclonal&#xD;
             antibody treatment&#xD;
&#xD;
          -  Severe heart failure (NYHA Class III or IV)&#xD;
&#xD;
          -  Unstable angina or myocardiac infarction within last 3 months or post-infarction heart&#xD;
             failure&#xD;
&#xD;
          -  Anaemia (haemoglobin &lt;10g/dL), Neutropenia (&lt;1000/mm3), Lymphopenia (&lt;900/mm3),&#xD;
             thrombocytopenia (&lt;100,000/mm3)&#xD;
&#xD;
          -  Renal insufficiency eGFR &lt;60&#xD;
&#xD;
          -  Liver insufficiency of ALT/ALT &gt; 2 times normal limit range&#xD;
&#xD;
          -  Positive test results for hepatitis C (HCV) serology at screening *Patients who are&#xD;
             HepBs Ag positive, or HepBs Ag negative and anti-HepBc Ab - positive: Patients who are&#xD;
             HepBs Ag positive - will be started on entecavir 0.5mg daily, and will be referred to&#xD;
             a gastroenterologist for further follow up.&#xD;
&#xD;
        Patients who are HepBs Ag negative, and HBc Ab positive, with detectable HepB DNA levels -&#xD;
        will be started on entecavir 0.5mg daily, and will be referred to a gastroenterologist for&#xD;
        further follow up.&#xD;
&#xD;
        Patients who are HepBs Ag negative, HBc Ab positive, with no detectable HepB DNA levels -&#xD;
        will be started on entecavir 0.5mg daily, and will be continued on entecavir for at least&#xD;
        18 months after completion of last dose of rituximab.&#xD;
&#xD;
          -  Blood test positive for HIV&#xD;
&#xD;
          -  Signs of active infection on CXR&#xD;
&#xD;
          -  Positive interferon gamma release assay Quantiferon or T.Spot TB test: must be treated&#xD;
             with at least 4 weeks post initiation of isoniazid or other TB therapy&#xD;
&#xD;
          -  Inherited or acquired severe immunodeficiency&#xD;
&#xD;
          -  History of malignancy&#xD;
&#xD;
          -  Patient with active severe infection (excluding fungal infections of the nail), which&#xD;
             has required antibiotic treatment within 2 week prior to study enrolment&#xD;
&#xD;
          -  Infection requiring hospitalisation or intravenous antibiotic treatment within the&#xD;
             last 8 weeks prior to enrolment&#xD;
&#xD;
          -  Past history of osteomyelitis, or fasciitis, septic arthritis within the last one year&#xD;
&#xD;
          -  Patients with drug induced pemphigus. A thorough medication history will be taken to&#xD;
             rule out drug induced pemphigus including D-penicillamine, angiotensin-converting&#xD;
             enzyme inhibitors, angiotensin receptor blockers and cephalosporins&#xD;
&#xD;
          -  Evidence of any new or uncontrolled concomitant disease that in the investigators'&#xD;
             judgement would preclude the patients participation&#xD;
&#xD;
          -  Patients with history of allergy or adverse events to IVIG or rituximab treatment10&#xD;
&#xD;
          -  Treatment with intravenous immunoglobulins, plasmaphoresis within the last 8 weeks&#xD;
             prior to randomization&#xD;
&#xD;
          -  Previous treatment with rituximab or any monoclonal antibody inducing profound&#xD;
             lymphopenia&#xD;
&#xD;
          -  Treatment with live or attenuated vaccine within the last 28 days prior to&#xD;
             randomization&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sze Man Wong, MBBS</last_name>
    <role>Principal Investigator</role>
    <affiliation>The University of Hong Kong</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Medicine</name>
      <address>
        <city>Central</city>
        <country>Hong Kong</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Hong Kong</country>
  </location_countries>
  <reference>
    <citation>Harman KE, Brown D, Exton LS, Groves RW, Hampton PJ, Mohd Mustapa MF, Setterfield JF, Yesudian PD. British Association of Dermatologists' guidelines for the management of pemphigus vulgaris 2017. Br J Dermatol. 2017 Nov;177(5):1170-1201. doi: 10.1111/bjd.15930. No abstract available.</citation>
    <PMID>29192996</PMID>
  </reference>
  <reference>
    <citation>Hertl M, Jedlickova H, Karpati S, Marinovic B, Uzun S, Yayli S, Mimouni D, Borradori L, Feliciani C, Ioannides D, Joly P, Kowalewski C, Zambruno G, Zillikens D, Jonkman MF. Pemphigus. S2 Guideline for diagnosis and treatment--guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV). J Eur Acad Dermatol Venereol. 2015 Mar;29(3):405-14. doi: 10.1111/jdv.12772. Epub 2014 Oct 22.</citation>
    <PMID>25338479</PMID>
  </reference>
  <reference>
    <citation>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, Beneton 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.</citation>
    <PMID>28342637</PMID>
  </reference>
  <reference>
    <citation>Lunardon L, Tsai KJ, Propert KJ, Fett N, Stanley JR, Werth VP, Tsai DE, Payne AS. Adjuvant rituximab therapy of pemphigus: a single-center experience with 31 patients. Arch Dermatol. 2012 Sep;148(9):1031-6. doi: 10.1001/archdermatol.2012.1522.</citation>
    <PMID>22710375</PMID>
  </reference>
  <reference>
    <citation>Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med. 2006 Oct 26;355(17):1772-9. doi: 10.1056/NEJMoa062930.</citation>
    <PMID>17065638</PMID>
  </reference>
  <reference>
    <citation>Feldman RJ, Christen WG, Ahmed AR. Comparison of immunological parameters in patients with pemphigus vulgaris following rituximab and IVIG therapy. Br J Dermatol. 2012 Mar;166(3):511-7. doi: 10.1111/j.1365-2133.2011.10658.x. Epub 2012 Jan 19.</citation>
    <PMID>21967407</PMID>
  </reference>
  <reference>
    <citation>Ahmed AR, Kaveri S. Reversing Autoimmunity Combination of Rituximab and Intravenous Immunoglobulin. Front Immunol. 2018 Jul 18;9:1189. doi: 10.3389/fimmu.2018.01189. eCollection 2018.</citation>
    <PMID>30072982</PMID>
  </reference>
  <reference>
    <citation>Ahmed AR, Nguyen T, Kaveri S, Spigelman ZS. First line treatment of pemphigus vulgaris with a novel protocol in patients with contraindications to systemic corticosteroids and immunosuppressive agents: Preliminary retrospective study with a seven year follow-up. Int Immunopharmacol. 2016 May;34:25-31. doi: 10.1016/j.intimp.2016.02.013. Epub 2016 Feb 23. Erratum In: Int Immunopharmacol. 2017 Jul;48:241.</citation>
    <PMID>26919279</PMID>
  </reference>
  <reference>
    <citation>Boulard C, Duvert Lehembre S, Picard-Dahan C, Kern JS, Zambruno G, Feliciani C, Marinovic B, Vabres P, Borradori L, Prost-Squarcioni C, Labeille B, Richard MA, Ingen-Housz-Oro S, Houivet E, Werth VP, Murrell DF, Hertl M, Benichou J, Joly P; International Pemphigus Study Group. Calculation of cut-off values based on the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and Pemphigus Disease Area Index (PDAI) pemphigus scoring systems for defining moderate, significant and extensive types of pemphigus. Br J Dermatol. 2016 Jul;175(1):142-9. doi: 10.1111/bjd.14405. Epub 2016 Apr 3.</citation>
    <PMID>26800395</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
  </reference>
  <reference>
    <citation>Murrell DF, Pena 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-Karakas 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, Mascaro 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.</citation>
    <PMID>29438767</PMID>
  </reference>
  <reference>
    <citation>Liu KSH, Seto WK, Lau EHY, Wong DK, Lam YF, Cheung KS, Mak LY, Ko KL, To WP, Law MWK, Wu JT, Lai CL, Yuen MF. A Territorywide Prevalence Study on Blood-Borne and Enteric Viral Hepatitis in Hong Kong. J Infect Dis. 2019 May 24;219(12):1924-1933. doi: 10.1093/infdis/jiz038.</citation>
    <PMID>30668746</PMID>
  </reference>
  <reference>
    <citation>Seto WK, Chan TS, Hwang YY, Wong DK, Fung J, Liu KS, Gill H, Lam YF, Lie AK, Lai CL, Kwong YL, Yuen MF. Hepatitis B reactivation in patients with previous hepatitis B virus exposure undergoing rituximab-containing chemotherapy for lymphoma: a prospective study. J Clin Oncol. 2014 Nov 20;32(33):3736-43. doi: 10.1200/JCO.2014.56.7081. Epub 2014 Oct 6.</citation>
    <PMID>25287829</PMID>
  </reference>
  <reference>
    <citation>Tsai YF, Yang CI, Du JS, Lin MH, Tang SH, Wang HC, Cho SF, Liu YC, Su YC, Dai CY, Hsiao HH. Rituximab increases the risk of hepatitis B virus reactivation in non-Hodgkin lymphoma patients who are hepatitis B surface antigen-positive or have resolved hepatitis B virus infection in a real-world setting: a retrospective study. PeerJ. 2019 Sep 9;7:e7481. doi: 10.7717/peerj.7481. eCollection 2019.</citation>
    <PMID>31565551</PMID>
  </reference>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>April 27, 2020</study_first_submitted>
  <study_first_submitted_qc>May 19, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 26, 2020</study_first_posted>
  <last_update_submitted>August 26, 2023</last_update_submitted>
  <last_update_submitted_qc>August 26, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 30, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The University of Hong Kong</investigator_affiliation>
    <investigator_full_name>Dr. Sze-Man Wong</investigator_full_name>
    <investigator_title>Honorary Clinical Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>Pemphigus</keyword>
  <keyword>intravenous immunoglobulins</keyword>
  <keyword>rituximab</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pemphigus</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rituximab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04400994
org study id: UW19-671
nct id: NCT04400994
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: relapse-free complete remission
time frame: From baseline up to 208 weeks
description: Percentage of participants who achieve relapse-free complete remission
measure: Time to protocol defined disease flare
time frame: From baseline up to 208 weeks
description: Time to protocol defined disease flare
measure: Duration of complete remission
time frame: From baseline up to 208 weeks
description: Duration of complete remission, evaluated by the PDAI activity score
measure: Number of protocol defined disease flares
time frame: From baseline up to 208 weeks
description: Number of protocol defined disease flares
measure: Time to initial complete remission
time frame: From baseline up to 208 weeks
description: Time to initial complete remission, evaluated by the PDAI activity score
measure: Change in health-related quality of life: Dermatology Life Quality Index (DLQI) Score
time frame: Baseline, Week 4, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192
description: 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.
measure: Occurrence of severe treatment adverse events
time frame: Baseline, week 4, 12, 24, 36, 48, 60, 72, 96, 120, 144, 168, 192
description: 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
measure: Blood DSG 1 and 3 levels
time frame: Baseline week 0, week 4, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192
description: Blood DSG 1 and 3 levels
measure: Blood lymphocyte level (CBC)
time frame: Baseline week 0, week 4, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192
description: Blood lymphocyte level (CBC)
measure: Blood CD19/20 mean B cell counts percentage
time frame: Week 0, week 4, 12, 24, 36, 48, 60, 72, 84, 96, 120, 144, 168, 192
description: Blood CD19/20 mean B cell counts percentage
measure: Number of rescue therapy given
time frame: Baseline up to Week 208
description: Number of rescue therapy given
arm group label: Rituximab only
arm group type: Active Comparator
description: 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
arm group label: Rituximab and IVIG
arm group type: Experimental
description: 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
intervention type: Drug
intervention name: Rituximab
description: 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
arm group label: Rituximab and IVIG
arm group label: Rituximab only
other name: MabThera
intervention type: Other
intervention name: IVIg
description: 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
arm group label: Rituximab and IVIG
other name: Privigen
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Sze Man Wong, MBBS
role: Principal Investigator
affiliation: The University of Hong Kong
facility: 
country: Hong Kong
citation: Harman KE, Brown D, Exton LS, Groves RW, Hampton PJ, Mohd Mustapa MF, Setterfield JF, Yesudian PD. British Association of Dermatologists' guidelines for the management of pemphigus vulgaris 2017. Br J Dermatol. 2017 Nov;177(5):1170-1201. doi: 10.1111/bjd.15930. No abstract available.
PMID: 29192996
citation: Hertl M, Jedlickova H, Karpati S, Marinovic B, Uzun S, Yayli S, Mimouni D, Borradori L, Feliciani C, Ioannides D, Joly P, Kowalewski C, Zambruno G, Zillikens D, Jonkman MF. Pemphigus. S2 Guideline for diagnosis and treatment--guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV). J Eur Acad Dermatol Venereol. 2015 Mar;29(3):405-14. doi: 10.1111/jdv.12772. Epub 2014 Oct 22.
PMID: 25338479
citation: 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, Beneton 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.
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citation: Lunardon L, Tsai KJ, Propert KJ, Fett N, Stanley JR, Werth VP, Tsai DE, Payne AS. Adjuvant rituximab therapy of pemphigus: a single-center experience with 31 patients. Arch Dermatol. 2012 Sep;148(9):1031-6. doi: 10.1001/archdermatol.2012.1522.
PMID: 22710375
citation: Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med. 2006 Oct 26;355(17):1772-9. doi: 10.1056/NEJMoa062930.
PMID: 17065638
citation: Feldman RJ, Christen WG, Ahmed AR. Comparison of immunological parameters in patients with pemphigus vulgaris following rituximab and IVIG therapy. Br J Dermatol. 2012 Mar;166(3):511-7. doi: 10.1111/j.1365-2133.2011.10658.x. Epub 2012 Jan 19.
PMID: 21967407
citation: Ahmed AR, Kaveri S. Reversing Autoimmunity Combination of Rituximab and Intravenous Immunoglobulin. Front Immunol. 2018 Jul 18;9:1189. doi: 10.3389/fimmu.2018.01189. eCollection 2018.
PMID: 30072982
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PMID: 26800395
citation: 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.
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PMID: 31565551
responsible party type: Principal Investigator
investigator affiliation: The University of Hong Kong
investigator full name: Dr. Sze-Man Wong
investigator title: Honorary Clinical Assistant Professor
mesh term: Pemphigus
mesh term: Rituximab
sharing ipd: No