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Trial record 20 of 117 for:    "Connective Tissue Disease" | "Methylprednisolone"

Synergetic B-cell Immunomodulation in SLE - 2nd Study. (SynBioSe-2)

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ClinicalTrials.gov Identifier: NCT03747159
Recruitment Status : Recruiting
First Posted : November 20, 2018
Last Update Posted : November 30, 2018
Sponsor:
Collaborators:
Dutch Kidney Foundation
GlaxoSmithKline
Information provided by (Responsible Party):
YTeng, Leiden University Medical Center

Tracking Information
First Submitted Date  ICMJE October 12, 2018
First Posted Date  ICMJE November 20, 2018
Last Update Posted Date November 30, 2018
Actual Study Start Date  ICMJE October 1, 2018
Estimated Primary Completion Date October 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 16, 2018)
Reduction of disease relevant auto-antibodies present at baseline, in particular anti-dsDNA [ Time Frame: 28 weeks ]
All disease relevant auto-antibodies will be measured at 28 weeks and compared to baseline with the hypothesis that a better reduction will be obtained in the RTX+BLM arm.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03747159 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 16, 2018)
  • Sustained reduction of autoantibody production [ Time Frame: 100 weeks ]
    The sustained reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies
  • Seroconversion of disease relevant auto-antibodies [ Time Frame: 100 weeks ]
    Seroconversion of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies
  • Reduction of memory B-cells [ Time Frame: 28 weeks ]
    The detection of (autoreactive) memory B-cells by standardized flowcytometry and in B-cell culture assays
  • Sustained reduction of memory B-cells [ Time Frame: 100 weeks ]
    The detection of (autoreactive) memory B-cells by standardized flowcytometry and in B-cell culture assays
  • Regression of immune complex-mediated excessive neutrophil extracellular traps (NET) formation [ Time Frame: 28 weeks ]
    The quantification of ex vivo NET induction with a 3-dimensional, confocal microscopy technique
  • Sustained regression of immune complex-mediated excessive neutrophil extracellular traps (NET) formation [ Time Frame: 100 weeks ]
    The quantification of ex vivo NET induction with a 3-dimensional, confocal microscopy technique
  • Evaluation of the clinical response [ Time Frame: 100 weeks ]
    The number of partial and complete renal responders in case of lupus nephritis
  • Evaluation of the clinical response by SLEDAI [ Time Frame: 100 weeks ]
    Patients will be monitored at frequent timepoint
  • Evaluation of the clinical response by SLICC [ Time Frame: 100 weeks ]
    SLICC score will be assesed at baseline, one year and two years
  • Evaluation of the clinical response by QoL questionnaires [ Time Frame: 100 weeks ]
    QoL questionnaires will be assessed at multiple time points
  • Evaluation of the clinical response by the amount of moderate and severe flares. [ Time Frame: 100 weeks ]
    Patients will be monitored at frequent timepoint
  • Evaluation of the clinical response by the ability to reduce concomitant immunosuppression without flares [ Time Frame: 100 weeks ]
    Patients will be monitored at frequent timepoint
  • Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: 100 weeks ]
    Patients will be monitored at frequent timepoint
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Synergetic B-cell Immunomodulation in SLE - 2nd Study.
Official Title  ICMJE A Randomized Trial to Investigate the Reset of Humoral Autoimmunity by Combining Belimumab With Rituximab in Severe Systemic Lupus Erythematosus
Brief Summary In follow-up of the previous SynBioSe Study the present study is a randomized controlled trial to assess the potential of the new therapeutic approach in lupus nephritis patients. The hypothesis is that by starting therapy with belimumab (anti-BAFF), migration of tissue residing B-cells is obtained before treatment with rituximab (anti-CD20) and aims to assess the possible better reduction and seroconversion of pathogenic autoantibodies compared to the control group.
Detailed Description

Rationale:

The SynBioSe-1 study is the first study to comprehensively describe the clinical and immunological effects of combining rituximab (RTX) and belimumab (BLM) in patients with systemic lupus erythematosus (SLE). In the pioneering SynBioSe-1 study it has been shown that combining rituximab and belimumab was safe and well-tolerated with important clinical responses. Immunologically, we unexpectedly observed that long-term B-cell depletion was not achieved due to migration of mature B-cells triggered by depletion of BAFF serum levels. The latter observation was in contrast to the study's null-hypothesis that combination therapy would lead to long-term B-cell depletion. The contrary was demonstrated, namely the relative early recirculation of mature B-cells. As such, the immunological lessons from the SynBioSe-1 study in conjunction with data from several large cohorts of belimumab treated SLE patients, have led to the postulation that starting treatment with belimumab (depleting BAFF from the circulation as well as tissues) followed by rituximab would result in an improved B-cell targeting strategy, notably on tissue-resident autoreactive B-cells. Therefore, the present SynBioSe-2 study is designed to further investigate the potential improvement of combination B-cell targeting by starting treatment with belimumab followed by rituximab.

Objectives:

The primary objective is to assess whether a combination treatment of belimumab with rituximab will lead to the improvement of pivotal, SLE-specific autoimmune phenomena compared SLE patients treated with conventional immunosuppression.

Study design:

A single-center, randomized, phase 2 proof-of-concept study

Study population:

SLE patients with a severe flare with major organ involvement or persistent high disease activity despite conventional treatment

Intervention:

In addition to standard therapy, SLE patients will receive self-administered, subcutaneous injections of belimumab every week for the entire study period and 2 infusions of rituximab 1000 mg on day 28 (week 4) and day 42 (week 6).

Main study parameters:

The primary endpoint is the reduction of disease relevant autoantibodies, in particular anti-dsDNA autoantibody production at 28 weeks. Secondary endpoints are non-biased immunological effects of the treatment summarized as follows: regression of immune complex-mediated excessive neutrophil extracellular traps (NET) formation at 28 weeks; sustained, long-term B-cell depletion during 2 years; sustained reduction of relevant anti-nuclear autoantibodies, including seroconversion during 2 years; and sustained regression of immune complex-mediated excessive neutrophil extracellular traps formation during 2 years. Additionally, the study will perform safety and toxicity monitoring according to World Health Organization (WHO) toxicity criteria and evaluate the clinical response, the reduction of concomitant immunosuppression and the number of moderate and severe flares during study follow-up.

Study duration: 28 weeks, followed by an extended follow-up study up to 100 weeks.

Nature and extent of the burden and risks associated with participation and potential benefits:

The study will include SLE patients with a severe flare necessitating remission induction treatment with intensive immunosuppression. The use of belimumab followed by rituximab can ameliorate disease activity even more than conventional treatment in the short-term and contribute to the successful tapering of concomitant immunosuppressive treatment. The latter will possibly lead to the reduction of infectious complication as compared to conventional treatment. The risks are predominantly related to the side effect profile of rituximab and belimumab and infectious complications of long-term B-cell depletion.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Single-center
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Lupus Erythematosus, Systemic
Intervention  ICMJE Drug: Belimumab Injection
Weekly injection of belimumab prior to two infusions of rituximab with continuation of the belimumab as maintenance therapy
Other Name: Benlysta subcutaneous injection of 200mg
Study Arms  ICMJE
  • Experimental: BLM+RTX treatment arm

    Intervention 1 Belimumab injection: subcutaneous weekly injections with 200mg belimumab (BML) for the duration of the entire study period of two years.

    Intervention 2 Rituximab infusion: Two intravenously infusions of 1000mg rituximab (RTX) at week 4 and week 6 after the start of belimumab.

    Intervention 3: Standard of care: induction therapy with three intravenously infusions methylprednisolone of 1000mg (or 500mg if weight is below 60kg), oral prednisolone 60mg with a quick tapering scheme to reach 5mg in 10 weeks and mycofenolate mofetil start dosis 500mg twice daily with maximum dosis of 2000mg twice daily depending on tolerance and area under curve (AUC) aimed at 60mg*hour/L.

    Intervention: Drug: Belimumab Injection
  • No Intervention: Standard of Care treatment arm

    Intervention 1: Standard of care: induction therapy with three intravenously infusions methylprednisolone of 1000mg (or 500mg if weight is below 60kg), oral prednisolone 60mg with a quick tapering scheme to reach 5mg in 10 weeks and mycofenolate mofetil start dosis 500mg twice daily with maximum dosis of 2000mg twice daily depending on tolerance and area under curve (AUC) aimed at 60mg*hour/L.

    Optional intervention: (if patients flare or are non-responders on mycofenolate mofetil + prednisolone) : Two intravenously infusions of 1000mg rituximab at week 4 and week 6 after the start of belimumab.

Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 16, 2018)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2023
Estimated Primary Completion Date October 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Have a clinical diagnosis of SLE according to the SLICC criteria 2012
  2. Severe, active SLE disease defined as a situation in which 1 or more of the following criteria are met:

    1. SLEDAI-2K (SLE Disease Activity Index) with 12 or more points
    2. New or worse SLE-related activity of major organs, i.e.: CNS-SLE (includes NPSLE), vasculitis, nephritis, pericarditis and/or myocarditis, myositis, thrombocytopenia < 60, hemolytic anemia < 4.4mmol/L (=7.0g/dL)
    3. high disease activity that requires or warrants induction treatment by switching to or increasing dosage of oral mycophenolate
  3. New, persisting or progressive disease activity despite the use of conventional maintenance immunosuppressive treatment (e.g. mycophenolate or azathioprine)
  4. Positive for relevant SLE-specific autoantibodies defined as a situation in which 1 or more of the following criteria are met:

    1. ANA seropositivity, as defined by a positive ANA-titer ≥ 1:80, before and at screening :

      • Positive test results from 2 independent time points within the study screening period; OR
      • One positive historical test result and 1 positive result during the screening period. Historical documentation of a positive test of ANA (eg, ANA by HEp-2 titer, ANA by ELISA) must include the date of the test.
    2. Anti-DNA seropositivity, as defined by a positive anti-dsDNA serum antibody ≥ 30 IU/mL, before and at screening:

      • Positive test results from 2 independent time points within the study screening period.
      • One positive historical test result and 1 positive result during the screening period. Historical documentation of a positive test of anti-dsDNA (eg, anti-dsDNA by Farr assay or ELISA) must include the date of the test.
  5. Female subjects are eligible to enter the study if she is:

    • Not pregnant or nursing
    • Of non-child-bearing potential (i.e. after hysterectomy, postmenopausal, bilateral ovariectomy or documented bilateral tubal ligation or other permanent female sterilization procedure)
    • in agreement to not become pregnant (if female subjects of childbearing potential) and therefore must be sexually inactive by abstinence or use contraceptive methods with a failure rate of < 1%.

Exclusion Criteria:

  1. Active pregnancy, as proven by a positive urine beta-HCG test or a positive serum beta-HCG
  2. Significant hypogammaglobulinemia (IgG < 4.0 g/L) or an IgA deficiency (IgA < 0.1 g/L)
  3. Immunization with a live vaccine 1 month before screening
  4. Active infection at time of screening, as follows:

    • Hospitalization for treatment of infection within previous 60 days of day 0 of the study
    • Use of parenteral (intravenous of intramuscular) antibiotics (including anti-bacterials, anti-virals, anti-fungals or anti-parasitic agents) within previous 60 days of day 0 of the study
    • Serological evidence of viral hepatitis defined as: patients positive for HbsAg test or HBcAb or a positive hepatitis C antibody not treated with antiviral medication
  5. Have a historically positive HIV test or test positive at screening for HIV
  6. Have a history of a primary immunodeficiency
  7. Have a neutrophil count of < 1.5x10E9/L
  8. Have a significant infection history that in the opinion of the investigator would make the candidate unsuitable for the study
  9. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies
  10. Have any other clinically significant abnormal laboratory value in the opinion of the investigator
  11. Have current drugs or alcohol abuse or dependence within 365 days prior to Day 0 of the study
  12. Have an active malignant neoplasm or one in the history of the last 5 years, except basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the uterine cervix treated locally and with no evidence of metastatic disease for 3 years
  13. Have evidence of serious suicide risk including any history of suicidal behavior in the last 6 months and/or any suicidal ideation in the last 2 months or who, in the investigator's opinion, poses a significant suicide risk
  14. Have any other clinically significant abnormal laboratory value, any intercurrent significant medical or psychiatric illness that in the opinion of the investigator would make the candidate unsuitable for the study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Dr. Y.K.O. Teng, MD, PhD T +31-(0)71-5262148 y.k.o.teng@lumc.nl
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03747159
Other Study ID Numbers  ICMJE NL65720.058.18
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party YTeng, Leiden University Medical Center
Study Sponsor  ICMJE Leiden University Medical Center
Collaborators  ICMJE
  • Dutch Kidney Foundation
  • GlaxoSmithKline
Investigators  ICMJE
Principal Investigator: Dr. Y.K.O. Teng, MD, PhD Leiden University Medical Center
PRS Account Leiden University Medical Center
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP