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Evaluate the Remission MAINtenance Using Extended Administration of Prednisone in Systemic Anti-neutrophil Cytoplasmic Antibodies (ANCA)-Associated Vasculitis. (MAINEPSAN)

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ClinicalTrials.gov Identifier: NCT03290456
Recruitment Status : Not yet recruiting
First Posted : September 25, 2017
Last Update Posted : October 16, 2017
Sponsor:
Information provided by (Responsible Party):
Hospices Civils de Lyon

Tracking Information
First Submitted Date  ICMJE August 24, 2017
First Posted Date  ICMJE September 25, 2017
Last Update Posted Date October 16, 2017
Estimated Study Start Date  ICMJE December 1, 2017
Estimated Primary Completion Date December 1, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 19, 2017)
Relapse-free survival, relapse being defined as BVAS > 0. [ Time Frame: from Screening to Month 24. ]
rate of relapse-free survival of patients continuing low-dose prednisone treatment until Month 10 VS those who will have prednisone treatment cessation at Month 1, on remission maintenance with Rituximab therapy, after achievement of remission of GPA or MPA, defined as a survival of patients maintaining a BVAS=0 at Month 24, in patient with newly-diagnosed or relapsing GPA or MPA and who will all have received glucocorticoids for 12 months after diagnosis or last flare before inclusion.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03290456 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 10, 2017)
  • Compare the rate of serious adverse events between Inclusion and Month 24 after randomization [ Time Frame: from Day 1 to Month 24 ]
    Proportion of patients with at least one adverse event between inclusion and Month 24.
    • Percentage of patients with at least one serious adverse event between inclusion and Month 24, corresponding to any adverse event that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity or congenital anomaly/birth defect or any other adverse event considered "medically significant".
    • Number of deaths, whatever the cause at Month 24.
  • Compare the rate of predefined severe events related to glucocorticoids between inclusion and Month 24 including osteoporotic fracture and weight gain. [ Time Frame: From Screening to Month 24. ]
    Percentage of patients with at least one predefined severe event corresponding to adverse events of grade 3 to 5 of the Common Terminology Criteria, including severe side effect related to glucocorticoids (infection requiring hospitalization or intravenous antibiotics, osteoporotic fracture, diabetes requiring medication, cardiovascular event, symptomatic osteonecrosis, psychiatric or mood disorder requiring drug administration, weight gain >10 kg) between inclusion and Month 24 - Weight gain between inclusion and Month 24
  • To compare the rate of vasculitis relapse at Month 24 [ Time Frame: from Day 1 to Month 24. ]
    Proportion of patients with minor or major vasculitis relapse between inclusion and Month 24 (BVAS >0) and time to first vasculitis relapse
  • To compare the prednisone use between inclusion and Month 24 [ Time Frame: from screening to Month 24. ]
    Prednisone area under the curve of administrated dose between inclusion and Month 24
  • To compare variation of the Bone mineral density and markers between inclusion and Month 24 [ Time Frame: From Screening to Month 24. ]
    Variation of the Bone mineral density between inclusion and Month 24 - Variation of the Bone markers including C-terminal crosslinked telopeptide of type I collagen (CTX) and serum procollagen type 1 amino-terminal propeptide (P1NP) between inclusion and Month 24
  • To compare sequelae assessed by BVAS (vasculitis activity) at 24 months [ Time Frame: From Screening to Month 24. ]
    BVAS (vasculitis activity) at 24 months - Variation of BVAS (Vasculitis activity)
  • To compare sequelae assessed by the Vasculitis Damage Index (VDI) at 24 months [ Time Frame: From screening to Month 24. ]
    • Vasculitis Damage Index at 24 months
    • Variation of VDI,
  • - To compare sequelae assessed by Combined Damage Assessment Index (CDA) at 24 months [ Time Frame: From Screening to Month 24. ]
    • Combined Damage Assessment Index at 24 months
    • Variation of CDA (damage),
  • - To compare functional disability at Month 24 after randomization (Day 1) in both arms [ Time Frame: From Day 1 to Month 24. ]
    Variation of HAQ (disability) between inclusion and at Month 24
  • To compare quality of life at Month 24 after randomization (Day 1) in both arms [ Time Frame: - From Day 1 to Month 24. ]
    - Variation of SF-36 (quality of life) between inclusion and at Month 24
  • - To compare healthcare resource utilization at Month 24 after randomization (Day 1) in both arms [ Time Frame: From Day 1 to Month 24. ]
    - Healthcare resource utilization between inclusion and Month 24 being defined as the percentage of patients being hospitalized at least once except only for rituximab infusions
Original Secondary Outcome Measures  ICMJE
 (submitted: September 19, 2017)
  • Compare the rate of serious adverse events between Inclusion and Month 24 after randomization (Day 1). [ Time Frame: from Day 1 to Month 24 ]
    Proportion of patients with at least one adverse event between inclusion and Month 24.
    • Percentage of patients with at least one serious adverse event between inclusion and Month 24, corresponding to any adverse event that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity or congenital anomaly/birth defect or any other adverse event considered "medically significant".
    • Number of deaths, whatever the cause at Month 24.
  • Compare the rate of predefined severe events related to glucocorticoids between inclusion and Month 24 including osteoporotic fracture and weight gain. [ Time Frame: From Screening to Month 24. ]
    Percentage of patients with at least one predefined severe event corresponding to adverse events of grade 3 to 5 of the Common Terminology Criteria, including severe side effect related to glucocorticoids (infection requiring hospitalization or intravenous antibiotics, osteoporotic fracture, diabetes requiring medication, cardiovascular event, symptomatic osteonecrosis, psychiatric or mood disorder requiring drug administration, weight gain >10 kg) between inclusion and Month 24 - Weight gain between inclusion and Month 24
  • To compare the rate of vasculitis relapse at Month 24 [ Time Frame: from Day 1 to Month 24. ]
    Proportion of patients with minor or major vasculitis relapse between inclusion and Month 24 (BVAS >0) and time to first vasculitis relapse
  • To compare the prednisone use between inclusion and Month 24 [ Time Frame: from screening to Month 24. ]
    Prednisone area under the curve of administrated dose between inclusion and Month 24
  • To compare variation of the Bone mineral density and markers between inclusion and Month 24 [ Time Frame: From Screening to Month 24. ]
    Variation of the Bone mineral density between inclusion and Month 24 - Variation of the Bone markers including C-terminal crosslinked telopeptide of type I collagen (CTX) and serum procollagen type 1 amino-terminal propeptide (P1NP) between inclusion and Month 24
  • To compare sequelae assessed by BVAS (vasculitis activity) at 24 months i.e. 36 months after diagnosis or relapse [ Time Frame: From Screening to Month 24. ]
    BVAS (vasculitis activity) at 24 months i.e. 36 months days after diagnosis or relapse - Variation of BVAS (vasculitis activity).
  • To compare sequelae assessed by the Vasculitis Damage Index (VDI) at 24 months i.e. 36 months after diagnosis or relapse [ Time Frame: From screening to Month 24. ]
    • Vasculitis Damage Index at 24 months i.e. 36 months days after diagnosis or relapse
    • Variation of VDI,
  • - To compare sequelae assessed by Combined Damage Assessment Index (CDA) at 24 months i.e. 36 months after diagnosis or relapse [ Time Frame: From Screening to Month 24. ]
    • Combined Damage Assessment Index at 24 months i.e. 36 months days after diagnosis or relapse
    • Variation of CDA (damage),
  • - To compare functional disability at Month 24 after randomization (Day 1) in both arms [ Time Frame: From Day 1 to Month 24. ]
    Variation of HAQ (disability) between inclusion and at Month 24
  • To compare quality of life at Month 24 after randomization (Day 1) in both arms [ Time Frame: - From Day 1 to Month 24. ]
    - Variation of SF-36 (quality of life) between inclusion and at Month 24
  • - To compare healthcare resource utilization at Month 24 after randomization (Day 1) in both arms [ Time Frame: From Day 1 to Month 24. ]
    - Healthcare resource utilization between inclusion and Month 24 being defined as the percentage of patients being hospitalised at least once except only for rituximab infusions
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluate the Remission MAINtenance Using Extended Administration of Prednisone in Systemic Anti-neutrophil Cytoplasmic Antibodies (ANCA)-Associated Vasculitis.
Official Title  ICMJE A Prospective, Multicentric, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Remission MAINtenance Using Extended Administration of Prednisone in Systemic Anti-neutrophil Cytoplasmic Antibodies (ANCA)-Associated Vasculitis.
Brief Summary

Immunosuppressive therapy of granulomatosis with polyangiitis (GPA, Wegener's) and microscopic polyangiitis (MPA) has transformed the outcome from death to a strong likelihood of disease control and temporary remission. However, most patients have recurrent relapses that lead to damage and require repeated treatment associated with long-term morbidity and death.

Rituximab has been shown to be as effective as cyclophosphamide to induce remission and maintenance of remission in severe GPA and MPA patients, with an acceptable safety profile . Although rituximab is becoming the standard of care for maintenance therapy in these patients, relapse still occurs and the optimal duration of prednisone therapy remains debated.

On the one hand, most US studies use early withdrawal (6-12 months) because of feared side effects. On the other hand, most European trials propose late withdrawal (>18 months) given a lower observed relapse rate on long-term low dose glucocorticoids treatment.

In a systematic review and meta-analysis, glucocorticoids regimen was the most significant variable explaining the variability between the proportions of ANCA-associated vasculitis patients with relapses. Nevertheless, it was an indirect estimation of treatment effect because of the absence of dedicated randomized trial. This meta-analysis concluded that combined longer-term (i.e. >12 months) use of low dose prednisone or nonzero glucocorticoids target is associated with a 20% reduction of relapse compared to early withdrawal (i.e. ≤12 months).

The relapse rate in patients with early glucocorticoids (10-12 months) withdrawal was provided in two studies and was of 37 and 34%, respectively. By contrast, the relapse rate in patients with late prednisone withdrawal (18-24 months) and receiving rituximab as maintenance treatment was 14% at 24 months in the MAINRITSAN trial. Of note, the decision to withdraw glucocorticoids after 18 months was left to physician's discretion in this study and two thirds of the nonsevere relapses occurred when patients were off prednisone.

The trial detailed here is the first prospective trial evaluating the length of glucocorticoid administration as remission adjunctive treatment for patients with GPA or MPA.

Detailed Description

Immunosuppressive therapy of granulomatosis with polyangiitis (GPA, Wegener's) and microscopic polyangiitis (MPA) has transformed the outcome from death to a strong likelihood of disease control and temporary remission. However, most patients have recurrent relapses that lead to damage and require repeated treatment associated with long-term morbidity and death.

Rituximab has been shown to be as effective as cyclophosphamide to induce remission and maintenance of remission in severe GPA and MPA patients, with an acceptable safety profile. Although rituximab is becoming the standard of care for maintenance therapy in these patients, relapse still occurs and the optimal duration of prednisone therapy remains debated.

On the one hand, most US studies use early withdrawal (6-12 months) because of feared side effects. On the other hand, most European trials propose late withdrawal (>18 months) given a lower observed relapse rate on long-term low dose glucocorticoids treatment.

In a systematic review and meta-analysis, glucocorticoids regimen was the most significant variable explaining the variability between the proportions of ANCA-associated vasculitis patients with relapses. Nevertheless, it was an indirect estimation of treatment effect because of the absence of dedicated randomized trial. This meta-analysis concluded that combined longer-term (i.e. >12 months) use of low dose prednisone or nonzero glucocorticoids target is associated with a 20% reduction of relapse compared to early withdrawal (i.e. ≤12 months).

The relapse rate in patients with early glucocorticoids (10-12 months) withdrawal was provided in two studies and was of 37 and 34%, respectively. By contrast, the relapse rate in patients with late prednisone withdrawal (18-24 months) and receiving rituximab as maintenance treatment was 14% at 24 months in the MAINRITSAN trial. Of note, the decision to withdraw glucocorticoids after 18 months was left to physician's discretion in this study and two thirds of the nonsevere relapses occurred when patients were off prednisone.

The trial detailed here is the first prospective trial evaluating the length of glucocorticoid administration as remission adjunctive treatment for patients with GPA or MPA.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Condition  ICMJE Granulomatosis With Polyangitis
Intervention  ICMJE
  • Drug: Prednisone 5mg/day extended of 9 additional months
    Prednisone 5mg/day orally during 9 Month + 1 mg/week tapering until 0mg.
  • Drug: Placebo 5mg/day extended of 9 additionnal months.
    1mg/week orally tapering Prednisone until Month 1 + Placebo orally 5mg/day until Month 10
Study Arms  ICMJE
  • Experimental: Prednisone 5mg/day extended of 9 additional months
    Prednisone 5mg/day will be administered from Day 1 to Month 9
    Intervention: Drug: Prednisone 5mg/day extended of 9 additional months
  • Placebo Comparator: Placebo 5mg/day extended of 9 additional months
    Placebo 5mg/day will be administered from Day 1 to Month 9
    Intervention: Drug: Placebo 5mg/day extended of 9 additionnal months.
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 Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: September 19, 2017)
146
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 1, 2021
Estimated Primary Completion Date December 1, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with a diagnosis of MPA or GPA independently of ANCA status,
  • Patient aged of 18 years or older,
  • Patients with newly-diagnosed disease or relapsing disease at the time of screening, with an inactive disease defined as a BVAS = 0,
  • Patients receiving maintenance infusion of rituximab 500 mg at 6 and 12 months after the start of vasculitis induction
  • Patients receiving 5-10 mg/day of prednisone at screening,
  • Patient able to give written informed consent prior to participation in the study.

Exclusion Criteria:

  • Patients with EGPA, or other vasculitides, defined by the ACR criteria and/or the Chapel Hill Consensus Conference,
  • Patients with vasculitis with active disease defined as a BVAS >0,
  • Patients with acute infections or chronic active infections (including HIV, HBV or HCV),
  • Patients with active cancer or recent cancer (<5 years), except basocellular carcinoma and prostatic cancer of low activity controlled by hormonal treatment,
  • Pregnant women and lactation. Patients with childbearing potential should have reliable contraception for the all duration of the study, Patients with other uncontrolled diseases, including drug or alcohol abuse, severe psychiatric diseases, that could interfere with participation in the trial according to the protocol,
  • Patients included in other investigational therapeutic study within the previous 3 months,
  • Patients suspected not to be observant to the proposed treatments,
  • Patients who have white blood cell count ≤4,000/mm3,
  • Patients who have platelet count ≤100,000/mm3,
  • Patients who have ALT or AST level greater than 3 times the upper limit of normal that cannot be attributed to underlying MPA-GPA disease,
  • Patients unable to give written informed consent prior to participation in the study.
  • Patients with contraindication to use rituximab,
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: Jean-Christophe LEGA, Pr 04.78.86.19.79 jean-christophe.lega@chu-lyon.fr
Contact: Xavier Puéchal, Dr 01.58.41.32.41 xavier.puechal@aphp.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03290456
Other Study ID Numbers  ICMJE 69HCL17_0020
Has Data Monitoring Committee Yes
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
Plan to Share IPD: No
Responsible Party Hospices Civils de Lyon
Study Sponsor  ICMJE Hospices Civils de Lyon
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jean-Christophe LEGA, Pr Hospices Civils de Lyon
PRS Account Hospices Civils de Lyon
Verification Date October 2017

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