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

This study is not yet open for participant recruitment.
Verified October 2017 by Hospices Civils de Lyon
Sponsor:
ClinicalTrials.gov Identifier:
NCT03290456
First Posted: September 22, 2017
Last Update Posted: October 16, 2017
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.
Information provided by (Responsible Party):
Hospices Civils de Lyon
  Purpose

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.


Condition Intervention
Granulomatosis With Polyangitis Drug: Prednisone 5mg/day extended of 9 additional months Drug: Placebo 5mg/day extended of 9 additionnal months.

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Official Title: 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.

Resource links provided by NLM:


Further study details as provided by Hospices Civils de Lyon:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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


Estimated Enrollment: 146
Anticipated Study Start Date: December 1, 2017
Estimated Study Completion Date: December 1, 2021
Estimated Primary Completion Date: December 1, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Prednisone 5mg/day extended of 9 additional months
Prednisone 5mg/day will be administered from Day 1 to Month 9
Drug: Prednisone 5mg/day extended of 9 additional months
Prednisone 5mg/day orally during 9 Month + 1 mg/week tapering until 0mg.
Placebo Comparator: Placebo 5mg/day extended of 9 additional months
Placebo 5mg/day will be administered from Day 1 to Month 9
Drug: Placebo 5mg/day extended of 9 additionnal months.
1mg/week orally tapering Prednisone until Month 1 + Placebo orally 5mg/day until Month 10

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.

  Eligibility

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.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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,
  Contacts and Locations
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): NCT03290456


Contacts
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

Locations
France
Centre Hospitalier Lyon Sud Not yet recruiting
Pierre-Bénite, France, 69310
Contact: Jean-Christophe LEGA, Pr    04.78.86.19.79    jean-christophe.lega@chu-lyon.fr   
Sponsors and Collaborators
Hospices Civils de Lyon
Investigators
Principal Investigator: Jean-Christophe LEGA, Pr Hospices Civils de Lyon
  More Information

Responsible Party: Hospices Civils de Lyon
ClinicalTrials.gov Identifier: NCT03290456     History of Changes
Other Study ID Numbers: 69HCL17_0020
First Submitted: August 24, 2017
First Posted: September 22, 2017
Last Update Posted: October 16, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Hospices Civils de Lyon:
Vasculitis
GPA
Granulomatosis with Polyangitis
MPA
Microscopic Polyangitis
Systemic anti-neutrophil cytoplasmic antibodies (ANCA)
Prednisone
glucocorticoids
Remission Maintenance
Rituximab
Cyclophosphamide

Additional relevant MeSH terms:
Vasculitis
Systemic Vasculitis
Vascular Diseases
Cardiovascular Diseases
Antibodies
Immunoglobulins
Antibodies, Antineutrophil Cytoplasmic
Prednisone
Immunologic Factors
Physiological Effects of Drugs
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents