Evaluate the Remission MAINtenance Using Extended Administration of Prednisone in Systemic Anti-neutrophil Cytoplasmic Antibodies (ANCA)-Associated Vasculitis.
- Conditions
- Granulomatosis With Polyangitis
- Interventions
- Drug: Prednisone 5mg/day extended of 12 additional monthsDrug: Placebo 5mg/day extended of 12 additionnal months.
- Registration Number
- NCT03290456
- Lead Sponsor
- Hospices Civils de Lyon
- 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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 146
- 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.
- At Inclusion visit day, patient must be between 5 and 10 mg/day prednisone and at randomization visit day (D1), patient must be at 5 mg/day prednisone
- 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,
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Prednisone 5mg/day extended of 12 additional months Prednisone 5mg/day extended of 12 additional months Prednisone 5mg/day will be administered from Day 1 to Month 12 Placebo 5mg/day extended of 12 additional months Placebo 5mg/day extended of 12 additionnal months. Placebo 5mg/day will be administered from Day 1 to Month 12
- Primary Outcome Measures
Name Time Method Relapse-free survival, relapse being defined as BVAS > 0. from Screening to Month 30. 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 30, 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
Name Time Method - To compare sequelae assessed by Combined Damage Assessment Index (CDA) at 30 months From Screening to Month 30. * Combined Damage Assessment Index at 30 months
* Variation of CDA (damage),- To compare functional disability at Month 30 after randomization (Day 1) in both arms From Day 1 to Month 30. Variation of HAQ (disability) between inclusion and at Month 30
Compare the rate of predefined severe events related to glucocorticoids between inclusion and Month 30 including osteoporotic fracture and weight gain. From Screening to Month 30 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 30
- Weight gain between inclusion and Month 30To compare the rate of vasculitis relapse at Month 30 from Day 1 to Month 30 Proportion of patients with minor or major vasculitis relapse between inclusion and Month 30 (BVAS \>0) and time to first vasculitis relapse
To compare variation of the Bone mineral density and markers between inclusion and Month 30 From Screening to Month 30 Variation of the Bone mineral density between inclusion and Month 30
- 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 30To compare sequelae assessed by BVAS (vasculitis activity) at 30 months From Screening to Month 30. BVAS (vasculitis activity) at 30 months
- Variation of BVAS (Vasculitis activity)To compare sequelae assessed by the Vasculitis Damage Index (VDI) at 30 months From screening to Month 30. * Vasculitis Damage Index at 30 months
* Variation of VDI,To compare quality of life at Month 30 after randomization (Day 1) in both arms - From Day 1 to Month 30. - Variation of SF-36 (quality of life) between inclusion and at Month 30
Compare the rate of serious adverse events between Inclusion and Month 30 after randomization from Day 1 to Month 30 Proportion of patients with at least one adverse event between inclusion and Month 30.
* Percentage of patients with at least one serious adverse event between inclusion and Month 30, 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 30.To compare the prednisone use between inclusion and Month 30 from screening to Month 30 Prednisone area under the curve of administrated dose between inclusion and Month 30
- To compare healthcare resource utilization at Month 30 after randomization (Day 1) in both arms From Day 1 to Month 30. - Healthcare resource utilization between inclusion and Month 30 being defined as the percentage of patients being hospitalized at least once except only for rituximab infusions
Trial Locations
- Locations (41)
CHU Amiens-Hôpital Nord
🇫🇷Amiens, France
Hôpital Louis Pradel
🇫🇷Bron, France
CHU Estaing
🇫🇷Clermont-Ferrand, France
CHU Gabriel Montpied
🇫🇷Clermont-Ferrand, France
CHRU François Mitterrand
🇫🇷Dijon, France
CHU Angers
🇫🇷Angers, France
Clinique Rhône-Durance
🇫🇷Avignon, France
Hôpital Jeanne d'Arc
🇫🇷Bar-le-Duc, France
Hôpital Avicenne
🇫🇷Bobigny, France
Hôpital La Cavale Blanche
🇫🇷Brest, France
Hôpital Louis Pasteur
🇫🇷Chartres, France
CHU de Caen - Cote de Nacre
🇫🇷Caen, France
CHRU Lille - Hôpital Claude Huriez
🇫🇷Lille, France
CHIC Créteil
🇫🇷Créteil, France
Centre Hospitalier Croix Rousse
🇫🇷Lyon, France
Hôpital Edouard Herriot
🇫🇷Lyon, France
Hôpital de la Conception
🇫🇷Marseille, France
Hôpital La Timone
🇫🇷Marseille, France
HP Site Belle Isle
🇫🇷Metz, France
CHU Nantes - Hôtel Dieu
🇫🇷Nantes, France
CHU de Nice - Hôpital Pasteur 2
🇫🇷Nice, France
Hôpital Saint Louis
🇫🇷Paris, France
Hôpital la Pitié Salpêtrière
🇫🇷Paris, France
Hôpital Cochin
🇫🇷Paris, France
Hôpital Européen G. Pompidou
🇫🇷Paris, France
Hôpital Haut Lévêque
🇫🇷Pessac, France
Centre Hospitalier Lyon Sud
🇫🇷Pierre-Bénite, France
CHU de Poitiers
🇫🇷Poitiers, France
Hôpital Charles Nicolle
🇫🇷Rouen, France
CH Lyon Sud
🇫🇷Pierre-Bénite, France
CHRU Rennes - Hôpital Sud
🇫🇷Rennes, France
CHU Strasbourg
🇫🇷Strasbourg, France
CHRU Hautepierre
🇫🇷Strasbourg, France
Hôpital Foch
🇫🇷Suresnes, France
Hopitaux Universaitaire de Strasbourg Hopitaux
🇫🇷Strasbourg, France
CH de Troyes
🇫🇷Troyes, France
CH Valenciennes
🇫🇷Valenciennes, France
CHRU Bretonneau
🇫🇷Tours, France
Hôpitaux de Brabois
🇫🇷Vandœuvre-lès-Nancy, France
CH de Verdun
🇫🇷Verdun, France
CH Bretagne Atlantique
🇫🇷Vannes, France