Clinical trial NCT03290456: Evaluate the Remission MAINtenance Using Extended Administration of Prednisone in Systemic Anti-neutrophil Cytoplasmic Antibodies (ANCA)-Associated Vasculitis.
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.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Granulomatosis With Polyangitis
Keywords: Vasculitis
GPA
Granulomatosis with Polyangitis
MPA
Microscopic Polyangitis
Systemic anti-neutrophil cytoplasmic antibodies (ANCA)
Prednisone
glucocorticoids
Remission Maintenance
Rituximab
Cyclophosphamide
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2017-09-25
Enrollment: 146
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility 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.
* 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

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,

Primary outcomes:
measure: Relapse-free survival, relapse being defined as BVAS > 0.
timeFrame: from Screening to Month 30.
Secondary outcomes:
measure: Compare the rate of serious adverse events between Inclusion and Month 30 after randomization
timeFrame: from Day 1 to Month 30
measure: Compare the rate of predefined severe events related to glucocorticoids between inclusion and Month 30 including osteoporotic fracture and weight gain.
timeFrame: From Screening to Month 30
measure: To compare the rate of vasculitis relapse at Month 30
timeFrame: from Day 1 to Month 30
measure: To compare the prednisone use between inclusion and Month 30
timeFrame: from screening to Month 30
measure: To compare variation of the Bone mineral density and markers between inclusion and Month 30
timeFrame: From Screening to Month 30
measure: To compare sequelae assessed by BVAS (vasculitis activity) at 30 months
timeFrame: From Screening to Month 30.
measure: To compare sequelae assessed by the Vasculitis Damage Index (VDI) at 30 months
timeFrame: From screening to Month 30.
measure: - To compare sequelae assessed by Combined Damage Assessment Index (CDA) at 30 months
timeFrame: From Screening to Month 30.
measure: - To compare functional disability at Month 30 after randomization (Day 1) in both arms
timeFrame: From Day 1 to Month 30.
measure: To compare quality of life at Month 30 after randomization (Day 1) in both arms
timeFrame: - From Day 1 to Month 30.
measure: - To compare healthcare resource utilization at Month 30 after randomization (Day 1) in both arms
timeFrame: From Day 1 to Month 30.
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Amiens-Hôpital Nord
city: Angers
country: France
facility: CHU Angers
city: Avignon
country: France
facility: Clinique Rhône-Durance
city: Bar-le-Duc
country: France
facility: Hôpital Jeanne d'Arc
city: Bobigny
country: France
facility: Hôpital Avicenne
city: Brest
country: France
facility: Hôpital La Cavale Blanche
city: Bron
country: France
facility: Hôpital Louis Pradel
city: Caen
country: France
facility: CHU de Caen - Cote de Nacre
city: Chartres
country: France
facility: Hôpital Louis Pasteur
city: Clermont-Ferrand
country: France
facility: CHU Estaing
city: Clermont-Ferrand
country: France
facility: CHU Gabriel Montpied
city: Créteil
country: France
facility: CHIC Créteil
city: Dijon
country: France
facility: CHRU François Mitterrand
city: Dijon
country: France
facility: CHRU François Mitterrand
city: Lille
country: France
facility: CHRU Lille - Hôpital Claude Huriez
city: Lyon
country: France
facility: Centre Hospitalier Croix Rousse
city: Lyon
country: France
facility: Hôpital Edouard Herriot
city: Lyon
country: France
facility: Hôpital Edouard Herriot
city: Marseille
country: France
facility: Hôpital de la Conception
city: Marseille
country: France
facility: Hôpital de la Conception
city: Marseille
country: France
facility: Hôpital La Timone
city: Metz
country: France
facility: HP Site Belle Isle
city: Nantes
country: France
facility: CHU Nantes - Hôtel Dieu
city: Nice
country: France
facility: CHU de Nice - Hôpital Pasteur 2
city: Paris
country: France
facility: Hôpital la Pitié Salpêtrière
city: Paris
country: France
facility: Hôpital Cochin
city: Paris
country: France
facility: Hôpital Européen G. Pompidou
city: Paris
country: France
facility: Hôpital Saint Louis
city: Pessac
country: France
facility: Hôpital Haut Lévêque
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon Sud
city: Pierre-Bénite
country: France
facility: CH Lyon Sud
city: Pierre-Bénite
country: France
facility: CH Lyon Sud
city: Poitiers
country: France
facility: CHU de Poitiers
city: Rennes
country: France
facility: CHRU Rennes - Hôpital Sud
city: Rouen
country: France
facility: Hôpital Charles Nicolle
city: Strasbourg
country: France
facility: CHU Strasbourg
city: Strasbourg
country: France
facility: CHRU Hautepierre
city: Strasbourg
country: France
facility: Hopitaux Universaitaire de Strasbourg Hopitaux
city: Suresnes
country: France
facility: Hôpital Foch
city: Tours
country: France
facility: CHRU Bretonneau
city: Troyes
country: France
facility: CH de Troyes
city: Valenciennes
country: France
facility: CH Valenciennes
city: Vandœuvre-lès-Nancy
country: France
facility: Hôpitaux de Brabois
city: Vannes
country: France
facility: CH Bretagne Atlantique
city: Verdun
country: France
facility: CH de Verdun
Study officials:
affiliation: Hospices Civils de Lyon
name: Jean-Christophe LEGA, Pr
role: PRINCIPAL_INVESTIGATOR
References: