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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Prednisone 5mg/day extended of 12 additional months | Experimental | Prednisone 5mg/day will be administered from Day 1 to Month 12 |
|
| Placebo 5mg/day extended of 12 additional months | Placebo Comparator | Placebo 5mg/day will be administered from Day 1 to Month 12 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Prednisone 5mg/day extended of 12 additional months | Drug | Prednisone 5mg/day orally during 12 Month + 1 mg/week tapering until 0mg. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Relapse-free survival, relapse being defined as BVAS > 0. | 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. | from Screening to Month 30. |
| Measure | Description | Time Frame |
|---|---|---|
| Compare the rate of serious adverse events between Inclusion and Month 30 after randomization | Proportion of patients with at least one adverse event between inclusion and Month 30.
|
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Jean-Christophe LEGA, Pr | Contact | 04.78.86.19.79 | jean-christophe.lega@chu-lyon.fr | |
| Xavier Puéchal, Dr | Contact | 01.58.41.32.41 | xavier.puechal@aphp.fr |
| Name | Affiliation | Role |
|---|---|---|
| Jean-Christophe LEGA, Pr | Hospices Civils de Lyon | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CHU Amiens-Hôpital Nord | Recruiting | Amiens | 80054 | France |
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| Placebo 5mg/day extended of 12 additionnal months. | Drug | 1mg/week orally tapering Prednisone until Month 1 + Placebo orally 5mg/day until Month 13 |
|
| from Day 1 to Month 30 |
| Compare the rate of predefined severe events related to glucocorticoids between inclusion and Month 30 including osteoporotic fracture and weight gain. | 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 30 | From Screening to Month 30 |
| To compare the rate of vasculitis relapse at Month 30 | Proportion of patients with minor or major vasculitis relapse between inclusion and Month 30 (BVAS >0) and time to first vasculitis relapse | from Day 1 to Month 30 |
| To compare the prednisone use between inclusion and Month 30 | Prednisone area under the curve of administrated dose between inclusion and Month 30 | from screening to Month 30 |
| To compare variation of the Bone mineral density and markers between inclusion and 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 30 | From Screening to Month 30 |
| To compare sequelae assessed by BVAS (vasculitis activity) at 30 months | BVAS (vasculitis activity) at 30 months - Variation of BVAS (Vasculitis activity) | From Screening to Month 30. |
| To compare sequelae assessed by the Vasculitis Damage Index (VDI) at 30 months |
| From screening to Month 30. |
| - To compare sequelae assessed by Combined Damage Assessment Index (CDA) at 30 months |
| From Screening to Month 30. |
| - To compare functional disability at Month 30 after randomization (Day 1) in both arms | Variation of HAQ (disability) between inclusion and at Month 30 | From Day 1 to Month 30. |
| To compare quality of life at Month 30 after randomization (Day 1) in both arms | - Variation of SF-36 (quality of life) between inclusion and at Month 30 | - From Day 1 to Month 30. |
| - To compare healthcare resource utilization at Month 30 after randomization (Day 1) in both arms | - 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 | From Day 1 to Month 30. |
| CHU Angers | Recruiting | Angers | 49933 | France |
|
| Clinique Rhône-Durance | Not yet recruiting | Avignon | 84000 | France |
|
| Hôpital Jeanne d'Arc | Not yet recruiting | Bar-le-Duc | 55000 | France |
|
| Hôpital Avicenne | Not yet recruiting | Bobigny | 93009 | France |
|
| Hôpital La Cavale Blanche | Recruiting | Brest | 29200 | France |
|
| Hôpital Louis Pradel | Recruiting | Bron | 69500 | France |
|
| CHU de Caen - Cote de Nacre | Recruiting | Caen | 14033 | France |
|
| Hôpital Louis Pasteur | Not yet recruiting | Chartres | 28018 | France |
|
| CHU Estaing | Recruiting | Clermont-Ferrand | 63003 | France |
|
| CHU Gabriel Montpied | Recruiting | Clermont-Ferrand | 63003 | France |
|
| CHIC Créteil | Not yet recruiting | Créteil | 94010 | France |
|
| CHRU François Mitterrand | Not yet recruiting | Dijon | 21000 | France |
|
| CHRU François Mitterrand | Not yet recruiting | Dijon | 21000 | France |
|
| CHRU Lille - Hôpital Claude Huriez | Not yet recruiting | Lille | 59037 | France |
|
| Centre Hospitalier Croix Rousse | Recruiting | Lyon | 69004 | France |
|
| Hôpital Edouard Herriot | Recruiting | Lyon | 69137 | France |
|
| Hôpital Edouard Herriot | Not yet recruiting | Lyon | 69137 | France |
|
| Hôpital de la Conception | Not yet recruiting | Marseille | 13005 | France |
|
| Hôpital de la Conception | Not yet recruiting | Marseille | 13005 | France |
|
| Hôpital La Timone | Not yet recruiting | Marseille | 13385 | France |
|
| HP Site Belle Isle | Not yet recruiting | Metz | 57045 | France |
|
| CHU Nantes - Hôtel Dieu | Recruiting | Nantes | 44093 | France |
|
| CHU de Nice - Hôpital Pasteur 2 | Recruiting | Nice | 06001 | France |
|
| Hôpital la Pitié Salpêtrière | Recruiting | Paris | 75013 | France |
|
| Hôpital Cochin | Recruiting | Paris | 75014 | France |
|
| Hôpital Européen G. Pompidou | Not yet recruiting | Paris | 75015 | France |
|
| Hôpital Saint Louis | Not yet recruiting | Paris | 75475 | France |
|
| Hôpital Haut Lévêque | Not yet recruiting | Pessac | 33600 | France |
|
| Centre Hospitalier Lyon Sud | Recruiting | Pierre-Bénite | 69310 | France |
|
| CH Lyon Sud | Recruiting | Pierre-Bénite | 69495 | France |
|
| CH Lyon Sud | Recruiting | Pierre-Bénite | 69495 | France |
|
| CHU de Poitiers | Not yet recruiting | Poitiers | 86021 | France |
|
| CHRU Rennes - Hôpital Sud | Recruiting | Rennes | 35200 | France |
|
| Hôpital Charles Nicolle | Recruiting | Rouen | 76031 | France |
|
| CHU Strasbourg | Not yet recruiting | Strasbourg | 67000 | France |
|
| CHRU Hautepierre | Not yet recruiting | Strasbourg | 67098 | France |
|
| Hopitaux Universaitaire de Strasbourg Hopitaux | Recruiting | Strasbourg | France |
|
| Hôpital Foch | Not yet recruiting | Suresnes | 92150 | France |
|
| CHRU Bretonneau | Not yet recruiting | Tours | 37044 | France |
|
| CH de Troyes | Recruiting | Troyes | 10003 | France |
|
| CH Valenciennes | Recruiting | Valenciennes | 59322 | France |
|
| Hôpitaux de Brabois | Not yet recruiting | Vandœuvre-lès-Nancy | 54511 | France |
|
| CH Bretagne Atlantique | Recruiting | Vannes | 56017 | France |
|
| CH de Verdun | Not yet recruiting | Verdun | 55100 | France |
|
| ID | Term |
|---|---|
| D014657 | Vasculitis |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D011241 | Prednisone |
| ID | Term |
|---|---|
| D011244 | Pregnadienediols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
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