NCT03492255

CYCLONES - CYClophosphamide LOw Dose and No Extra Steroid

• Status: Terminated
• Phase: N/A
• Study type: Interventional
• Enrollment: 49 (actual)
• Sponsor: University of Sao Paulo General Hospital · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

Glucocorticoids (GC) use has increased survival of patients with systemic lupus erythematosus (SLE), particularly in cases of nephritis and a more significant improvement to 80% with the introduction of therapy combined with immunosuppressants. This therapeutic scheme, however, results in a very high incidence of irreversible damage that is associated in more than 70% of the cases to GC use and in a smaller proportion to the use of high dose cyclophosphamide. CYCLONES is a Controlled Randomized Clinical Trial with the aim of evaluating the efficacy of a regimen for lupus nephritis treatment using only intravenous corticosteroid administration. This intravenous corticosteroid regimen has already been tested (with Rituximab instead of Cyclophosphamide) with high response rates for lupus nephritis and significant reduction of side effects. After selection, patients will be randomized in two arms: 116 patients will receive Euro-Lupus nephritis regimen and other 116 will undergo treatment with CYCLONES regimen. The primary endpoint is the partial response (protein/creatinine ratio \< 3 with decrease at least of 50% of the initial value and increase of creatinine not higher than 15% of the initial value) or complete response (protein/creatinine ratio \< 500 with decrease at least of 50% of the initial value and increase of creatinine not higher than 15% of the initial value in 6 months. Secondary outcome measures will be evaluated such as osteoporosis and bone metabolism parameters, ophthalmologic evaluation of the collateral effects related to glucocorticoids, lipid profile and therapy adherence.

Detailed description

The use of glucocorticoids (GC) greatly increased the survival of patients with SLE, particularly in cases of nephritis and a more significant improvement to 80% with the introduction of therapy combined with immunosuppressants in the late 1960s. This therapeutic regimen, however, results in a very high incidence of irreversible damage to the patient that is associated in more than 70% of the cases to GC use and in a smaller proportion to the use of a high dose of cyclophosphamide. In the last years, some less toxic schemes have been proposed. The use of low-dose cyclophosphamide has been shown to have equal efficacy as high dose for the induction of remission of lupus nephritis with a fifteen-year follow-up. Regarding GC, lower doses of methylprednisolone (MP) pulse have been shown to have similar efficacy and lower risk of infection. In addition, retrospective studies have found that high doses of oral GC during the induction period are associated with a higher incidence of side effects without a corresponding increase in efficacy . But it was only in 2013 that the first study was published that did not use oral GC in the treatment of lupus nephritis induction with excellent results. In transplantation area, there are already several trials minimizing the use of GC proposing in the first days after transplantation the use the methylprednisolone (MP) IV pulse (day 1, 500mg, day 2, 250mg and day 3, 125mg) followed by oral GC for 4 days (60mg, 40mg, 30mg and 20mg). In this study, the same incidence of acute rejection occurred when compared to patients who were treated with oral GC for a prolonged period. Regarding the route of administration of GC, it is important to emphasize that MP is three times more active through non-genomic pathway than through genomic pathway, which, in theory, results in a higher efficiency and lower collateral effect, when compared to the GC oral route that has similar potency through the two pathways. In addition, MP has a simpler and dose-proportional pharmacokinetics, whereas for oral prednisolone this kinetics is more complex and difficult to predict the dose required to achieve a specific concentration. Therefore, the present study intends to evaluate the efficacy and adverse effects of cyclophosphamide (EUROLUPUS scheme) associated to usual GC dose compared with EUROLUPUS with no extra oral GC regimen. The estimated number of patients was 116 patients for each arm (considering an error α = 0.05 and a power (1-β) of 80%). In moderate flares, due to other systemic manifestations, the use of a maximum of 20mg / day of prednisone for 1 month and a progressive reduction of 5mg every 15 days until withdrawal is allowed. Other immunosuppressive, biological, intravenous immunoglobulin or plasmapheresis will be prohibited. Regarding statistics, an Intention-To-Treat (ITT) analysis will be performed for the randomized patients, so that patients presenting side effects or low adherence to treatment will remain in the randomized group and will be evaluated at week 24. The proportion of patients achieving complete and partial remission at week 24 will be compared by the chi-square test or the Fisher's exact test, as appropriate. The same statistical methodology will be applied to compare the number of events listed as secondary endpoints.

Conditions

• Systemic Lupus Erythematosus (SLE)

Interventions

Type	Name	Description
DRUG	Cyclophosphamide	Patients in both EUROLUPUS group and CYCLONES Group will receive for 3 months Cyclophosphamide (6 doses of 500mg/biweekly)
DRUG	Methylprednisolone	Patients in EUROLUPUS group will receive Methylprednisolone \[750 mg for three consecutive days). Patients in CYCLONES Group will receive Methylprednisolone \[500 mg (day 0 and day 15), 250 mg (day 30 and day 45) and 125 mg (day 60 and day 75).
DRUG	Prednisone	Patients in EUROLUPUS group will receive oral prednisone ≤ 30 mg/day with a reduction of 5mg/month until complete withdrawal.
DRUG	Mycophenolate Mofetil	From the third month of protocol, patients in both EUROLUPUS group and CYCLONES Group will receive mycophenolate mofetil (2-3 g/day) until the sixth month of study.

Timeline

• Start date: 2018-04-12
• Primary completion: 2021-07-02
• Completion: 2021-07-02
• First posted: 2018-04-10
• Last updated: 2021-07-21

Locations

2 sites across 1 country: Brazil