CYCLONES - CYClophosphamide LOw Dose and No Extra Steroid

Study Overview
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Brief Summary
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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
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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.

Official Title
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CYCLONES - CYClophosphamide LOw Dose and No Extra Steroid

Conditions
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Systemic Lupus Erythematosus (SLE)

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Methylprednisolone
* Drug: Prednisone
* Drug: Mycophenolate Mofetil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All the criteria below have to be completed: Systemic lupus erythematosus (SLE) according to the American College of Rheumatology (ACR) classification criteria and/or SLICC: according to the thematic protocol (Petri M, et al., Arthritis Rheum, 2012); Age ≥18 years; Lupus Glomerulonephritis Class III, IV or V according to the International Society of Nephrology (ISN)/Renal Pathology Society (RPS) Classification confirmed on renal biopsy (according to the routine protocol of our outpatient clinic) performed up to 3 months to 1 year prior to selection; Menopause or use contraception method; Informed consent. Exclusion Criteria: Creatinine clearance < 40 ml/min calculated (Cockcroft & Gault); Intolerance to medication; Absolute neutrophil count < 1,000/mm3; Pregnancy or breastfeeding; Infection requiring hospitalization; Patients who used Cyclophosphamide in the last 6 months or biological in the last year; Thrombotic renal microangiopathy; Chronic terminal renal disease and/or class VI biopsy; Non-adhesion profile; Need to use another therapeutic scheme; GC dose in the last 3 months not greater than 20mg/day. 11.Central nervous system (CNS) disorders or hemolytic anemia and severe thrombocytopenia (< 50,000 platelets/mm3).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Eurolupus: Cyclophosphamide + Methylprednisolone + oral GC<br>The EUROLUPUS group will receive Cyclophosphamide (6 doses of 500 mg / fortnightly) + 3 doses of Methylprednisolone (750 mg) initial + oral glucocorticoid (GC) (prednisone) ≤ 30 mg/day with a gradual reduction of 5 mg/month (EUROLUPUS). From the 3rd month, the group will receive oral mycophenolate mofetil (MMF) (2-3 g) until 6 months with gradual reduction of GC from 5 mg/month until the minimum dose of 5 mg/month. | Drug: Cyclophosphamide<br>* Patients in both EUROLUPUS group and CYCLONES Group will receive for 3 months Cyclophosphamide (6 doses of 500mg/biweekly)<br>Drug: Methylprednisolone<br>* 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).<br>Drug: Prednisone<br>* Patients in EUROLUPUS group will receive oral prednisone ≤ 30 mg/day with a reduction of 5mg/month until complete withdrawal.<br>Drug: Mycophenolate Mofetil<br>* 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.<br>|
| Experimental: Cyclones Group: Cyclophosphamide+Methylprednisolone no oral GC<br>CYCLONES Group will receive for 3 months Cyclophosphamide (6 doses of 500mg / fortnightly) + Methylprednisolone [500 mg (day 0 and day 15), 250 mg (day 30 and day 45) and 125 mg (day 60 and day 75)] without oral glucocorticoid (GC). From the third month, the group will receive only oral MMF (2-3 g) until the 6th month. Patients using GC ≤ 20 mg/day may enter the protocol with immediate reduction to 15 mg/day with a reduction of 5mg/month until complete withdrawal. | Drug: Cyclophosphamide<br>* Patients in both EUROLUPUS group and CYCLONES Group will receive for 3 months Cyclophosphamide (6 doses of 500mg/biweekly)<br>Drug: Methylprednisolone<br>* 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).<br>Drug: Mycophenolate Mofetil<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Partial renal response | The primary endpoint is partial renal response, a composition of: urinary protein/creatinine ratio < 3g/g with decrease of at least 50% of the initial value and increase of creatinine (mg/dL) not higher than 15% of the initial value | Six months | 
| Complete renal response | Complete renal response, according to a composition of: urinary protein/creatinine ratio < 0,5 (g/g) with decrease of at least 50% of the initial value and increase of creatinine (mg/dL) not higher than 15% of the initial value. | Six months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Osteoporosis evaluation | Evaluation of osteoporosis by bone densitometry (DXA) | 6 months | 
| Bone structure evaluation | Evaluation of bone structure by high resolution peripheral quantitative computed tomography (HRpQCT)] | 6 months | 
| Glaucoma evaluation | Ophthalmologic evaluation for glaucoma secondary to glucocorticoids use | 15 days, 30 days and 3 months | 
| Cataract evaluation | Ophthalmologic evaluation for cataract secondary to glucocorticoids use | 3 months | 
| Change from baseline Total cholesterol at 6 months | Lipid profile evaluation including total cholesterol in mg/dL | Baseline and 6 months | 
| Change from baseline Low-density lipoprotein (LDL) at 6 months | Lipid profile evaluation including Low-density lipoprotein (LDL) in mg/dL | Baseline and 6 months | 
| Change from baseline High-density lipoprotein (HDL) at 6 months | Lipid profile evaluation including High-density lipoprotein (HDL) in mg/dL | Baseline and 6 months | 
| Change from baseline Triglycerides at 6 months | Lipid profile evaluation including triglycerides in mg/dL | Baseline and 6 months | 
| Change from baseline Anti-High-density lipoprotein (anti-HDL) at 6 months | Lipid profile evaluation including anti-High-density lipoprotein (anti-HDL) | Baseline and 6 months | 
| Therapy adherence by a self-report medication adherence measure (8-item Morisky Medication Adherence Scale) | Therapy adherence will be evaluated by a self-report medication adherence measure (8-item Morisky Medication Adherence Scale). A total score of all items are calculated with a sum score ranging from 0 to 8 for adherence. The scores will be trichotomized into the following 3 levels of adherence: high adherence (score 8), medium adherence (score 6 to <8), and low adherence (score <6). | Baseline | 
| Change from baseline Serum levels of prednisone using Area Under the Curve [AUC] at 30 days, 3 months and 6 months | Serum levels of prednisone will be measured along the follow up using Area Under the Curve [AUC] | Baseline, 30 days, 3 months and 6 months |