Clinical trial NCT03492255: CYCLONES - CYClophosphamide LOw Dose and No Extra Steroid
Official title: CYCLONES - CYClophosphamide LOw Dose and No Extra Steroid
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Systemic Lupus Erythematosus (SLE)
Lead sponsor: University of Sao Paulo General Hospital
Sponsor class: OTHER
Collaborators: name: Fundação de Amparo à Pesquisa do Estado de São Paulo
First posted: 2018-04-10
Enrollment: 49
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria:

All the criteria below have to be completed:

1. 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);
2. Age ≥18 years;
3. 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;
4. Menopause or use contraception method;
5. Informed consent.

Exclusion Criteria:

1. Creatinine clearance \< 40 ml/min calculated (Cockcroft \& Gault);
2. Intolerance to medication;
3. Absolute neutrophil count \< 1,000/mm3;
4. Pregnancy or breastfeeding;
5. Infection requiring hospitalization;
6. Patients who used Cyclophosphamide in the last 6 months or biological in the last year;
7. Thrombotic renal microangiopathy;
8. Chronic terminal renal disease and/or class VI biopsy;
9. Non-adhesion profile;
10. Need to use another therapeutic scheme;
11. 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).

Primary outcomes:
measure: Partial renal response
timeFrame: Six months
measure: Complete renal response
timeFrame: Six months
Secondary outcomes:
measure: Osteoporosis evaluation
timeFrame: 6 months
measure: Bone structure evaluation
timeFrame: 6 months
measure: Glaucoma evaluation
timeFrame: 15 days, 30 days and 3 months
measure: Cataract evaluation
timeFrame: 3 months
measure: Change from baseline Total cholesterol at 6 months
timeFrame: Baseline and 6 months
measure: Change from baseline Low-density lipoprotein (LDL) at 6 months
timeFrame: Baseline and 6 months
measure: Change from baseline High-density lipoprotein (HDL) at 6 months
timeFrame: Baseline and 6 months
measure: Change from baseline Triglycerides at 6 months
timeFrame: Baseline and 6 months
measure: Change from baseline Anti-High-density lipoprotein (anti-HDL) at 6 months
timeFrame: Baseline and 6 months
measure: Therapy adherence by a self-report medication adherence measure (8-item Morisky Medication Adherence Scale)
timeFrame: Baseline
measure: Change from baseline Serum levels of prednisone using Area Under the Curve [AUC] at 30 days, 3 months and 6 months
timeFrame: Baseline, 30 days, 3 months and 6 months
Other outcomes:
Locations:
city: São Paulo
country: Brazil
facility: Rheumatology Division of Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo
state: Sao Paulo
city: São Paulo
country: Brazil
facility: Hospital das Clinicas da Faculdade de Medicina da USP
Study officials:
References:
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