An interventional study of Cyclophosphamide and Methylprednisolone in Systemic Lupus Erythematosus (SLE), sponsored by University of Sao Paulo General Hospital. Terminated at 2 sites in Brazil. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2021-07-21.
Sponsored by University of Sao Paulo General Hospital · Not applicable, Interventional, and Treatment
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.
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.
1,207 studies on the registry are indexed under Lupus Erythematosus, Systemic; 405 are open to participants now.
This study's enrollment of 49 is close to the median of 52 across 876 interventional studies indexed under Lupus Erythematosus, Systemic.
Browse Lupus Erythematosus, Systemic studies →University of Sao Paulo General Hospital is the lead sponsor of 611 studies on the registry; 98 are open to participants now.
Of its 8 completed or terminated interventional studies of FDA-regulated products, 0 (0%) have results posted.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
All the criteria below have to be completed:
Exclusion Criteria:
11.Central nervous system (CNS) disorders or hemolytic anemia and severe thrombocytopenia (\< 50,000 /mm3).
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Biopsy and archival tissue
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Creatinine clearance (CrCl)
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Absolute neutrophil count (ANC)
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Platelets
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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 · Drug: Methylprednisolone · Drug: Prednisone · Drug: Mycophenolate Mofetil
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 · Drug: Methylprednisolone · Drug: Mycophenolate Mofetil
Patients in both EUROLUPUS group and CYCLONES Group will receive for 3 months Cyclophosphamide (6 doses of 500mg/biweekly)
Patients in EUROLUPUS group will receive Methylprednisolone \[750 mg for three consecutive days). Patients in CYCLONES Group will receive Methylprednisolone \[500 mg (day 0 and day 15), 250 mg (day 30 and day 45) and 125 mg (day 60 and day 75).
Patients in EUROLUPUS group will receive oral prednisone ≤ 30 mg/day with a reduction of 5mg/month until complete withdrawal.
From the third month of protocol, patients in both EUROLUPUS group and CYCLONES Group will receive mycophenolate mofetil (2-3 g/day) until the sixth month of study.
Partial renal response
The primary endpoint is partial renal response, a composition of: urinary protein/creatinine ratio \< 3g/g with decrease of at least 50% of the initial value and increase of creatinine (mg/dL) not higher than 15% of the initial value
Time frame: Six months
Complete renal response
Complete renal response, according to a composition of: urinary protein/creatinine ratio \< 0,5 (g/g) with decrease of at least 50% of the initial value and increase of creatinine (mg/dL) not higher than 15% of the initial value.
Time frame: Six months
Osteoporosis evaluation
Evaluation of osteoporosis by bone densitometry (DXA)
Time frame: 6 months
Bone structure evaluation
Evaluation of bone structure by high resolution peripheral quantitative computed tomography (HRpQCT)\]
Time frame: 6 months
Glaucoma evaluation
Ophthalmologic evaluation for glaucoma secondary to glucocorticoids use
Time frame: 15 days, 30 days and 3 months
Cataract evaluation
Ophthalmologic evaluation for cataract secondary to glucocorticoids use
Time frame: 3 months
Change from baseline Total cholesterol at 6 months
Lipid profile evaluation including total cholesterol in mg/dL
Time frame: 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
Time frame: 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
Time frame: Baseline and 6 months
Change from baseline Triglycerides at 6 months
Lipid profile evaluation including triglycerides in mg/dL
Time frame: 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)
Time frame: 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).
Time frame: 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 \[AUC\]
Time frame: Baseline, 30 days, 3 months and 6 months
Plan to share: No
Ran from Apr 2018 to primary completion in Jul 2021, 38 months.
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This study is terminated, as verified in Apr 2021. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Cyclophosphamide
Lupus Erythematosus, Systemic →
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