CYCLONES - CYClophosphamide LOw Dose and No Extra Steroid

NCT03492255 | Terminated DMC

• 1 other identifier: CYCLONES
• Study Type: interventional
• Target: 49
• Locations: 1 country
• Sites: 2

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.

Conditions

Systemic Lupus Erythematosus (SLE)

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (11)

• Osteoporosis evaluation

  6 months

• Bone structure evaluation

  6 months

• Glaucoma evaluation

  15 days, 30 days and 3 months

• Cataract evaluation

  3 months

• Change from baseline Total cholesterol at 6 months

  Baseline and 6 months

Study Arms (2)

Eurolupus: Cyclophosphamide + Methylprednisolone + oral GC

ACTIVE COMPARATOR

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: Cyclophosphamide+Methylprednisolone no oral GC

EXPERIMENTAL

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

Interventions

Cyclophosphamide DRUG

Patients in both EUROLUPUS group and CYCLONES Group will receive for 3 months Cyclophosphamide (6 doses of 500mg/biweekly)

Cyclones Group: Cyclophosphamide+Methylprednisolone no oral GC; Eurolupus: Cyclophosphamide + Methylprednisolone + oral GC

Methylprednisolone DRUG

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).

Cyclones Group: Cyclophosphamide+Methylprednisolone no oral GC; Eurolupus: Cyclophosphamide + Methylprednisolone + oral GC

Prednisone DRUG

Patients in EUROLUPUS group will receive oral prednisone ≤ 30 mg/day with a reduction of 5mg/month until complete withdrawal.

Eurolupus: Cyclophosphamide + Methylprednisolone + oral GC

Mycophenolate Mofetil DRUG

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.

Cyclones Group: Cyclophosphamide+Methylprednisolone no oral GC; Eurolupus: Cyclophosphamide + Methylprednisolone + oral GC

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• Central nervous system (CNS) disorders or hemolytic anemia and severe thrombocytopenia (\< 50,000 platelets/mm3).

Sponsors & Collaborators

• University of Sao Paulo General Hospital: lead
• Fundação de Amparo à Pesquisa do Estado de São Paulo: collaborator

Study Sites (2)

Rheumatology Division of Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo

São Paulo, São Paulo, 05403-000, Brazil

Location

Hospital das Clinicas da Faculdade de Medicina da USP

São Paulo, 05403-000, Brazil

Location

Related Publications (16)

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• Gladman DD, Urowitz MB, Rahman P, Ibanez D, Tam LS. Accrual of organ damage over time in patients with systemic lupus erythematosus. J Rheumatol. 2003 Sep;30(9):1955-9.

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• Ruiz-Arruza I, Lozano J, Cabezas-Rodriguez I, Medina JA, Ugarte A, Erdozain JG, Ruiz-Irastorza G. Restrictive Use of Oral Glucocorticoids in Systemic Lupus Erythematosus and Prevention of Damage Without Worsening Long-Term Disease Control: An Observational Study. Arthritis Care Res (Hoboken). 2018 Apr;70(4):582-591. doi: 10.1002/acr.23322. Epub 2018 Mar 7.

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• Condon MB, Ashby D, Pepper RJ, Cook HT, Levy JB, Griffith M, Cairns TD, Lightstone L. Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis. 2013 Aug;72(8):1280-6. doi: 10.1136/annrheumdis-2012-202844. Epub 2013 Jun 5.

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  PMID: 22553077 BACKGROUND

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• Ruiz-Irastorza G, Danza A, Khamashta M. Glucocorticoid use and abuse in SLE. Rheumatology (Oxford). 2012 Jul;51(7):1145-53. doi: 10.1093/rheumatology/ker410. Epub 2012 Jan 23.

  PMID: 22271756 BACKGROUND

• Rohatagi S, Barth J, Mollmann H, Hochhaus G, Soldner A, Mollmann C, Derendorf H. Pharmacokinetics of methylprednisolone and prednisolone after single and multiple oral administration. J Clin Pharmacol. 1997 Oct;37(10):916-25. doi: 10.1002/j.1552-4604.1997.tb04266.x.

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• Levic Z, Micic D, Nikolic J, Stojisavljevic N, Sokic D, Jankovic S, Kendereski A, Mavra M. Short-term high dose steroid therapy does not affect the hypothalamic-pituitary-adrenal axis in relapsing multiple sclerosis patients. Clinical assessment by the insulin tolerance test. J Endocrinol Invest. 1996 Jan;19(1):30-4. doi: 10.1007/BF03347855.

  PMID: 8851689 BACKGROUND

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  PMID: 7936181 BACKGROUND

• Contreras G, Pardo V, Leclercq B, Lenz O, Tozman E, O'Nan P, Roth D. Sequential therapies for proliferative lupus nephritis. N Engl J Med. 2004 Mar 4;350(10):971-80. doi: 10.1056/NEJMoa031855.

  PMID: 14999109 BACKGROUND

• Petri M, Buyon J, Kim M. Classification and definition of major flares in SLE clinical trials. Lupus. 1999;8(8):685-91. doi: 10.1191/096120399680411281.

  PMID: 10568907 BACKGROUND

• Gladman DD, Urowitz MB, Goldsmith CH, Fortin P, Ginzler E, Gordon C, Hanly JG, Isenberg DA, Kalunian K, Nived O, Petri M, Sanchez-Guerrero J, Snaith M, Sturfelt G. The reliability of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index in patients with systemic lupus erythematosus. Arthritis Rheum. 1997 May;40(5):809-13. doi: 10.1002/art.1780400506.

  PMID: 9153540 BACKGROUND

• Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, Li LS, Mysler E, Sanchez-Guerrero J, Solomons N, Wofsy D; Aspreva Lupus Management Study Group. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009 May;20(5):1103-12. doi: 10.1681/ASN.2008101028. Epub 2009 Apr 15.

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MeSH Terms

Conditions

Lupus Erythematosus, Systemic

Interventions

Cyclophosphamide; Methylprednisolone; Prednisone; Mycophenolic Acid

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Pregnadienediols; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 16, 2018
• First Posted: April 10, 2018
• Study Start: April 12, 2018
• Primary Completion: July 2, 2021
• Study Completion: July 2, 2021
• Last Updated: July 21, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

BR (2)