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1 Clinical Trial Details (PDF Generation Date :- Wed, 20 Jun :15:28 GMT) CTRI Number Last Modified On 29/12/2012 Post Graduate Thesis Type of Trial Type of Study Study Design Public Title of Study Scientific Title of Study CTRI/2013/01/ [Registered on: 07/01/2013] - Trial Registered Retrospectively Yes Interventional Drug Randomized, Parallel Group, Active Controlled Trial A TRIAL TO COMPARE EFFICACY AND SAFETY OF CYCLOPHOSPHAMIDE VERSUS TACROLIMUS AND MYCOPHENOLICACID COMBINATION IN PROLIFERATIVE LUPUS NEPHRITIS. COMPARATIVE STUDY OF OUTCOME OF PROLIFERATIVE LUPUS NEPHRITIS WITH NIH REGIMEN VERSUS TACROLIMUS AND MYCOPHENOLICACID COMBINATION AS INDUCTION THERAPY Secondary IDs if Any Secondary ID Identifier Details of Principal Investigator or overall Trial Coordinator (multi-center study) Details Contact Person (Scientific Query) Details Contact Person (Public Query) NIL Designation Affiliation Phone Fax Designation Affiliation Phone Fax Designation Affiliation NIL Details of Principal Investigator KRISHNA PATIL POST DOCTORAL TRAINEE IPGMER SSKM HOSPITAL NEPHROLOGY DEPARTMENT IPGMER,SSKM HOSPITAL AJC BOSE ROAD KOLKATA WEST BENGAL, INDIA AJC BOSE ROAD KOLKATA WEST BENGAL, INDIA Kolkata WEST BENGAL India kpatil1008@gmail.com Details Contact Person (Scientific Query) RAJENDRA PANDEY HEAD OF THE DEPARTMENT OF NEPHROLOGY IPGMER SSKM HOSPITAL NEPHROLOGY DEPARTMENT IPGMER,SSKM HOSPITAL AJC BOSE ROAD KOLKATA WEST BENGAL, INDIA AJC BOSE ROAD KOLKATA WEST BENGAL, INDIA Kolkata WEST BENGAL India rajensankrityan@gmail.com Details Contact Person (Public Query) KRISHNA PATIL POST DOCTORAL TRAINEE IPGMER SSKM HOSPITAL NEPHROLOGY DEPARTMENT IPGMER,SSKM HOSPITAL AJC BOSE ROAD KOLKATA WEST BENGAL, INDIA AJC BOSE ROAD KOLKATA WEST BENGAL, INDIA page 1 / 8

2 Source of Monetary or Material Support Primary Sponsor Details of Secondary Sponsor Countries of Recruitment Sites of Study Details of Ethics Committee Regulatory Clearance Status from DCGI Health Condition / Problems Studied Intervention / Comparator Agent Phone Fax Kolkata WEST BENGAL India kpatil1008@gmail.com Source of Monetary or Material Support > NEPHROLOGY DEPARTMENT IPGMER SSKM HOSPITAL Type of Sponsor DR RAJENDRA PANDEY List of Countries India of Principal Investigator KRISHNA PATIL Primary Sponsor Details IPGMER SSKM HOSPITAL KOLKATA NEPHROLOGY DEPARTMENT IPGMER, SSKM HOSPITAL AJC BOSE ROAD KOLKATA WESTBENGAL, INDIA. Government medical college NEPHROLOGY DEPARTMENT IPGMER, SSKM HOSPITAL AJC BOSE ROAD KOLKATA of Site Site Phone/Fax/ NEPHROLOGY DEPARTMENT IPGMER SSKM HOSPITAL AJC BOSE ROAD KOLKATA Kolkata WEST BENGAL kpatil1008@gmail.com of Committee Approval Status Date of Approval Is Independent Ethics Committee? IPGME&R Approved 05/05/2011 No Status Not Applicable Health Type Patients Date No Date Specified Condition PROLIFERATIVE LUPUS NEPHRITIS Type Details Intervention Comparator Agent Inj.Methylprednisolone 500 mg iv OD for 3 days, Oral TACROLIMUS 0.1mg/kg in 2 divided doses for 6 months, Oral MYCOPHENOLATE SODIUM 1080MG-1440MG PER DAY DIVIDED IN 2-3 DOSES for 6 months, TAB. PREDNISOLONE 0.5 MG/KG OD tapered over 6 months, Methylprednisolone 500 mg iv infusion daily for 3 days followed by oral Tacrolimus (0.1 mg/kg /day divided in 2 doses 12 hour apart) plus Mycophenolate sodium (1080MG-1440 mg daily in 2-3 divided doses) plus oral Prednisolone 0.5mg/kg/day tapered to minimum dose of 7.5 mg over 3 months,total duration of this induction phase being 6 months. INJ.METHYLPREDNISOLONE Methylprednisolone 500 mg iv 500 MG OD FOR 3 DAYS,INJ.C infusion daily for 3 days YCLOPHOSPHAMIDE followed by iv page 2 / 8

3 Inclusion Criteria Age From Age To Gender Details 750MG/SQUARE METER BSA cyclophosphamide 0.75gm/m2 IV INFUSION IN 500ML NS monthly (increased upto 1 gm if MONTHLY FOR 6 MONTHS, tolerated,with target nadir total TAB.PREDNISOLONE 1MG/KG leucocyte count of 4000) for 6 BODY WEIGHT OD tapered months plus oral prednisolone over 6 months. 1mg/kg/day continued till decrease in proteinuria and then tapered to 7.5 mg / day over 3 months Year(s) Year(s) Both Inclusion Criteria 1. All those patients who met at least 4 of the 11 criteria for diagnosis of SLE according to the American college of rheumatology. 2. Those with histopathological diagnosis of proliferative Lupus Nephritis as per ISN/RPS classification, and willing for regular treatment and followup. Exclusion Criteria Method of Generating Random Sequence Method of Concealment Blinding/Masking Details Random Number Table An Open list of random numbers Open Label Exclusion Criteria 1. Patients who had egfr 2. Those who refused treatment or lost to follow up or were poorly compliant during the induction phase. 3. Those with history of allergy to macrolide antibiotics were excluded from arm II. 4. Abnormal glucose tolerance (fasting blood glucose >110 mg/dl, postprandial glucose >200 mg/dl, or hemoglobin (Hb)A1c >5.9%) were excluded from arm II. 5. Patients detected to have HIV,HEPATITIS B OR C, Malignancy,active life threatening infection at the initiation of induction will be excluded. Primary Outcome Outcome Timepoints 1. COMPLETE OR PARTIAL RENAL REMISSION. 2. ESRD 3. MORTALITY SIX MONTHS Secondary Outcome Outcome Timepoints Daily urinary protein excretion, urinary RBC count, serum creatinine, anti-ds-dna antibody, complement C3, systemic lupus erythematosus disease activity index (SLEDAI) creatinine clearance, and glucocorticoid dose. as well as the normalization rates for PROTEINURIA urinary RBC anti-dsdna antibody, and the complement (C3) level. SIX MONTHS Target Sample Size Total Sample Size=40 page 3 / 8

4 Phase of Trial Date of First Enrollment (India) Date of First Enrollment (Global) Estimated Duration of Trial Recruitment Status of Trial (Global) Recruitment Status of Trial (India) Publication Details Brief Summary Sample Size from India=40 N/A 21/03/2011 No Date Specified Years=1 Months=9 Days=0 Not Applicable Completed NOT YET PUBLISHED Aims and Objectives of the Study : Comparing the rapidity of renal remission in the two groups Comparing the rate of remission in both the groups Comparing the rate of relapse in both the groups 4. Comparing the refractoriness of the disease to therapy in either arms Comparing the side effect profile of both the regimen. 6. Comparing ESRD and mortality in both groups. INTRODUCTION : Lupus nephritis (LN) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus. Patient and renal survival of SLE patients has improved considerably over the past few decades, in part, due to earlier recognition of renal disease, aggressive immunosuppression, and prevention of complications of therapies. 1-3 page 4 / 8

5 Until recently, the majority of nephrologists and rheumatologists relied on one standard approach to the treatment of severe LN, based upon a series of trials at the National Institutes of Health. 4-7 Studies at the National Institutes of Health proved that concomitant i.v. methylprednisolone with monthly pulse i.v. CYC 5,6 was more effective in the short term than either therapy alone. In longer follow-up of the same population, the combination regimen had no greater toxicity than CYC alone, but far superior renal outcomes. Although clearly effective, this regimen is associated with both short-term and long-term adverse effects including increased risk of severe infections, gonadal damage 5,8,9, and malignancy. 10 A significant proportion of patients (up to 22%) fail to achieve remission with this regimen or relapse after treatment and some patients still progress to end-stage renal disease. 11 Lupus nephritis carries a worse morbidity and mortality prognosis in patients with SLE, with renal survival without dialysis after 5 and 10 years ranging from 83% to 92% and 74% to 84%, respectively. 12,13 The burden of lupus nephritis on patients with SLE is reported as high as 60% with in 5 years of diagnosis. 13 Glomerulonephritis not responding to conventional treatment is page 5 / 8

6 a major risk factor for subsequent renal deterioration and poor long term outcome. 14 In view of this, there has been increasing attention on developing alternate therapies that promptly and effectively induce remission, prevent relapse, and maximize patient and renal survival while incurring the least toxicity. Now focus is on the concept of induction treatment with vigorous initial therapies, followed by maintenance treatment with lower doses of less toxic regimens. Such strategies include minimizing the use of CYC with lower dosages, use of sequential therapies with different immunosuppressive agents, and eliminating exposure to CYC entirely with use of alternative agents. Mycophenolate mofetil (MMF), tacrolimus, rituximab, and newer biologics are all being studied in controlled, randomized trials. Several studies have shown that Mycophenolate mofetil (MMF) is as effective if not more than cyclophosphamide pulse as induction therapy for lupus nephritis, with rates of complete and partial remission of % and % respectively These studies have contributed to the increasing use of MMF in the treatment of lupus nephritis ; however, improvement of protein excretion to less than 1 gm / day occurs in less than half page 6 / 8

7 of those treated with MMF and failure rates remain high The combination therapy of MMF and Tacrolimus (FK506) is successful and frequently used for immunosupression in solid organ transplantation. 26,27 So currently there has been rising interest for using this regimen for treatment of lupus nephritis. Although there are some trials of this regimen conducted in US and China showing encouraging results, there has been no such study in Indian population of lupus nephritis.therefore we have conducted this study to compare the results of combination therapy with Tacrolimus, MMF and prednisolone versus the NIH regimen constituting combination of Pulse CYC monthly with initial pulse of Methylprednisolone for three days followed by oral prednisolone. REFERENCES : 1. Fiehn C, Hajjar Y, Mueller K et al. Improved clinical outcome of lupus nephritis during the past decade: importance of early diagnosis and treatment. Ann Rheum Dis 2003; 62: Bono L, Cameron JS, Hicks JA. The very long-term prognosis and complications of lupus nephritis and its treatment. QJM 1999; 92: Uramoto KM, Michet Jr CJ, Thumboo J et al. Trends in the incidence and mortality of systemic lupus erythematosus Arthritis Rheum 1999; 42: Boumpas DT, Austin III HA, Vaughn EM et al. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 1992; 340: Gourley MF, Austin III HA, Scott D et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis, A randomized, controlled trial. Ann Intern Med 1996; 125: Illei GG, Austin HA, Crane M et al. Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med 2001; 135: Austin III HA, Klippel JH, Balow JE et al. Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med 1986; 314: page 7 / 8

8 Powered by TCPDF ( PDF of Trial 8. Boumpas DT, Austin III HA, Vaughan EM et al. Risk for sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy. Ann Intern Med 1993; 119: Mok CC, Lau CS, Wong RW. Risk factors for ovarian failure in patients with systemic lupus erythematosus receiving cyclophosphamide therapy. Arthritis Rheum 1998; 41: Radis CD, Kahl LE, Baker GL et al. Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis. A 20-year follow-up study. Arthritis Rheum 1995; 38: Korbet SM, Lewis EJ, Schwartz MM et al. Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaborative Study Group. Am J Kidney Dis 2000; 35: Donadio Jr. JV, Hart GM, Bergstralh EJ, Holley KE.Prognostic determinants in lupus nephritis : a long term clinicopathologic study. Lupus 1995; 4 : Moc CC, Wong RW, Lau CS. Lupus nephritis in southern Chinese patients: clinicopathologic findings and long term outcome. Am J Kidney Dis 1999; 34: Korbet SM, Lewis EJ, Schwartz MM, Reichlin M, Evans J, Rohde RD, Factors predictive of outcome in severe lupus nephritis. Lupus nephritis collaborative study group. Am J Kidney Dis 2000; 35 : Cross J, Dwomoa A, Andrews P, et al. Mycophenolate mofetil for remission induction in severe lupus nephritis.nephron clin pract 2005; 100: c Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 2005; 353(21): Chan TM, Li FK, Tang CS, et al. Efficasy of Mycophenolate mofetil in patients with diffuse proliferative lupus nephritis.hong Kong-Guangzhou Nephrology Study Group.N Engl J Med 2000; 343: Kapitsinou PP, Boletis JN, Skopouli FN, Boki KA, Moutsopoulos HM. Lupus Nephritis: treatment with Mycophenolate mofetil.rheumatology(oxford) 2004; 43: Hu W, Liu Z, Chen H, et al. Mycophenolate mofetil vs cyclophosphamide therapy for patients with diffuse proliferative lupus nephritis. Chin Med J (Engl) 2002; 115: Zhu B, Chen N, Lin Y, et al.mycophenolate mofetil in induction and maintenance therapy of severe lupus nephritis: a meta-analysis of randomized controlled trials. Nephrol Dial Transplant 2007; 22: Glicklich D, Acharya A. Mycophenolate mofetil therapy for lupus nephritis refractory to intravenous cyclophosphamide. Am J Kidney Dis 1998; 32: Dooley MA, Cosio FG, Nachman PH, et al. Mycophenolate mofetil therapy in lupus nephritis: clinical observations. J Am Soc Nephrol 1999; 10 : Sinclair A, Appel G, Dooley MA, et al. Mycophenolate mofetil as induction and maintenance therapy in lupus nephritis: rationale and protocol for the randomized, controlled Aspreva Lupus Management Study(ALMS).Lupus 2007; 16: Elyan M,Ballous. The effectiveness and safety of. Mycophenolate mofetil therapy in lupus nephritis. Clin Rheumatol 2009; 28: Lu F, Tu Y, Peng X,et al. A Prospective Multicentre study of Mycophenolate mofetil combined with prednisolone as induction therapy in 213 patients with active lupus nephritis. Lupus 2008; 17 : Mendez R. FK506 and Mycophenolate mofetil in renal transplant receipients: six- month results of a multi center, randomized dose ranging trial. FK506 MMF Dose-Ranging Kidney Transplant Study Group. Transplant Proc 1998; 30 : Mendez R, Gonwa T, Yang HC,Weinstein S, Jensik S, Steinberg S.A prospective, randomized trial of Tacrolimus in combination with Sirolimus or Mycophenolate mofetil in Kidney Transplantation: Results at 1 Year. Transplantation 2005; 80: page 8 / 8