CTRI Number	CTRI/2019/09/021287 [Registered on: 17/09/2019] Trial Registered Prospectively
Last Modified On:	12/02/2020
Post Graduate Thesis	No
Type of Trial	Interventional
Type of Study Modification(s)	Drug
Study Design	Randomized, Parallel Group, Active Controlled Trial
Public Title of Study Modification(s)	Decreased immunosuppression in Primary Membranous Nephropathy
Scientific Title of Study Modification(s)	Standard versus low-dose cyclical Cyclophosphamide and Steroids in the treatment of Primary Membranous Nephropathy- a randomised controlled trial
Secondary IDs if Any Modification(s)	Secondary ID  Registry  INT/IEC/2019/801551 (9th August 2019)  Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study) Modification(s)	Name  Raja Ramachandran  Address  Department of Nephrology AKU ward, PGIMER, Sector 12 Chandigarh CHANDIGARH 160012 India  Phone  9216958874   Fax     Email  drraja_1980@yahoo.co.in
Details Contact Person Scientific Query Modification(s)	Name  Raja Ramachandran  Address  Department of Nephrology. AKU ward, PGIMER, Sector 12 Chandigarh CHANDIGARH 160012 India  Phone  9216958874   Fax     Email  drraja_1980@yahoo.co.in
Details Contact Person Public Query	Name  Raja Ramachandran  Address  Sector 12 Sector 12 Chandigarh 160036 Chandigarh CHANDIGARH 160012 India  Phone  9216958874   Fax     Email  drraja_1980@yahoo.co.in
Source of Monetary or Material Support Modification(s)	Director, PGIMER, Chandigarh
Primary Sponsor	Name  Postgraduate Institute of Medical Education and Research  Address  Sector 12, Chandigarh  Type of Sponsor  Research institution
Details of Secondary Sponsor	Name  Address  None  None
Countries of Recruitment	India
Sites of Study Modification(s)	No of Sites = 11   Contact Person  Name of Site  Site Address  Phone/Fax/Email  Dr Namrata Rao  Dr. Ram Manohar Lohia Institute of Medical Sciences  Dept Of Nephrology, Vibhuti Khand, Gomti Nagar, Lucknow, Uttar Pradesh 226010 Lucknow   9454360872 snamratarao@yahoo.co.in  Dr Vivek Sood  Army R & R Hospital  Dept of Nephrology,11, Dhaulakuan Delhi Cantt Delhi - 110010 New Delhi   8974321019 viverit@gmail.com  Dr Indranil Ghosh  Command Hospital  Dept of Nephrology, Medical Division, 56 Churha, Cariappa Road, Lucknow Cantt, Lucknow - 226002, Central Command Lucknow   9876268895 rajpro_5@yahoo.com  Dr Neeraj Inamdar  Dr. Ram Manohar Lohia Hospital and Postgraduate Institute of Medical Education and Research  Dept of Nephrology, Baba Kharak Singh Marg, Near Gurudwara Bangla Sahib, Connaught Place, New Delhi, Delhi 110001 New Delhi   9225821487 nainamdar@gmail.com  Dr Dipankar Sircar  IPGMER, Kolkata  Dept of Nephrology , Harish Mukherjee Road , Bhiwani pore, 700020 Kolkata   9433407355 deepsircar@gmail.com  Dr Gopalakrishnan  Madras Medical College  Dept Of Nephrology, Near Park Town Station, Park Town, Chennai, Tamil Nadu 600003 Chennai   9444085404 srigola751@yahoo.com  Dr Manisha Sahay  Osmania General Hospital  Dept Of Nephrology, Afzalgunj Rd, Afzal Gunj, Hyderabad, Telangana 500012 Hyderabad   9849097507 drmanishasahay@gmail.com  Dr Raja Ramachandran  PGIMER  Dept of Nephrology, c block, Sector 12 Chandigarh-160012 Chandigarh   9216958874 drraja_1980@yahoo.co.in  Dr Narayan Prasad  Sanjay Gandhi Postgraduate Institute of Medical Sciences  Dept Of Nephrology, Rae Bareli Road, Lucknow 226014 Lucknow   9415403140 narayan.nephro@gmail.com  Dr Sanjeev Nair  Saveetha Medical College and Hospital  Dept Of Nephrology, Thandalam, Chennai 602105 Chennai   9840649846 docsvn@gmail.com  Dr Mayuri Trivedi  SL Raheja Fortis Hospital  Dept Of Nephrology, Raheja Rugnalaya Marg, Mahim West, Mahim, Mumbai, Maharashtra 400016 Mumbai   9870265655 mayuritrivedi80@yahoo.co.in
Details of Ethics Committee Modification(s)	No of Ethics Committees= 4   Name of Committee  Approval Status  IEC, Osmania hospital, Hyderabad  Approved  IEC, R and R Delhi  Approved  Institute Ethics Committee   Approved  Institute review  Approved
Regulatory Clearance Status from DCGI	Status  Not Applicable
Health Condition / Problems Studied	Health Type  Condition  Patients  Nephrotic syndrome with diffuse membranous glomerulonephritis
Intervention / Comparator Agent Modification(s)	Type  Name  Details  Intervention  Low-Dose Cyclical Cyclophosphamide and Steroid  Oral prednisolone 0.5 mg/kg per day in the first, third, and fifth month and oral Cyclophosphamide at 1-1.5 mg/kg per day in the second, fourth, and sixth month  Comparator Agent  Standard Cyclical Cyclophosphamide and Steroids   Intravenous methylprednisolone 1 g/day in 100 mL normal saline will be administered over 45 min on three consecutive days followed by oral prednisolone 0.5 mg/kg per day for 27 days in the first, third, and fifth month and oral cyclophosphamide at 2-2.5 mg/kg per day in the second, fourth, and sixth month
Inclusion Criteria	Age From  16.00 Year(s) Age To  70.00 Year(s) Gender  Both  Details  1. Biopsy proven primary membranous nephropathy 2. Persistent nephrotic syndrome (>4 g/day with a serum albumin of < 3.5g/dL) despite NIAT (ACEi or ARBs and statin therapy) months (Mean SBP/DBP ≤ 150/90 mmHg in the last three months) for 3 months or PMN with deep vein thrombosis (DVT)/requiring hospitalisation for complications for nephrotic syndrome 3. Patients showing severe or disabling symptoms related to nephrotic syndrome, or severe hypoalbuminemia (<2 g/dL) that can be included before the completion of 3 month observation period at the discretion of the investigator independent of the proteinuria value.
ExclusionCriteria	Details  1)Patients with eGFR >45 ml/min/1.73m2 2)Prior, active infection including hepatitis B/C and HIV infection, 3)Positive for anti-nuclear factor, 4) Monoclonal proteins in serum/urine, 5)Any suggestion of malignancy on ultrasonography, 6)Hypocomplementaemia, 7)Presence of tubular atrophy and 8)Pre-existing DM, 9)Abnormal liver function tests and secondary MN 10)Any immunosuppressive therapy in the last 12 months
Method of Generating Random Sequence	Computer generated randomization
Method of Concealment	An Open list of random numbers
Blinding/Masking	Open Label
Primary Outcome	Outcome  TimePoints  Remission rates  12 and 24 months
Secondary Outcome	Outcome  TimePoints  1.Adverse events in both the groups. 2.The number of patients with an increase ≥ 50% of serum creatinine (SCr) from baseline at 12 and 18 and the end of the follow-up. 3.The proportion of patients with preserved renal function (estimated GFR ≥ 60 ml/min) in both treatment arms after the treatment period. 4.Serum levels of anti-phospholipase A2 receptor antibodies (anti-PLA2R), before of treatment and at 3, 6, 9, 12 and18 months of study, in both treatment arms. 5.CR and PR  12 and 24 months
Target Sample Size	Total Sample Size="114" Sample Size from India="114"
Phase of Trial	Post Marketing Surveillance
Date of First Enrollment (India) Modification(s)	23/09/2019
Date of First Enrollment (Global)	No Date Specified
Estimated Duration of Trial	Years="2" Months="5" Days="0"
Recruitment Status of Trial (Global) Modification(s)	Not Applicable
Recruitment Status of Trial (India)	Open to Recruitment
Publication Details Modification(s)	none yet
Brief Summary Modification(s)	Since PMN is self-limiting in up to 32% of cases, non-immunosuppressive antiproteinuric therapy (NIAT) is recommended as first-line therapy. Kidney Disease, Improving Global Outcomes (KDIGO) recommends immunosuppressive therapy (IST) in NIAT refractory PMN.2 ISTs in PMN include cyclophosphamide (CTX), chlorambucil, cyclosporine (CSA), tacrolimus (TAC), and rituximab. Both alkylating agents and calcineurin inhibitors (CNIs) have been tried mostly in combination with steroids. Modified Ponticelli regimen (MPR), i.e. therapy of steroids and CTX has been associated with both short-term and long-term success and has been recommended as the first line. Renal survival of greater than 90% after a decade of follow-up is reported with the use of this regimen. Cyclical therapy of steroids and CTX is associated with significant cumulative toxicity in the form of opportunistic infections, reactivation of viral infections, gonadal failure, hemorrhagic cystitis and development of diabetes. The regimen involves the use of pulse steroids for a total of 9 doses, with greater than 90% of patients having a normal renal function, and the disease is slowly progressive, pulse steroids are unwarranted. Also, the treatment of CTX of 2-2.5 mg/kg/day, considering the indolent nature of the disease may be an overdose. Hence, the present study is undertaken to compare a regimen using reduced dose immunosuppression (without pulse steroids and oral CTX at 1-1.5 mg/kg/day) with the standard cyclical CTX/GC.