CRO2035

Imperial College London; Joint Research Compliance Office

Room 221, Medical School Building, St Mary’s Campus, Norfolk Place, London, United Kingdom, W2 1PG

Professor Liz Lightstone, Imperial College London, l.lightstone@imperial.ac.uk

Professor Liz Lightstone, Imperial College London, l.lightstone@imperial.ac.uk

No

No

No

Final

17 May 2018

Yes

16 Oct 2017

Yes

13 Dec 2017

Yes

The trial aimed to demonstrate that a regimen free of oral steroids but with rituximab and MMF is non-inferior to a regimen based on oral steroids and MMF in achieving the primary outcome of complete renal response at one year.

Data Monitoring Committee Pharmacovigilance On-site and remote monitoring including source data verification Detailed informed consent process

15 May 2014

No

Yes

United Kingdom: 25

25

25

0

0

0

0

0

1

24

0

0

Overall trial (overall period)

Randomised - controlled

Not applicable - this is an open label trial

Yes

Mycophenolate Mofetil (MMF)

Tablet

Oral use

Dosing in adults: start MMF 500mg bd and increase weekly by 250mg bd to a maximum dose of 1g bd if 60kg or less and 1.5g bd if >60kg. Within these guidelines the maximum dose will be titrated against white blood cells, tolerability or trough mycophenolic acid levels where available but should be no less than 500mg bd. At 6 months, if patients have responded, as defined by stabilisation of serum creatinine, and proteinuria non nephrotic and >50% reduction from baseline, the maximum dose of MMF will be reduced to 1g bd in those on higher dose initially. Dosing in children aged 12-18: Commence MMF dosing at 600mg/m2 for 3 days up to a maximum of 1g and then increased to 600mg/m2 bd.

Oral prednisolone

Tablet

Oral use

Oral prednisolone commencing at 0.5mg/kg/day (max 60mg/day, minimum 20mg/day) tapered thus: o From week 2: if commencing on >45mg/day, decreased by 10mg/day every 2 weeks to 40mg/day followed by decrease by 5mg/day every 2 weeks until down to 20mg/day if clinical status permits. o From week 2: if commencing on 45mg/day or less, decreased by 5mg/day every 2 weeks until down to 20mg/day if clinical status permits. o However, the dose should be no more than 20mg/day at 12 -13 weeks. o Once down to a dose of 20mg/day, this should be maintained for 4 weeks. o Thereafter, reduced by 2.5mg/day every week down to 10mg/day if clinical status permits. o However, the dose should be no more than 10mg/day once daily by 26 weeks at the latest o Once down to a dose of 10mg/day, this should be maintained for a minimum of 6 weeks. o Thereafter, the steroid dose can be tapered according to clinical status and at a rate determined by clinician.

Methyl prednisolone

Infusion

Intravenous use

500mg Methyl prednisolone IV at Infusion 1/Visit 1 and Infusion 2/Visit 3. If patients have received methyl prednisolone within the 4 weeks prior to randomisation, the dose will be modified to ensure maximum methyl prednisolone given will not exceed 3g in total.

Mycophenolate Mofetil (MMF)

Tablet

Oral use

Dosing in adults: start MMF 500mg bd and increase weekly by 250mg bd to a maximum dose of 1g bd if 60kg or less and 1.5g bd if >60kg. Within these guidelines the maximum dose will be titrated against white blood cells, tolerability or trough mycophenolic acid levels where available but should be no less than 500mg bd. At 6 months, if patients have responded, as defined by stabilisation of serum creatinine, and proteinuria non nephrotic and >50% reduction from baseline, the maximum dose of MMF will be reduced to 1g bd in those on higher dose initially. Dosing in children aged 12-18: Commence MMF dosing at 600mg/m2 for 3 days up to a maximum of 1g and then increased to 600mg/m2 bd.

Rituximab

Solution for infusion

Intravenous use

Rituximab 1g infusion at Infusion 1/Visit 1 and Infusion 2/Visit 3 (The dose in children will be 750mg/m2 (maximum 1g) at Infusion 1/Visit 1 and Infusion 2/Visit 3 ). Concomitant IV or oral antihistamines and IV or oral paracetamol will be administered prior to administration of Rituximab.

Methyl prednisolone

Infusion

Intravenous use

500mg Methyl prednisolone IV at Infusion 1/Visit 1 and Infusion 2/Visit 3. If patients have received methyl prednisolone within the 4 weeks prior to randomisation, the dose will be modified to ensure maximum methyl prednisolone given will not exceed 3g in total.

Control

Rituximab

Control

Rituximab

CR is defined as: - uPCR ≤50mg/mmol (=<0.5mg/mg) in a spot urine AND - eGFR ≥60ml/min, or if <60ml/min at screening, not fallen by >20% compared to screening/randomisation (whichever worse) AND - In the rituximab arm without the need to prescribe oral steroids within 1 year (beyond the first 8 wks depending on duration of prior steroids), except for 1 course of oral prednisolone max 30mg for a maximum of 14 d OR one intramuscular, one intravenous injection or two intra-articular injections of steroids, each maximum 120mg methylprednisolone or equivalent (in addition to the planned IV methyl prednisolone in the protocol) OR - in the steroid arm without the need for additional steroids over and above the prescribed taper, except for one course of oral prednisolone maximum 30mg for a maximum of 14d OR one intramuscular, one intravenous injection or two intra-articular injections of steroids, maximum 120mg methylprednisolone or equivalent (in addition to planned IV methyl pred)

Primary

Week 52 or closest visit

Control v Rituximab

25

Pre-specified

1.38

2-sided

The proportion of patients achieving partial renal response (PR) at week 52 where PR is defined as: - eGFR - no more than a 20% decrease from the baseline value, AND - if not nephrotic at baseline (urine PCR <300mg/mmol (3mg/mg)), 50% improvement in spot urine PCR OR - if nephrotic at baseline (urine PCR >300mg/mmol (3mg/mg)), 50% improvement in spot urine PCR AND urine PCR <300mg/mmol

Secondary

52 weeks or closest visit

Control v Rituximab

25

Pre-specified

1.13

2-sided

From the time of signing the consent form up to the final study visit.

21

Control

Rituximab