Mycophenolate Mofetil and Tacrolimus vs Tacrolimus Alone for the Treatment of Idiopathic Membranous Glomerulonephritis (IMG)
Phase: PHASE4
Conditions: Glomerulonephritis, Membranous
Sponsor: Imperial College Healthcare NHS Trust

 
1 
MTAC Clinical Trial protocol 
 
 
June 2008 
 
 
 
 
 
 
 
Version 2 
West London Renal and Transplant Unit  
 
EudraCT Number 2008-001009-41 
REC reference number 08/H072090 
 
Full trial name -Mycophenylate mofetil and tacrolimus vs tacrolimus alone for 
the treatment of idiopathic membranous glomerulonephritis 
 
Abbrieviated trial name      MTAC 
 
 
Summary 
 
Membranous nephropathy is a common cause of nephrotic syndrome in adults. It is 
difficult to treat and if persistent leads to end stage renal failure in a significant 
number of patients. It is currently treated in this institution with tacrolimus 
monotherapy. This is effective in the majority of patients in reducing proteinuria but 
the remissions are often partial and patients tend to relapse when the tacrolimus 
treatment is stopped. We propose to use mycophenylate mofetil in combination with 
tacrolimus with the aim of obtaining a more complete initial response to treatment, a 
decreased rate of relapse on withdrawal of therapy and less progression of renal 
failure. 
 
Principal Investigators 
Drs Megan Griffith   Tom Cairns and  Neill Duncan 
Renal Unit 
 4th floor Ham House  
Hammersmith Hospital  
Du Cane Road 
LondonW12 OHS 
 
Sponsorship  provided by Imperial College Healthcare NHS Trust ref no GRIM1001 

 
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Contents 
 
 
 
 
 
 
 
 
 
Page number 
Title Page 
 
 
 
 
 
 
 
 
1 
 
Contents 
 
 
 
 
 
 
 
 
2 
1.Background   
 
 
 
 
 
 
 
3 
1.1Membranous Glomerulonephritis  
 
 
 
3 
1.2 Mycophenylate Mofetil in membranous glomerulonephritis 
3 
2.Aims of MTAC   
 
 
 
 
 
 
 
4 
3.Hypothesis  
 
 
 
 
 
 
 
4 
4. Trial Design 
 
 
 
 
 
 
 
4 
4.1 Eligibility  
 
 
 
 
 
 
5 
4.2 Trial Protocol 
 
 
 
 
 
 
5 
4.3 Evaluations 
 
 
 
 
 
 
6 
4.4 Withdrawal and treatment failure  
 
 
 
6 
4.5 End points  
 
 
 
 
 
 
 
a) Primary Endpoints  
 
 
 
 
 
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b) Secondary end points  
 
 
 
 
 
7 
4.6 Statistic Analysis  
 
 
 
 
 
7 
4.7 Duration  
 
 
 
 
 
 
8 
5.  Adverse Events and Data Monitoring 
 
 
 
 
8 
6. Internal and External Review 
 
 
 
 
 
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Appendix 1         MTAC Trial Overview 
 
 
 
 
10 
Appendix 2:       Membership of the Glomerulonephritis Research Group  11 
   West London Renal and Transplant Unit Feb 2008.  
Appendix 3:       References  
 
 
 
 
 
12 

 
3 
 
 
1.Background  
 
1.1 Membranous Glomerulonephritis 
 
Idiopathic membranous nephropathy is the most common cause of nephrotic 
syndrome in Caucasian adults and up to 40% of patients eventually develop end stage 
renal failure (1). Historically used treatment regimes include high dose prednisolone, 
chlorambucil, and cyclophosphamide. Although these are effective in some patients 
there are significant side effects from the treatment hence the need to seek alternative 
immunosuppresive regimes. Cyclosporin is a well tolerated immunosuppresive agent 
used widely in transplantation, this has been shown to be effective in membranous 
nephropathy but there is a high incidence of relapse on withdrawal of therapy and 
long term risks of a decline in renal function due to nephrotoxicity (2). Tacrolimus is 
an alternative calcineurin inhibitor with less nephrotoxicity which has been shown to 
be very effective in the treatment of membranous nephropathy but there remains a 
high risk of relapse on withdrawal of therapy (3).  Tacrolimus alone is the current 
standard therapy in this institution. 
 
1.2 Mycophenylate Mofetil in membranous glomerulonephritis 
 
Experimental models of membranous glomerulonephritis show that damage to the 
glomerular basement membrane by the deposition of immunoglobulin results in 
proteinuria (4). Mycophenylate mofetil (MMF) is an immuosuppressive agent which 
inhibits de novo purine nucleotide synthesis and the depletion of guanosine 
triphosphate (GTP) in lymphocytes and monocytes. Thus it selectively suppresses T 
and B lymphocyte proliferation and antibody formation, and is therefore likely to be 
effective in modifying this process. It has been used widely in other autoimmune 
diseases and has low toxicity (5). It has been shown to be effective in the treatment of 
membranous nephropathy when used in combination with high dose steroids (6,7,8). 
However there are significant side effects from the steroids and we wish to avoid 
these in our patients. MMF has been used in combination with tacrolimus in 

 
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transplantation, and this regime is better tolerated than those containing even low dose 
steroids (9). We hope that the addition of MMF to tacrolimus will result in improved 
remission rates from proteinuria for patients, improved preservation of renal function, 
will be well tolerated and will allow the eventual withdrawal of immunosuppressive 
agents without relapse thus avoiding the long term toxicity of ongoing treatment with 
these agents.  
 
 
 
 
2. Aims of MTAC   
 
To investigate if combining mycophenylate mofetil (MMF) with tacrolimus has a 
beneficial effect over tacrolimus therapy alone in the treatment of membranous 
glomerulonephritis. Tacrolimus alone is often effective in producing remission from 
heavy proteinuria but patients often relapse when the tacrolimus is withdrawn. We 
wish to investigate whether the addition of MMF will allow the subsequent 
withdrawal of tacrolimus without precipitating relapse. We will also study whether 
the addition of MMF to standard therapy with tacrolimus will be more effective in 
obtaining remission of proteinuria  and  preserving renal function 
 
3.Hypothesis 
 
When MMF is added to tacrolimus in the treatment of membranous 
glomerulonephritis, it is likely to improve the initial response to treatment and reduce 
the risk of relapse on stopping therapy. 
 
4. Trial Design 
 
This will be a randomized controlled trial in a single centre of tacrolimus alone vs 
tacrolimus and MMF therapy in 32 patients with heavy proteinuria secondary to 

 
5 
idiopathic membranous glomerulonephritis diagnosed by renal biopsy. We aim to 
recruit 32 patients 16 to each arm of the trial. 
 
4.1 Eligibility 
 
a) Inclusion criteria (requires all) 
1 .Idiopathic membranous glomeulonephritis on renal biopsy 
2.Proteinura – protein/creatinine ratio (PCR) >100units with hypoalbuminaemia or 
PCR >300 units with normal serum albumin despite 3 months treatment with 
maximum tolerated doses of ace inhibitors and angiotensin 2 antagonists; (or shorter 
if life threatening complications of nephrotic syndrome require institution of 
immediate immunosuppression.) 
3. Male or female patients aged 18 to 80 years. 
 
b) Exclusion Criteria 
1 Hepatits B hepatitis C or HIV positive 
2 Malignancy (all patients must have a CT chest abdomen and pelvis and other 
investigations if clinically indicated). 
3. Untreated infection 
4. Females who are pregnant, breast feeding, or at risk of pregnancy and not using a 
medically acceptable form of contraception. 
5. Any condition judged by the investigator that would cause the study to be 
detrimental to the patient. 
 
. 
 
4.2 Trial Protocol 
The research will be conducted via the glomerulonephritis clinc at Hammersmith 
Hospital. All patients with significant proteinuria secondary to membranous 
glomerulonephritis on renal biopsy will be considered for the trial. Patients will be 
screened for hepatitis B, C and HIV, and undergo CT chest, abdomen and pelvis to 
exclude viral and malignant causes for their membranous nephropathy (these are the 

 
6 
current standard investigations in all patients with membranous nephropathy.) All 
patients will be initially treated with maximum tolerated doses of ace inhibitors and 
angiotensin two antagonists for at least 3 months as is standard current treatment. 
Patients who remain significantly proteinuric (PCR>100units with hypoalbuminaemia 
or PCR >300 units with normal serum albumin) despite treatment with maximum 
tolerated doses of ACE inhibitors and angiotensin two antagonists will be randomised 
to receive tacrolimus monotherapy or tacrolimus in combination with mycophenylate 
mofetil therapy. The initial dose of tacrolimus will be 2mg twice a day and this would 
be titrated to achieve levels of 5-12 ng/ml. The initial dose of mycophenylate mofetil 
would be 500mg twice a day, and this would be titrated to achieve mycophenolic acid 
levels of 1.5-3.0 mg/L. Patients with a previous history of tuberculosis, or deemed at 
high risk due to Asian origin will receive isoniazid 150mg once a day and pyridoxine 
50mg once a week. 
 
Treatment will be initially for 1 year. Remission of proteinuria will be defined as 
complete if urinary PCR <30 units, and partial if urine PCR decreases by >50% but is 
still above 30 units. Patients not obtaining complete or partial remission after 1 year 
will be withdrawn from the trial and alternative therapies considered.  When patients 
have been in remission for 12 months on treatment the tacrolimus will be withdrawn 
over 6 months. Those on MMF and tacrolimus will then have their MMF stopped  
prior to tacrolimus withdrawal over 6 months. Patients will be offered a renal biopsy 
prior to withdrawal of therapy. This will help predict relapse and show any evidence 
of tacrolimus toxicity which may help guide subsequent therapy in the case of relapse. 
Continuation in the trial is not dependent on undergoing renal biopsy. Patients will be 
followed for at least 3 years. Patients may withdraw from the trial at any point without 
any compromise to their clinical care. 
 
 
 
4.3 Evaluations 
 
The patients will initially be seen weekly until stable and then monthly until remission 
is achieved. They will then be reviewed 2-3 monthly for the rest of the trial depending 
on clinical need. Prior to entry all patients will have blood sent for hepatitis B 

 
7 
hepatitis C and HIV and have a CT scan of chest abdomen and pelvis to exclude 
malignancy. 
At each clinic visit blood samples will be sent for full blood count, biochemical 
profile, drug level monitoring and selective proteinuria. Urine samples will be sent for 
PCR and selective proteinuria.  
 
4.4 Withdrawal and treatment failure 
 
Patients can be withdrawn at patient or physician request. The reason for withdrawal 
will be recorded in the patients records. 
Patients not achieving remission at 1 year will be withdrawn from the trial and 
alternative treatments considered. They will remain under follow up in the clinic as is 
current standard practice. 
 
 
4.5 End points 
 
a) Primary Endpoints 
 
Efficacy of MMF in preventing relapse of nephrotic syndrome on withdrawal of 
tacrolimus therapy. This will be initially measured at 6 months post withdrawal of 
tacrolimus therapy. 
 
b) Secondary end points  
 
The time to obtaining remission from proteinuria 
The degree of remission of proteinuria obtained (complete or partial) 
The rate of decline of renal function measured by the MDRD equation for glomerular 
filtration rate 
 
4.6 Statistic Analysis 
 

 
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This will be carried out under the direction of Mr Bernard North -Statistics 
department Imperial College London. The sample size was based on the main 
outcome measure, time to relapse, and compared using a 1-sided  log rank test 
assuming a 1% drop-out rate and a 50% relapse free survival rate in the tacrolimus 
group and a 95% relapse free survival rate in the tacrolimus and MMF group with an 
alpha level of 0.05 and 80% power. The NCSS PASS package was used. Hintze J 
(2004) Number Crunching Statistical Systems (PASS). The statistical analysis will be 
done by using a 1 sided log rank test. 
 
4.7 Duration 
 
 5 years, with 24 months recruitment and 36 months follow up. Primary end points 
will be analysed when patients obtaining remission for 1 year have stopped tacrolimus 
therapy for 6 months. Secondary end point analysis of response to treatment will 
occur when patients have been on treatment for 12 months. 
 
 
5.  Adverse Events and Data Monitoring 
 
It is anticipated that the treatment will be well tolerated as this regime has been 
extensively used in renal transplant recipients. All adverse events will be actively sort 
and recorded in the patients’ notes. The data and progress of the trial will be reported 
to and monitored by the West London Renal and Transplant Glomerulonephritis 
Research Group at Hammersmith Hospital , on a monthly basis (appendix 2). 
All Serious Adverse Events (SAE) and Suspected Unexpected Serious Adverse Drug 
Reactions (SUSADR) will be reported within 24 hours to the committee chairman Dr 
Liz Lightstone and to the sponsor, Dr Rodney Gale, i.e all events irrespective of their 
relation to study medications, that are either life threatening, result in hospitalization, 
result in death, result in persistent or significant disability or incapacity . The sponsor 
will report any such SAE or SUSAR to the regulatory authority in accordance with 
the European Directive 2001/20/EC. 
 
 
 

 
9 
6. Internal and External Review 
 
The trial has been extensively reviewed, modified and approved by the West London 
Renal and Transplant Glomerulonephritis Research Group at Hammersmith Hospital. 
It has been externally reviewed and approved by Professor Patrick Maxwell, Professor 
of Medicine, The Rayne Institute, University College London WC1E 6JF. 
 
 

 
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Appendix 1          
 MTAC Trial Overview 
Entry  
(eligibility criteria)  
 
↓ 
Randomisation 
( 16 patients per limb) 
↓  
 
 
 
 
 
↓ 
Tacrolimus 2mg bd   
 
 
 
MMF 500mg bd  
adjusted to obtain levels of 5-11 
adjusted to obtain levels of 1.5-3.0 
and Tacrolimus 2mg bd adjusted to 
obtain levels of 5-12ng/L 
 
(treatment for minimum 12months maximum 24 months) 
 
 
 
↓ 
 Patients in remission for 12 months 
        ↓ 
 
 
 
 
 
↓ 
 
 
 
 
 
 
 
Stop MMF 
Withdrawal of tacrolimus over 6 months     Withdrawal of tacrolimus over 6 months  
 
 
↓ 
Monitor patients for relapse of nephrotic syndrome 

 
11 
Appendix 2: Membership of the Glomerulonephritis Research Group West 
London Renal and Transplant Unit Feb 2008 
 
 
Professor Terry Cook  
Consultant Pathologist 
Dr Tom D Cairns 
 
Consultant Nephrologist 
Rania Betmouni 
  
Renal Pharmacist 
Prof Charles Pusey 
 
Consultant Nephrologist  
Dr Marie Conlon 
 
Renal Registrar 
Dr Liz Lightstone 
 
Consultant Nephrologist  
Dr Alan Salama 
 
Consultant Nephrologist 
Dr Megan Griffith 
 
Consultant Nephrologist 
Dr Frederick Tam 
 
Consultant Nephrologist 
Dr Ann Marie Habib  
Renal Registrar 
Sister Jane C Owen 
 
Outpatient Sister  
Dr Jeremy Levy 
 
Consultant Nephrologist  
Dr Gill Gaskin 
 
Consultant Nephrologist 
Dr  Ruth Pepper 
 
Renal Registrar 
 
 
 

 
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Appendix 3: References 
 
1.Cattran DC. Membranous nephropathy: quo vadis? [comment]. Kidney Int 2002; 
61: 349-350. 
2. Cattran DC, Appel GB, Herbert LA, North America Nephrotic Syndrome Study 
Groupet al. Cyclosporin in patients with steroid resistant membranous nephropathy: a 
randomised trial. Kidney International 2001; 59: 1484-1490. 
3. Praga M, Barrio V, Juarez GF, Lumo J; Tacrolimus monotherapy in membranous 
nephropathy: a randomised controlled trial. Kidney International 2007 May 924-30. 
 
4. Kerjaschki D, Neale TJ, Molecular mechanisms of glomerular injury in rat 
experimental membranous nephropathy (Heymann nephritis). J Am Soc Nephrol 
1996; 7: 2518-2526 
 
5. Appel GB, Radhakrishnan J, Ginzler EM. Use of mycophenolate mofetil in 
autoimmune and renal diseases.Transplantation. 2005 Oct 15;80(2 Suppl):S265-71. 
Review. 
 
6. Chan TM, Lin AW, Tang SC, Qian JQ, Lam MF, Ho YW, Tse KC, Chan KW, Lai 
KN, Tang CS. Prospective controlled study on mycophenolate mofetil and 
prednisolone in the treatment of membranous nephropathy with nephrotic syndrome. 
Nephrology (Carlton). 2007 Dec;12(6):576-81.  
 
7. Senthil LN, Ganguli A, Rathi M, Kohli HS, Gupta KL, Joshi K, Sakhuja V, Jha V. 
Mycophenolate mofetil or standard therapy for membranous nephropathy and focal 
segmental glomerulosclerosis: a pilot study. 
Nephrol Dial Transplant. 2007 Nov 7; (Epub ahead of print) 
 
8. Branten AJ, du Buf-Vereijken PW, Vervloet M, Wetzels JF. Mycophenylate 
mofetil in idiopathic membranous nephropathy; a clinical trial with comparison to a 
historic control group treated with cyclophosphamide.Am J Kidney Dis 2007 Aug 
50,(2) 248-56. 
 

 
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9.Borrows R, Chan K, Loucaidou M, Lawrence C, Van Tromp J, Cairns T, Griffith 
M, Hakim N, McLean A, Palmer A, Papalois V, Taube D. 
Five years of steroid sparing in renal transplantation with tacrolimus and 
mycophenolate mofetil. Transplantation. 2006 Jan 15;81(1):125-8