Tacrolimus vs Prednisolone for the Treatment Minimal Change Disease
Phase: PHASE4
Conditions: Minimal Change Disease
Sponsor: Imperial College Healthcare NHS Trust

 
1
 
MINTAC 
 
 
 
 
Tacrolimus vs prednisolone for the treatment of nephrotic syndrome secondary 
to minimal change disease: A Randomised Control Trial 
 
 
Version 5 
02/02/2013 
 
 
West London Renal and Transplant Unit  
 
EudraCT Number 2009-014292-52 
REC reference number  
 
Abbrieviated trial name      MinTAC 
 
 
Principal Investigators 
Drs Megan Griffith  and Dr Tom Cairns 
Renal Unit 
4th floor Ham House  
Hammersmith Hospital  
Du Cane Road 
LondonW12 OHS 
m.e.griffith@imperial.ac.uk 
 
Sponsorship  provided by Imperial College Healthcare NHS Trust ref no GRIM1002 
 
 

 
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Contents 
 
 
 
 
 
 
 
 
 
Page number 
Title Page 
 
 
 
 
 
 
 
 
1 
 
Contents 
 
 
 
 
 
 
 
 
2 
Study Summary 
 
 
 
 
 
 
 
4 
Trial Overview 
 
 
 
 
 
 
 
5 
1.Introduction  
 
 
 
 
 
 
 
6
 
1.1Background 
 
 
 
 
 
 
6 
 
1.2 Rationale for current study 
 
 
 
 
6 
2.Aims of MinTAC    
 
 
 
 
 
 
7 
 
2.1 Hypothesis 
 
 
 
 
 
 
7 
3. Study Design 
 
 
 
 
 
 
 
8 
 
3.1 Study outcome measures  
 
 
 
 
8 
4. Participant Entry 
 
 
 
 
 
 
 
9 
 
4.1 Inclusion criteria  
 
 
 
 
 
9 
 
4.2 Exclusion criteria  
 
 
 
 
 
9 
 
4.3 Withdrawal criteria 
 
 
 
 
 
9 
5. Treatments  
 
 
 
 
 
 
 
10 
6.Interaction with other drugs  
 
 
 
 
 
10 
7.Assessment and follow up  
 
 
 
 
 
11 
8.Loss to follow up 
 
 
 
 
 
 
 
11 
9.Trial closure  
 
 
 
 
 
 
 
12 
10.Statistics and data analysis 
 
 
 
 
 
13 
11.Data monitoring and adverse events 
 
 
 
 
14 
12.Regulatory issues  
 
 
 
 
 
 
14 
 
12.1 Clinical trials 
 
 
 
 
 
 
14 
 
12.2 Ethics approval  
 
 
 
 
 
14 
 
12.3 Consent  
 
 
 
 
 
 
14 
 
12.4 Confidentiality  
 
 
 
 
 
14 
 
12.5 Indemnity 
 
 
 
 
 
 
15 
 
12.6 Sponsor  
 
 
 
 
 
 
15 
13.Duration 
 
 
 
 
 
 
 
 
15 
 
 
 

 
3
Appendix 1         Bibliography 
 
 
 
 
 
16 
Appendix 2 
    West London Renal and Transplant Unit Feb 2008  
18 
 
 
 
 
 
 

 
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STUDY SUMMARY 
 
TITLE 
Tacrolimus (prograf) vs prednisolone for the treatment of 
nephrotic syndrome secondary to minimal change disease: A 
Randomised Control Trial 
 
DESIGN 
Prospective randomised control trial 
 
AIMS 
To compare the effectiveness  of tacrolimus (prograf) vs prednisolone 
for the treatment of nephrotic syndrome secondary to minimal change 
disease 
 
OUTCOME MEASURES  
Primary outcome- proportion of patients achieving complete remission 
at 8 weeks 
Secondary outcome- proportion of patients achieving complete  
remission at 16 and 24  weeks, prevention of relapse, nature and 
severity of side effects, change in glomerular filtration rate 
 
POPULATION  
 
 
52 patients (26 in each arm of the study) 
 
ELIGIBILITY  
 
 
All patients presenting to participating centres with nephrotic  
syndrome secondary to minimal change disease 
 
TREATMENT 
 
 
Tacrolimus (prograf) vs prednisolone 
 
DURATION  5 years 
 

 
5
 
 
TRIAL OVERVIEW 
MINTAC 
 
 
 
Nephrotic syndrome secondary to idiopathic minimal change disease 
 
 
↓ 
 
                                                               Randomise 
 
 
 
 
 
 
 
↓  
 
 
 
 
 
 
 
Tacrolimus (prograf) 0.05mg/kg bd  
 Prednisolone 1mg/kg max 60mg od 
(levels 6-12ng/ml) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
↓ 
  
 
 
 
 
 
 
 
 
 
 
                                        
 Achieval of complete remission 
 
 
 
 
 
 
 
 
 
 
 
↓ 
 
 
 
 
 
↓ 
 
 
 
 
 
 
Tacrolimus (prograf) maintenance for 3/12  
Tapered steroid withdraw 
tapered withdrawal over 1-2/12 
                 to give total course of at least 4/12   
 
 
 
 
 
 
 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
 
Monitoring for relapse over 2 years

 
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1. 
INTRODUCTION  
 
1.1 
BACKGROUND 
 
Minimal change disease is a common cause of nephrotic syndrome in adults. Standard 
treatment is with high dose steroids which is often effective in controlling the nephrotic 
syndrome but has a high morbidity due to the side effects of the steroids. There is also a 
high relapse rate of up to 67% (1), therefore many patients require long term steroid 
therapy to control their disease which has significant morbidity and mortality. Some 
patients are or also become steroid resistant. There are studies showing the effectiveness of 
alkylating agents such as cyclophosphamide but the use of these drugs is limited by their 
toxicity, including increased rates of infection, cancers and infertility (2). Treatment with 
the calcineurin inhibitor cyclosporine has been shown to be effective, there have been 
concerns about the nephrotoxicity (3) of this agent although with careful monitoring this 
can be minimised (4). 
 
1.2  RATIONALE FOR CURRENT STUDY 
 
Tacrolimus (prograf) is a T-cell specific calcineurin inhibitor that shares similar 
immunosuppressive actions with cyclosporine A.  It complexes with immunophilin FK506 
binding protein and inhibits the phosphatase activity of calcineurin, resulting in decreased 
interleukin 2 transcription and inhibition of T-cell activation. Tacrolimus (prograf)  is also 
capable of inhibiting the production of tumour necrosis factor – alpha and interferon-
gamma by activated T-cells.  In other glomerular diseases such as focal segmental 
glomerulosclerosis and membranous glomerulonephritis, prograf has been shown to be a 
very effective treatment for proteinuria.  This may be due to the immunomodulatory 
effects on the underlying disease, but there may also be a direct effect of tacrolimus 
(prograf) on the podocyte, stabilising the actin cytoskeleton and therefore decreasing 
protein leak (5). Therefore tacrolimus (prograf) is likely to be effective in reducing 
proteinuria in minimal change disease. 
 

 
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Tacrolimus (prograf) has recently been shown to be an effective treatment for steroid 
resistant nephrotic syndrome in children with no significant effect on glomerular filtration 
rate (6). Studies in our own unit in patients with focal segmental glomerulosclerosis and 
membranous glomerulonephritis have also shown tacrolimus (prograf) to be a safe agent 
with no detrimental effect on glomerular filtration rate (7,8). It has also been shown to 
have a good side effect profile when used to allow the avoidance of steroids in 
transplantation (9). We have used tacrolimus (prograf) in our unit to treat relapsing 
minimal change disease in individual patients suffering from steroid toxicity with good 
effect, and have also used it as primary therapy in patients with steroid resistant nephrotic 
syndrome and for patients, in whom steroids were relatively contraindicated, again with 
good results in individual patients.  To date there are no randomised trials comparing 
steroids with tacrolimus (prograf) in this group (10). This study aims to prospectively 
study if tacrolimus (prograf) is effective as treatment for minimal change disease 
compared with standard therapy with steroids, and whether it has advantages in terms of 
side effect profile and prevention of relapse. 
 
2. AIMS OF MinTAC   
To compare the effectiveness of tacrolimus (prograf)  vs prednisolone for the treatment of 
nephrotic syndrome secondary to minimal change disease. The effectiveness of each 
treatment will be compared by the initial response rate (the proportion of patients 
achieving complete remission), the time taken to achieve complete remission, and the 
relapse rate post withdrawal of therapy, and the frequency, nature and severity of the side 
effects. 
 
2.1 HYPOTHESIS 
 
Tacrolimus (prograf)  is not inferior to prednisolone in the treatment of nephrotic 
syndrome secondary to minimal change disease, has a preferable side effect profile and 
may decrease relapse rate. 
  
 

 
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3.  STUDY DESIGN 
 
This is a prospective open label randomised  trial comparing tacrolimus (prograf) with 
prednisolone in the treatment of nephrotic syndrome secondary to minimal change disease  
There will be 52 patients randomised at a 1:1 ratio to each group (26 patients in each 
group). 
The sample size has been calculated to assess non inferiority of tacrolimus (prograf) to 
prednisolone. The expected complete remission rate for patients treated with steroids at 8 
weeks has been estimated at 60% (11), and tacrolimus (prograf) at 84% (6). The delta 
value has been set at -0.1. Clinically this has been chosen as a 10% worse remission rate in 
tacrolimus (prograf) compared to steroids, is likely to be clinically acceptable in view of 
the potential benefits of a non steroid based regime. 
 
 
3.1 
STUDY OUTCOME MEASURES 
 
1. Primary Outcomes 
 
Proportion of patients achieving complete remission from nephrotic syndrome 
(normalisation of serum albumin and urine PCR <50 units) at 8 weeks. 
 
2.Secondary Outcomes 
 
Proportion of patients achieving complete remission from nephrotic syndrome 
(normalisation of serum albumin and urine PCR <50 units) at 16 and 24 weeks. 
Proportion of patients achieving remission who then relapse. 
Nature, severity and frequency of adverse events. 
Change in baseline glomerular filtration rate 
 
 

 
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4. 
PARTICIPANT ENTRY  
 
 
4.1 
INCLUSION CRITERIA 
 
1. Patients presenting to the WLRTC with nephrotic syndrome (hypoalbuminaemia and 
protein creatinine ratio (PCR) >100units), secondary to minimal change disease. 
2. Age over 18. 
                                                                                                                                                                          
 
4.2 
EXCLUSION CRITERIA 
 
1.   Hepatitis B, hepatitis C or HIV infection 
                                2.  Untreated infection 
3. Females who are pregnant, breast feeding, or at risk of pregnancy and not using a            
medically acceptable form of contraception. 
4. Patients who have had immunosuppression for nephrotic syndrome in the last 18 
months or immunosuppression that may effect the outcome of their current episode of 
nephrotic syndrome. 
5. Patients who have had more than 3 relapses of nephrotic syndrome within 5 years 
6.  Any condition judged by the investigator that would cause the study to be 
detrimental to the patient 
 
4.3 WITHDRAWAL CRITERIA 
 
If  patients show no response by 6 months, then treatment will be withdrawn and 
alternative regimes implemented as clinically indicated. 
Patients are free to withdraw from the trial at any point. This will not affect their 
clinical care in anyway. 
 
 
 

 
10 
 
 
5. 
TREATMENTS 
 
 
Arm 1:  Tacrolimus (prograf) 0.05mg/kg bd aiming for trough tacrolimus levels of 6-
8ng/l, however if at 8 weeks the patient is not responding, the target tacrolimus levels 
will rise to 9-12ng/l. This will be continued for 12 weeks from the time of complete 
remission, then tapered and stopped over 4-8 weeks. 
 
Arm 2:  Prednisolone 1mg/kg/day (maximum 60mgs/day). 
 Omeprazole 20mgs/day (for gastric protection), calcichew D3 (for bone protection) 2 
tablets /day. 
One week post  complete remission from proteinuria urine PCR <50 units, the  steroid 
dose will be halved for 4-6 weeks, then tailed off over a further 4-6 weeks to ensure a 
minimum of 16 weeks therapy. 
 
In addition all patients will receive  
 
Angiotensin Receptor Blocker (+ / - ACEI) titrated to keep BP <125/75 
Statin to maintain cholesterol < 4 
Prophylactic low molecular weight Heparin if Albumin < 20mg/L 
Aspirin 75mg OD if Albumin > 20<30mg/L 
 
If South Asian, previous known TB or considered high risk for TB: 
Isoniazid 150mg OD 
Pyridoxine 50mg weekly 
 
 
If there has been no response after 6 months, then alternative treatment will be 
considered on clinical grounds. 
 
6.INTERACTION WITH OTHER DRUGS 
 

 
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The patients will be advised not to take any new drugs without discussing them with 
us first in case they interact with the study medication. 
 
 
7. ASSESSMENT AND FOLLOW-UP  
 
At baseline:  
 
Full blood count, glucose, biochemical profile, immunoglobulins and electrophoresis 
Viral screen: Hep B & C, HIV 
Urine PCR  
Weight  
BP 
 
Weekly for 4 weeks 
Blood count, glucose, biochemical profile 
Tacrolimus levels (patients in arm 1)  
Urine PCR 
Weight  
BP 
 
Monthly for 6 months 
 
Blood count, glucose, biochemical profile 
Tacrolimus levels (patients in arm 1)  
Urine PCR 
Weight  
BP 
  
 
A repeat renal biopsy will be offered at 6 months to all patients who have not 
achieved complete remission if clinically indicated. 
 

 
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Once complete remission has been obtained and treatment withdrawn patients will be 
monitored in clinic every 1-3 months as clinically indicated for the next 2 years. 
Standard blood/urine tests will be carried out as per standard clinical care. 
 
 
8. LOSS TO FOLLOW-UP 
 
Attempts will be made to contact the patient and if they have moved their treatment to 
another centre at that point they shall be excluded from the trial as data collection may 
not be reliable. 
 
9.TRIAL CLOSURE 
 
Recruitment to the trial will be terminated once there are 26 patients in each arm. 
 
 
10.STATISTICS AND DATA ANALYSIS    
 
 
Primary Outcome:  
 
Proportion of patients achieving complete remission from nephrotic syndrome 
(normalisation of serum albumin and urine PCR <50 units) at 8 weeks. 
 
Primary Analysis: 
 
Non inferiority of tacrolimus (prograf) to prednisolone will be assessed by testing 
whether the difference in proportion of subjects achieving complete remission in the 
tacrolimus and prednisolone groups is greater than the non inferiority margin. 
Alternatively, and equivalent in testing procedure, the lower limit of the 95% 
confidence interval for the difference in proportion may be compared to the non 
inferiority margin (12). 
 
Secondary Outcomes: 

 
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Proportion of patients achieving complete remission from nephrotic syndrome 
(normalisation of serum albumin and urine PCR <50 units) at 16 and 24 weeks. 
Proportion of patients achieving remission who then relapse. 
Nature, severity and frequency of adverse events. 
Change in baseline glomerular filtration rate 
 
Secondary analysis 
 
Non inferiority of tacrolimus (prograf) to prednisolone will be assessed at 16 and 24 
weeks using a test of proportion (Chi-square or Fishers exact). 
The proportion of patients relapsing with nephrotic syndrome over 2 years will be 
assessed using a test of proportions (chi-squared or Fishers exact). 
The severity and frequency of adverse events will be compared between groups using 
contingency table approaches such as the Cochran-Armitage trend test for ordinal 
severity data and Fisher exact test for counts. The analysis may be stratified by type or 
nature adverse events. 
The change in glomerular filtration rate will be assessed using an unpaired t-test if 
data found to be normal or a Mann-Whitney test otherwise. 
 
11 DATA MONITORING AND ADVERSE EVENTS 
 
Data will be anonymised post randomisation. Data will be recorded on the case report 
forms and entered into a database which will be password protected. 
It is anticipated that the treatment will be well tolerated as tacrolimus (prograf) 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, Dr Megan Griffith, Chief investigator, and to the sponsor, Dr Robina 
Coker, i.e. all events irrespective of their relation to study medications, that are either 

 
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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. 
 
 
 
 
12.REGULATORY ISSUES 
 
12.1 CLINICAL TRIALS 
 
Clinical Trials Approval will be obtained from the MHRA prior to commencement of 
the trial. 
 
12.2 ETHICS APPROVAL 
 
Ethics approval will be obtained from the local ethics committee prior to 
commencement of the trial. 
 
12.3 CONSENT  
 
Consent to enter the study will be sought from each participant only after a full 
explanation has been given, an information leaflet offered and time allowed for 
consideration. The time allowed for consideration will be determined by the clinical 
urgency of the need to commence treatment and will vary from a few hours to few 
days. The right of the participant to refuse to participate without giving reasons will 
be respected.  After the participant has entered the trial the clinician remains free to 
give alternative treatment to that specified in the protocol at any stage if he/she feels it 
is in the participant’s best interest, but the reasons for doing so will be recorded.  In 
these cases the participants remain within the study for the purposes of follow-up and 
data analysis.  All participants are free to withdraw at any time from the protocol 
treatment without giving reasons and without prejudicing further treatment. 
 

 
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12.4 CONFIDENTIALITY 
 
Participants’ identification data will be required for the registration process. 
Subsequent data will be anonymised. 
 
12.5 
INDEMNITY 
Imperial College NHS Trust holds Public Liability ("negligent harm") and Clinical 
Trial ("non-negligent harm") insurance policies which apply to this trial. 
 
12.6 
SPONSOR 
Dr Robina Coker of Imperial College NHS Trust will act as the main sponsor for this 
study.  
 
 
13.  DURATION 
5 years, with 24 months recruitment and 36 months follow up.  
 
 
 APPENDICES 
 
 
 
 
Bibliography 
 
 
Membership of West London Renal and Transplant Centre 
Glomerulonephritis Research Group 

 
16 
 
BIBLIOGRAPHY 
 
1.Takei T, Koike M, Suzuki K, Shirota S, Itabashi M, Ohtsubo S, Sugiura H, Suzuki 
K, Kajima C, Takahashi M, ino J, Ogawa T, Uchida K, Tsuchiya K, Yumara W, Nitta 
K. The characteristics of relapse in adult onset minimal change nephrotic syndrome. 
Clin Exp Nephrol. 2007 Sep 11(3): 214-7. 
 
2. Mason P. Minimal Change Disease and Primary Focal Segmental 
Glomerulosclerosis in Comprehensive Clinical Nephrology Ed R Johnson and J 
Feehally, Harcott Publishers Ltd. 2000. 
 
3. Cattran DC, Alexopoulos E, Heering P, Hoyer PF, Johnston A, Meyrier A, 
Ponticelli C, Saito T, Choukroun G, Nachman P, Paga M, Yoshikawa N. Cyclosporin 
in idiopathic glomerular disease assosciated with the nephrotic syndrome: workshop 
recommendations. Kidney Int. 2007 Dec; 72 (12):1429-47. 
 
4. Kranz B, Vester U, Buscher R, Wingen AM, Hayer PF. Cyclosporin A induced 
nephrotoxicity in children with minimal change nephrotic syndrome : long-term 
treatment up to 10 years. Pediatr Nephrol. 2008 Apr; 23(4): 581-6. 
 
5. Faul C. et al The actin cytoskeleton of kidney podocytes is a direct target of the 
antiproteinuric effect of cyclosporine A.  2008  Nature Medicine. 14:9. 931-938 
 
6. Gulati S, Prasad N, Sharma KS, Kumar A, Gupta A, and Baburaj VP. Tacrolimus: 
the new therapy for steroid-resistant nephrotic syndrome in children. Nephrology, 
Dialysis, Transplantation 2008 23 (3): 910-913. 
 
7. Duncan N, Dhaygude A, Owen J, Cairns TD, Griffith M, Mclean AG, Palmer A, 
Taube D. Treatment of focal and segmental glomerulosclerosis in adults with 
tacrolimus monotherapy. Nephrol, Dial Transplant 2004 Dec (12) 3062-7. 
 

 
17 
8. Lever N. et al.  Maintenance Tacrolimus Monotherapy for Idiopathic Membranous 
Nephropathy: Medium Term Experience. (2007). American Society of Nephrology 
Meeting San Francisco.  Featured Abstract. 
 
9. Borrows R et al Steroid Sparing with Tacrolimus and Mycophenolate Mofetil in Renal 
Transplantation (2004) Am J Transplantation 4: 1945-1951 
 
10. Palmer SC, Nand K, Strippoli GFM. Interventions for minimal change disease in 
adults with nephrotic syndrome (Review). The Cochrane Collaberation pub The Cochrane 
Library 2009 Issue 2. 
 
11. Nolasco F, Cameron JS, Heywood EF et al. Adult onset minimal change nephrotic 
syndrome: a long term follow up. Kidney Int 1986 29: 1215-23. 
 
12.Chow SC, Shao J, Wang H. Sample size calculations in clinical research. Second 
edition (2008). 

 
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Appendix 2: Membership of the Glomerulonephritis Research Group West 
London Renal and Transplant Unit July 2009 
 
Dr Liz Lightstone 
 
Consultant Nephrologist  (Chairman) 
Professor Terry Cook  
Consultant Pathologist 
Dr Candice Roufosse  
Consultant Pathologist 
Dr Tom D Cairns 
 
Consultant Nephrologist 
Rania Betmouni 
  
Renal Pharmacist 
Prof Charles Pusey 
 
Consultant Nephrologist  
Dr Marie Conlon 
 
Renal Registrar 
Dr Alan Salama 
 
Consultant Nephrologist 
Dr Megan Griffith 
 
Consultant Nephrologist 
Dr Neill Duncan 
 
Consultant Nephrologist 
Dr Marina Loucaidou  
Consultant Nephrologist 
Dr Ruth Tarzi  
 
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  Nick Mansfield 
 
Renal Registrar 
Dr  Anisha Tanner 
 
Renal Registrar 
 
Data Monitoring committe for tacrolimus vs prednisolone for minimal change disease  
EudraCT number 2009-014292-52