Clinical Trial Results:
mycophenylate mofetil and tacrolimus vs tacrolimus alone for the treatment of nephrotic syndrome secondary to idiopathic membranous glomerulonephritis
Summary
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EudraCT number |
2008-001009-41 |
Trial protocol |
GB |
Global end of trial date |
19 Sep 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Oct 2019
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First version publication date |
04 Oct 2019
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
grim1001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00843856 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
ImperialCollegeNHSTrust
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Sponsor organisation address |
Du Cane Road, London, United Kingdom,
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Public contact |
Megan Griffith, Imperial College NHS Trust, +44 0208383527, megan.griffith1@nhs.net
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Scientific contact |
Megan Griffith, ImperialCollegeNHSTrust, +44 0208383527, megan.griffith1@nhs.net
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
14 Jan 2019
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
19 Sep 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To investigate if the addition of mycophenylate mofetil to standard therapy with tacrolimus prevents relapse of nephrotic syndrome in patients with idiopathic membranous glomerulonephritis
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Protection of trial subjects |
All patients were regularly seen and monitored in the renal clinic at Hammersmith Hospital London.
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Background therapy |
All patients were given supportive therapy which included ace inhibitors angiotensin receptor blockers diuretics, statins and anticoagulation as clinically indicated. | ||
Evidence for comparator |
Calcineurin inhibitors (CNIs) such as cyclosporin and tacrolimus (TAC) are commonly used for the treatment of Membranous Glomerulonephritis (MGN) and are effective in inducing remission. Their antiproteinuric effect has been clearly documented; however relapses after discontinuation are common and there is a concern about nephrotoxicity after prolonged use. Although their main mode of action is immunomodulatory they also have a significant antiproteinuric effect which is attributed to their haemodynamic effect on glomerular perfusion as well as to their direct effect on podocytes. A study comparing tacrolimus to placebo showed that TAC alone is effective in achieving remission but patients often relapse after treatment withdrawal . A recent trial comparing rituximab to cyclosporine also showed a high relapse rate of the cyclosporine arm after treatment withdrawal. Mycophenolate mofetil (MMF) has been used for the treatment of MGN in regimens of variable dosing and duration, either alone or in combination with steroids. MMF monotherapy is not effective in inducing remission; however it has been successfully used in combination with steroids. MMF has a long history of use in combination with CNIs in transplantation with a good safety profile and this combination has also been used in nephrotic syndrome secondary to other glomerulonephritides such as lupus nephritis. The presence of anti-PLA2R auto-antibodies in a significant number of patients with MGN suggests that an immunosuppressive agent such as MMF, that suppresses B lymphocyte proliferation and antibody formation, may be particularly effective in inducing and maintaining immunological and clinical remission in MGN. We therefore compared the efficacy of combination treatment with tacrolimus and mycophenolate mofetil versus tacrolimus alone for achieving sustained remission in patients with Idiopathic Membranous Glomerulonephritis. | ||
Actual start date of recruitment |
03 Mar 2009
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 40
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Worldwide total number of subjects |
40
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EEA total number of subjects |
40
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
34
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From 65 to 84 years |
6
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients were recruited from the glomerulonephritis clinic at Hammersmith Hospital, London from march 2009 to December 2014. | |||||||||||||||
Pre-assignment
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Screening details |
Patients with Membranous Glomerulonephritis, diagnosed on renal biopsy, with nephrotic syndrome after 3 months of ace inhibitors or angiotensin receptor blockers. | |||||||||||||||
Period 1
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Period 1 title |
tacrolimus vs mycophenylate mofetil (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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tacrolimus | |||||||||||||||
Arm description |
2mg twice daily tacrolimus titrated to archive whole blood levels of 5-12ng/ml | |||||||||||||||
Arm type |
Active comparator | |||||||||||||||
Investigational medicinal product name |
tacrolimus
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
2mg twice daily
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Arm title
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tacrolimus and mycophenylate mofetil | |||||||||||||||
Arm description |
tacrolimus and mycophenylate mofetil | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
tacrolimus
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Investigational medicinal product code |
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Other name |
prograff
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
2mg twice a day titrated to achieve blood levels of 5-12ng/L
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Investigational medicinal product name |
mycophenylate mofetil
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Investigational medicinal product code |
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Other name |
cellcept
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
500mg twice a day titrated to achieve blood mycophenylate acid levels of 1.5-3 mg/L
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Baseline characteristics reporting groups
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Reporting group title |
tacrolimus
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Reporting group description |
2mg twice daily tacrolimus titrated to archive whole blood levels of 5-12ng/ml | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
tacrolimus and mycophenylate mofetil
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Reporting group description |
tacrolimus and mycophenylate mofetil | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
tacrolimus
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Reporting group description |
2mg twice daily tacrolimus titrated to archive whole blood levels of 5-12ng/ml | ||
Reporting group title |
tacrolimus and mycophenylate mofetil
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Reporting group description |
tacrolimus and mycophenylate mofetil |
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End point title |
number of patients who gained remission from the nephrotic syndrome who subsequently relapsed | |||||||||
End point description |
In the TAC group 16/20 achieved remission compared to 19/20 (95%) in the TAC/MMF group (p=0.34). There was no difference between the groups in the number of patients who subsequently relapsed. In the TAC group 8/16 patient(50%) relapsed and in the TAC/MMF group 8/19 patients (42%) relapsed (p=0.7).
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End point type |
Primary
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End point timeframe |
Initially measured at 6 months after stopping treatment and monitored until the end of the trial.
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Notes [1] - number of patients who achieved remission [2] - number of patients who achieved remission |
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Statistical analysis title |
Relapsed | |||||||||
Comparison groups |
tacrolimus v tacrolimus and mycophenylate mofetil
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Number of subjects included in analysis |
35
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Analysis specification |
Post-hoc
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Analysis type |
superiority | |||||||||
P-value |
= 0.7 | |||||||||
Method |
Fisher exact | |||||||||
Confidence interval |
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End point title |
Number of patient archieved remission | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
1 year
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No statistical analyses for this end point |
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Adverse events information [1]
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Timeframe for reporting adverse events |
Reported throughout the trial, 10 years
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Adverse event reporting additional description |
Review of patients in OP and reporting of all admissions
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
10
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Reporting groups
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Reporting group title |
tacrolimus
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Reporting group description |
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Reporting group title |
tacrolimus and mycophenolate mofetil
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Reporting group description |
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Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: None serious adverse event occurred. |
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/31492152 |