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Trial registered on ANZCTR


Registration number
ACTRN12611000798965
Ethics application status
Approved
Date submitted
28/07/2011
Date registered
29/07/2011
Date last updated
16/04/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
Pharmacokinetics of Enteric Coated Mycophenolate Sodium in Lupus Nephritis
Scientific title
Pharmacokinetics and measurement of drug levels of Enteric Coated Mycophenolic sodium in Lupus Nephritis Patients
Secondary ID [1] 262713 0
QRBW/426
Universal Trial Number (UTN)
Trial acronym
POEMSLUN Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lupus Nephritis patients 270419 0
Condition category
Condition code
Renal and Urogenital 270558 270558 0 0
Kidney disease
Inflammatory and Immune System 270596 270596 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Determine the effect of Mycophenolate Sodium (MPS)on clinical improvement in patients with Lupus Nephritis by measuring drug levels.
Drug levels measured: Mycophenolic acid(MPA) , derivative of MPS.
Partipants in this arm will receive MPS according to drug levels .
Oral MPS dose will be modified according to Area Under Curve(AUC 0-12). MPS dosage will be adjusted to AUC 40mg/L.h to 60mg/L h. The dosage will be reduced if the AUC is above 60 mg/L h. The dosage will be reduced once there is complete remission to maintain an AUC to 30 to 50 mg/L h.
MPS will be adminstered orally twice daliy to achieve this levels.
MPS will be continued for a total period of 12 months.
Sixteen partipants will be receiving MPS dosage based on drug levels to acheive remission of Lupus Nephritis .

Drug Level measurement: Blood samples will be collected at 15 time points for 8 hourly sampling, and where patients consent, 17 samples for 12 hours sampling (including time points from previously described Limited sample strategy (LSS)data for mycophenolate sodium at 0, 1.5, 4 and 8 hours post-dose - as suggested by He et al in their unpublished data, that an AUC from 0-8 hours can be calculated with four blood samples and correlates favourably with an AUC0-12

Samples for the 8 hour sample collected will be collected at 0 (pre-dose fasted), 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 and 8 hours.
Samples for the 12 hour sample collected will be collected at 0 (pre-dose fasted), 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 and 8, 10 and 12 hours.

Samples will be kept on ice until centrifugation (3000rpm for 10-minutes) and will then be analysed by High Performance Liquid Chromatography at Pathology Queensland (Royal Brisbane and Women’s Hospital, Herston, Australia).
Intervention code [1] 267054 0
Treatment: Drugs
Comparator / control treatment
Sixteen participants will be enrolled in this arm. MPA drug levels will be measured but the participants will receive a fixed dose of the MPS

Dose: Oral MPS 30mg/kg body weight /day.MPS will be adminstered orally twice daliy in equal doses.
MPS dosage will be reduced by 180 mg bd on achieving complete remission or if there are side effects such as diarrhea, leucopenia ( total white cell count <3500/mm3 or opportunistic infections.

MPS will be continued only on a fixed dosage to acheive remission for a total period of 12 months.

These patients also will have MPA drug levels measured but the treating doctor will be blinded to the levels.

Drug Level measurement: Blood samples will be collected at 15 time points for 8 hourly sampling, and where patients consent, 17 samples for 12 hours sampling (including time points from previously described- Limited sample strategy data for mycophenolate sodium at 0, 1.5, 4 and 8 hours post-dose - as suggested by He et al in their unpublished data, that an AUC from 0-8 hours can be calculated with four blood samples and correlates favourably with an AUC 0-12

Samples for the 8 hour sample collected will be collected at 0 (pre-dose fasted), 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 and 8 hours.

Samples for the 12 hour sample collected will be collected at 0 (pre-dose fasted), 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 and 8, 10 and 12 hours.

Samples will be kept on ice until centrifugation (3000rpm for 10-minutes) and will then be analysed by High Performance Liquid Chromatography at Pathology Queensland (Royal Brisbane and Women’s Hospital, Herston, Australia).
Control group
Active

Outcomes
Primary outcome [1] 269300 0
To determine whether Therapeutic drug monitoring(TDM) guided dosing of EC-MPS results in achieving established targets of MPA exposure compared to the standard empirical dosing in participants with biopsy proven LN.
Timepoint [1] 269300 0
12 months
Secondary outcome [1] 279333 0
To determine the effect of MPS in improvement in SLE Disease Activity Index (SLEDAI), C3, C4 and anti-dsDNA levels;
Timepoint [1] 279333 0
12 months
Secondary outcome [2] 279334 0
To study the relationship between disease activity of Lupus nephritis and MPA blood concentration
Timepoint [2] 279334 0
12 months
Secondary outcome [3] 279335 0
To develop a pharmacokinetic model that can be used to develop MPS dosing recommendations in LN patients treated with MPS
Timepoint [3] 279335 0
12 months
Secondary outcome [4] 302330 0
Secondary endpoint is to determine the effect of MPS on clinical improvement in patients with LN as measured by complete or prtial remission Complete remission is defined as a decrease in urinary protein measured over 24 h, to <0.3 g/24 h with normal urinary sediment, normal serum albumin and stabilsation ( equal to or <25%) or improvement in serum creatinine levels at week 24. Partial remission is defined as stable or improved renal function with reduction of proteinuria by >50%, proteinuria within the range of 0.3 to 3g/24h and serum albumin >30g/l
Timepoint [4] 302330 0
12 months

Eligibility
Key inclusion criteria
Patients with clinically defined signs and symptoms of Lupus nephritis and on Mycphenolate Sodium for 2 weeks
Minimum age
18 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1.Patients with a history of psychological illness or condition which interferes with their ability to understand or comply with the requirements of the study.
2.Patients unable to give consent.
3.Pregnant or nursing (lactating) women,

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central Randomsation
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation of partcipants will be based on computer generated numbers
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Patients will be randomised in permuted blocks with stratification for induction and maintenance therapy with MPS.
Phase
Phase 3
Type of endpoint(s)
Pharmacokinetics
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 267529 0
Hospital
Name [1] 267529 0
Royal Brisbane Hospital research Foundation
Address [1] 267529 0
Herston Road,
Herston,Qld, 4029
Country [1] 267529 0
Australia
Funding source category [2] 267530 0
Commercial sector/Industry
Name [2] 267530 0
Novartis Pharmaceuticals Australia
Address [2] 267530 0
54 Waterloo Road
North Ryde, NSW 2113
Australia
Country [2] 267530 0
Australia
Primary sponsor type
Hospital
Name
Royal Brisbane
Address
Herston Road,Herston, Qld, 4029
Country
Australia
Secondary sponsor category [1] 266585 0
Commercial sector/Industry
Name [1] 266585 0
Novartis Pharmaceuticals Australia
Address [1] 266585 0
54 Waterloo Road
North Ryde, NSW 2113
Australia
Country [1] 266585 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 269508 0
Human Research and Ethics Committee
Ethics committee address [1] 269508 0
Royal Brisbane & Women's Hospital
Building 7,Herston, Qld, 4029
Ethics committee country [1] 269508 0
Australia
Date submitted for ethics approval [1] 269508 0
Approval date [1] 269508 0
19/01/2011
Ethics approval number [1] 269508 0
HREC/10/QRBW/426

Summary
Brief summary
The drug Mycophenolate mofetil (MMF) was introduced into routine clinical practice in 1995 to prevent the rejection of kidney transplants in the USA and in Europe in 1996. A second formulation of its active metabolite, mycophenolic acid (MPA), became available as an enteric-coated tablet called mycophenolate sodium (EC-MPS). and clinical trials showed that EC-MPS was as effective and safe as MMF. Equipotent doses of EC-MPS and MMF result in equivalent amounts of active metabolite ie MPA in the blood. On this basis MMF was trialled in patients with autoimmune and several immunologically mediated renal diseases. A recent meta-analysis of randomized controlled trials showed that MMF was not only better at gaining control of severe lupus nephritis (LN), an immunologically mediated kidney disease,, but also caused fewer side effects than the historically best treatment of pulsed cyclophosphamide.
Up to 2 g of MMF each day were initially used to treat LN. Subsequent dosing regimens started with 2g MMF/day but subsequently titrated up to a maximum of 3 g/day . In one study a median dosage of 42mg/kg body weight MMF was used for 20-24 weeks and most patients (91.3%) tolerated MMF doses of up to 2.5-3.0 g/day. MMF 1000mg equates to about 720mg of MPS .
However the amount of MPA in the blood varies from patient to patient. The factors causing these differences have been studied in transplant patients but not in LN patients. Nor has the relationship between MPA concentration and its effect on the kidney disease been described in LN patients. We propose using therpeutic drug monitoring of MPS to
1) describe any inter–patient variability in MPA blood concentrations among LN patients treated with MPS
2) correlate dose used with its efficacy and safety and
3) explore the relationship between treatment failures and underdosing of MPS in patients with LN.
The results of these studies will tell us whether we ought to change our clinical practice, specifically whether therapeutic drug monitoring, not currently done, and consequent personalisation of MPS doses ought to become part of how we manage LN.
Trial website
N/A
Trial related presentations / publications
N/A
Public notes

Contacts
Principal investigator
Name 32930 0
Dr Dwarakanathan Ranganathan
Address 32930 0
Royal Brisbane & Women's Hospital Herston,Qld, 4029
Country 32930 0
Australia
Phone 32930 0
+61 07 36368576
Fax 32930 0
Email 32930 0
dwarakanathan_ranganathan@health.qld.gov.au
Contact person for public queries
Name 16177 0
Dr Dr Dwarakanathan Ranganathan
Address 16177 0
Royal Brisbane & Hospital
Herston,Qld, 4029
Country 16177 0
Australia
Phone 16177 0
+61-07-36368576
Fax 16177 0
+61-07-36368572
Email 16177 0
dwarakanathan_ranganathan@heath.qld.gov.au
Contact person for scientific queries
Name 7105 0
Dr Dr Dwarakanathan Ranganathan
Address 7105 0
Royal Brsbane & Hospital
Herston,Qld, 4029
Country 7105 0
Australia
Phone 7105 0
+61-07-36368576
Fax 7105 0
+61-07-36368572
Email 7105 0
dwarakanathan_ranganathan@heath.qld.gov.au

No information has been provided regarding IPD availability
Summary results
No Results