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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]

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

Condition category

Condition code

Renal and Urogenital

Kidney disease

Inflammatory and Immune System

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strategy (LSS)data for mycophenolate sodium at 0, 1.5, 4 and 8 hours post-dose - as suggested by He et al in their unpublished data, that an AUC from 0-8 hours can be calculated with four blood samples and correlates favourably with an AUC0-12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]

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]

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]

12 months

Secondary outcome [1]

To determine the effect of MPS in improvement in SLE Disease Activity Index (SLEDAI), C3, C4 and anti-dsDNA levels;

Timepoint [1]

12 months

Secondary outcome [2]

To study the relationship between disease activity of Lupus nephritis and MPA blood concentration

Timepoint [2]

12 months

Secondary outcome [3]

To develop a pharmacokinetic model that can be used to develop MPS dosing recommendations in LN patients treated with MPS

Timepoint [3]

12 months

Secondary outcome [4]

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]

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

Sex

Both males and females

Can healthy volunteers participate?

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

1/09/2011

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]

Hospital

Name [1]

Royal Brisbane Hospital research Foundation

Address [1]

Herston Road,
Herston,Qld, 4029

Country [1]

Australia

Funding source category [2]

Commercial sector/Industry

Name [2]

Novartis Pharmaceuticals Australia

Address [2]

54 Waterloo Road
North Ryde, NSW 2113
Australia

Country [2]

Australia

Primary sponsor type

Hospital

Name

Royal Brisbane

Address

Herston Road,Herston, Qld, 4029

Country

Australia

Secondary sponsor category [1]

Commercial sector/Industry

Name [1]

Novartis Pharmaceuticals Australia

Address [1]

54 Waterloo Road
North Ryde, NSW 2113
Australia

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Human Research and Ethics Committee

Ethics committee address [1]

Royal Brisbane & Women's Hospital
Building 7,Herston, Qld, 4029

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

19/01/2011

Ethics approval number [1]

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

Dr Dwarakanathan Ranganathan

Address

Royal Brisbane & Women's Hospital Herston,Qld, 4029

Country

Australia

Phone

+61 07 36368576

Fax

[email protected]

Contact person for public queries

Name

Dr Dwarakanathan Ranganathan

Address

Royal Brisbane & Hospital
Herston,Qld, 4029

Country

Australia

Phone

+61-07-36368576

Fax

+61-07-36368572

[email protected]

Contact person for scientific queries

Name

Dr Dwarakanathan Ranganathan

Address

Royal Brsbane & Hospital
Herston,Qld, 4029

Country

Australia

Phone

+61-07-36368576

Fax

+61-07-36368572

[email protected]

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Basic results	No			343252-(Uploaded-19-11-2019-14-50-50)-Basic results summary.pdf
Plain language summary	No		Not applicable

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Pharmacokinetics of Enteric-Coated Mycophenolate Sodium in Lupus Nephritis (POEMSLUN).	2019	https://dx.doi.org/10.1097/FTD.0000000000000658

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically