URTI and relapses Around 50% of relapses are preceded by an URTI If - - PowerPoint PPT Presentation

The Wellcome Trust Children’s Clinical Research Facility is supported by the National Institute for Health Research

PREDNOS 2 study

University of Birmingham 190514

Nicholas J A Webb: Chief Investigator Consultant Paediatric Nephrologist Director Wellcome Trust Children’s Clinical Research Facility Royal Manchester Children’s Hospital, UK www.childrenscrf.org

URTI and relapses

• Around 50% of relapses are preceded by an URTI
• If URTI occurs, around 50% chance of a relapse

developing

• It seems logical that URTI is pivotal and attempts to

ameliorate the URTI driven process are appropriate

Pre-emptive treatment of relapses Gulati et al. CJASN 2011

• 100 children - FRNS on AD prednisolone (32 on levamisole)
• At time of development of URTI randomised to 7 days of

– daily prednisolone at same dose – Remained on AD prednisolone

• URTI defined as

– Fever >38, rhinorrhoea, cough, diarrhoea

• Incidence of URTI-related relapse reduced

– Relapse rate reduced by 0.7/y (95%CI 0.3-1.1: p<0.01)

Unanswered questions

• Does this intervention work in developed countries,

where URTI is significantly different (lower incidence

• f fever, absence of diarrhoea etc.)?
• Does this work in children receiving alternate day

prednisolone in conjunction with other immunosuppressive therapies e.g. levamisole, ciclosporin, tacrolimus and MMF?

Unanswered questions

• Is there an increase in prednisolone-related adverse

effects, including behavioural abnormality?

• Is the intervention cost-effective?
• Can we understand the disease mechanism better?

PREDNOS 2: Study Design

Child with relapsing steroid sensitive nephrotic syndrome (≥2 relapses in preceding 12 months Randomised Active treatment arm Control arm No change to current prednisolone at time of first URTI with use of placebo medicine to blind study Prednisolone administered daily for 6 days commenced within 24 hours of onset of first URTI Prednisolone administered daily for 6 days commenced within 24 hours of onset of each subsequent URTI over 12 month follow-up period No change to current prednisolone at time of each subsequent URTI over 12 months follow-up period with use of placebo medicine to blind study Child with relapsing steroid sensitive nephrotic syndrome (≥2 relapses in preceding 12 months Randomised Active treatment arm Control arm No change to current prednisolone at time of first URTI with use of placebo medicine to blind study Prednisolone administered daily for 6 days commenced within 24 hours of onset of first URTI Prednisolone administered daily for 6 days commenced within 24 hours of onset of each subsequent URTI over 12 month follow-up period No change to current prednisolone at time of each subsequent URTI over 12 months follow-up period with use of placebo medicine to blind study

Primary study objective

• To determine whether a six day course of oral

prednisolone given at the time of URTI reduces the incidence of first URTI-related relapse in children with relapsing steroid sensitive nephrotic syndrome

Secondary study objectives

To determine whether a six day course of oral prednisolone given at the time of URTI:

• reduces the overall rate of URTI-related relapse
• reduces the overall rate of relapse
• reduces the cumulative dose of prednisolone received
• reduces the incidence of adverse effects of

prednisolone (including behavioural)

• affects use of other immunosuppressive agents
• is cost effective

Health economic analysis

Health Economist: Dr Emma Frew - Health Economics Unit, University of Birmingham. Objective: To measure the cost-effectiveness of long term tapering versus standard prednisolone therapy for the treatment of the initial episode of childhood nephrotic syndrome. Results: Presented using ‘cost per Quality-Adjusted Life Year (QALY)’ gained (primary analysis) and cost per ‘relapse of proteinuria’ (secondary analysis)

Mechanistic studies

• A single 10ml sample of blood will be collected for

DNA and RNA extraction

– GWAS to look for possible genetic loci associated with steroid sensitive nephrotic syndrome

• Kleta / Bockenhauer ICH, UCL

– Other DNA and RNA methodologies

• Koziell / Saleem KCL and Bristol

Sample size

• To detect an 35% proportional reduction in URTI-

related relapse rate (i.e. from 50% to 32.5%), with 80% power and alpha=0.05, requires 250 subjects in total.

• If we allow for between 10 and 20% drop-out, then

this will require recruitment of between 280 and 320 subjects.

• Target recruitment therefore 300 children (150 in

each arm)

Inclusion Criteria

• 1-18 years of age (inclusive)
• Frequently relapsing steroid sensitive nephrotic syndrome with 2
• r more relapses in the preceding 12 months.

– on no long-term immunosuppressive therapy – on alternate day prednisolone at ≤15mg/m2 AD – on alternative immunosuppressive therapy, including levamisole, ciclosporin, tacrolimus, MMF, mycophenolate sodium and azathioprine – on alternate day prednisolone at ≤15mg/m2 AD and alternative immunosuppressive therapy, including levamisole, ciclosporin, tacrolimus, MMF, mycophenolate sodium and azathioprine – If have received cyclophosphamide or rituximab, must be at least 3m post therapy and must have experienced at least one post-treatment relapse (and two in the past 12 months)

• Understand the definition of URTI and the need to commence

study drug once this definition has been met.

• Consent

Exclusion Criteria

• Steroid resistant nephrotic syndrome
• Receiving, or within 3 months of completing a course of oral
• r intravenous cyclophosphamide
• Receiving, or within 3 months of receiving a course of

rituximab

• Daily prednisolone therapy at time of recruitment
• Long term maintenance prednisolone dose of greater than

15mg/m2 on alternate days at time of recruitment

• Documented history of significant non-adherence with

medical therapy

• Will be transferred from paediatric to adult services during

the 12 month study period

• Unable to take prednisolone tablets, even in crushed form
• Allergy to prednisolone.

Study Design

Child with relapsing steroid sensitive nephrotic syndrome (≥2 relapses in preceding 12 months Randomised Active treatment arm Control arm No change to current prednisolone at time of first URTI with use of placebo medicine to blind study Prednisolone administered daily for 6 days commenced within 24 hours of onset of first URTI Prednisolone administered daily for 6 days commenced within 24 hours of onset of each subsequent URTI over 12 month follow-up period No change to current prednisolone at time of each subsequent URTI over 12 months follow-up period with use of placebo medicine to blind study Child with relapsing steroid sensitive nephrotic syndrome (≥2 relapses in preceding 12 months Randomised Active treatment arm Control arm No change to current prednisolone at time of first URTI with use of placebo medicine to blind study Prednisolone administered daily for 6 days commenced within 24 hours of onset of first URTI Prednisolone administered daily for 6 days commenced within 24 hours of onset of each subsequent URTI over 12 month follow-up period No change to current prednisolone at time of each subsequent URTI over 12 months follow-up period with use of placebo medicine to blind study

Recruitment and randomisation

• Patient randomised at routine clinic visit

– not acutely at time of development of URTI

• Baseline data collected
• Family provided with information re indications for starting

study drug and dose of study drug to administer

– written information, fridge magnet – patient diary

• Study package sent to family home from central pharmacy

– Study drug (2 pots of 50 tablets of prednisolone or placebo) – Electronic tympanometric thermometer

Recruitment and randomisation

• Once criteria for URTI met, family will start

– Active treatment arm: Daily prednisolone 15mg/m2 for a total of 6 days. – Control arm: Daily placebo (matching number of tablets) for a total of 6 days

• This should be repeated each and every time

the child develops an URTI over the 12 month study period

Definition of URTI

• The presence of at least 2 of

the following for at least 24 hours:

– sore throat – ear pain/discharge – runny nose – cough (dry/barking) – hoarse voice – fever >37OC (measured using tympanometric electronic thermometer)

Study drug dosing – subjects not on long term AD prednisolone

• Prednisolone commenced

at 15mg/m2 daily for six days (or equivalent number of placebo tablets)

– Patient of 1.0m2 will receive 3 x 5mg prednisolone tablets or 3 x placebo tablets

At / after time of URTI

• Family may contact local centre if uncertain

about whether to start treatment or uncertain about dose

• If centre unavailable or uncertain, PREDNOS 2

hotline can be contacted 08:00 – 20:00

– 07896 818647

• Parents must contact centre as soon as

possible (preferably within 24h) of starting study drug to inform them of this

Urine monitoring

• Parents to test urine throughout study in

keeping with routine clinical care

• Relapse is defined as Albustix positive

proteinuria (+++ or greater) for 3 consecutive days or the presence of generalised oedema plus 3+ proteinuria.

• Parents to contact local centre in event of

relapse in keeping with routine clinical care

Relapse treatment

• ISKDC relapse regimen

– Prednisolone 60mg/m2 daily until urine negative

• r trace for 3 consecutive days, then 40mg/m2 for

28 days (14 doses)

Subject assessments

At months 0 (randomisation), 3, 6, 9, 12

• Documentation of history of URTI +/- relapse and

commencement of study drug

• Recent medical and drug history, including use of
• ther prescribed/purchased medications
• Adverse event documentation
• Compliance check (pill count with triangle)
• Clinical exam, inc height, weight, BP, evidence of

prednisolone adverse effects

Subject assessments

At months 0 (randomisation), 3, 6, 9, 12

• Reassessment of dose of study drug to be

administered in the event of URTI

• Achenbach Child Behaviour Checklist
• PedsQL
• CHU-9D and EQ-5D
• Single 10ml blood sample on one occasion only

– Sample sent in stamped addressed packaging to Institute

• f Child Health, London

What do I do now?

• Identify suitable patients in your centre
• Send the family the PIS and arrange for review

with regard to recruitment

• Your LCRN team will be able to help
• Please do not hesitate to ask for assistance

from the BCTU team

– We are very responsive to email correspondence

Thank you

Contact details nicholas.webb@cmft.nhs.uk www.childrenscrf.org www.bctu.bham.ac.uk/prednos2 Google PREDNOS 2 PREDNOS2@trials.bham.ac.uk