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 The Wellcome Trust Children’s Clinical Research Facility is supported by the National Institute for Health Research
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 of 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 Child with relapsing steroid sensitive nephrotic syndrome ( ≥ 2 relapses in preceding 12 months syndrome ( ≥ 2 relapses in preceding 12 months Randomised Randomised Active treatment arm Active treatment arm Control arm Control arm Prednisolone administered daily for 6 days Prednisolone administered daily for 6 days No change to current prednisolone at time of first No change to current prednisolone at time of first URTI with use of placebo medicine to blind study URTI with use of placebo medicine to blind study commenced within 24 hours of onset of first URTI commenced within 24 hours of onset of first URTI Prednisolone administered daily for 6 days Prednisolone administered daily for 6 days No change to current prednisolone at time of each No change to current prednisolone at time of each subsequent URTI over 12 months follow-up period subsequent URTI over 12 months follow-up period commenced within 24 hours of onset of each commenced within 24 hours of onset of each with use of placebo medicine to blind study with use of placebo medicine to blind study subsequent URTI over 12 month follow-up period subsequent URTI over 12 month follow-up period
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 or 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 or 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 Child with relapsing steroid sensitive nephrotic syndrome ( ≥ 2 relapses in preceding 12 months syndrome ( ≥ 2 relapses in preceding 12 months Randomised Randomised Active treatment arm Active treatment arm Control arm Control arm Prednisolone administered daily for 6 days Prednisolone administered daily for 6 days No change to current prednisolone at time of first No change to current prednisolone at time of first URTI with use of placebo medicine to blind study URTI with use of placebo medicine to blind study commenced within 24 hours of onset of first URTI commenced within 24 hours of onset of first URTI Prednisolone administered daily for 6 days Prednisolone administered daily for 6 days No change to current prednisolone at time of each No change to current prednisolone at time of each subsequent URTI over 12 months follow-up period subsequent URTI over 12 months follow-up period commenced within 24 hours of onset of each commenced within 24 hours of onset of each with use of placebo medicine to blind study with use of placebo medicine to blind study subsequent URTI over 12 month follow-up period subsequent URTI over 12 month follow-up period
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/m 2 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 >37 O C (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 1.0m 2 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
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