Transcript Slide 1

Childhood nephrotic syndrome:
an update
Dr Nick Webb
Consultant Paediatric Nephrologist
Director Wellcome Trust Children’s Clinical Research Facility
Royal Manchester Children’s Hospital
www.bctu.bham.ac.uk/prednos/
The Wellcome Trust Children’s Clinical Research Facility
is supported by the National Institute for Health Research
New Royal Manchester Children’s Hospital
ISKDC regimen
• Prednisone (Prednisolone) 60mg/m2 (max 80mg) daily for 4
weeks followed by 40mg/m2 (max 60mg) on alternate days
for 4 weeks
• Has been the ‘gold standard’ regimen against which all others
have been compared
Cochrane meta-analysis
2 months vs. ≥3 months prednisolone
Problems with meta-analysis
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Small – 6 trials: 422 patients
Methodological problems in many trials
Not placebo controlled
Inconsistent reporting of prednisolone-related AEs
Cochrane report and further personal discussion
confirms requirement for properly conducted, large,
double blind, placebo controlled RCT
Ksiazec et al Acta Paediatr 1995 84 889-893
Prednisolone adverse effects: APN trial
Cosmetic adverse-effects of corticosteroids
↓ Adherence
• Behaviour assessed
prospectively in 12 children
with SSNS using Achenbach
Child Behaviour Checklist
• Assessed at time of diagnosis
and after 4 weeks of
prednisolone
• Control group
• Significant increase in the total
behaviour score (p=0.03)
– specifically in aggressive and
poor attention behavior items
Variation in practice exists
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Taper steroids at urinary remission
ISKDC regimen
ISKDC regimen followed by steroid taper
12 week regimen (APN)
12 week regimen followed by steroid taper
Other
Lande et al Pediatr Nephrol 2000 14 766-769
14%
13%
36%
7%
14%
15%
APN regimen
Initial-Therapie mit Prednison
– 60 mg/ m2/Tag (max. 80 mg)
6 Wochen
– anschließend
40 mg/ m2 alternierend 6 Wochen
Italy
(courtesy of R Coppo)
• Depends upon where child is treated
• District general hospitals tend to use ISKDC regimen
• Tertiary nephrology centres (~50% of children treated in
these) tend to use longer regimens
– 4-6w at 2mg/kg/day
– Then 8 weeks on alternate days
– Then reducing by 0.5mg/kg every 10 days
Finland
(courtesy of C Holmberg)
• 60 mg/m2 for 4-6 weeks reducing to 40mg/m2
alternate days
– then reducing 10mg/m2/week stopping after a
month.
• ACTH-test performed and replacement therapy with
hydrocortisone until this is normal.
Russia
(courtesy of Svetlana Paunova)
• APN regimen with some caveats
• If very rapid response or evidence of steroid toxicity,
will change to alternate day therapy after 4 weeks
– where this is done, alternate day treatment is
continued for a total of 8 weeks
Switzerland
(courtesy of Thomas Neuhaus)
• 60 mg/m2 per day in a single morning dose, maximal
dose 75 mg prednisone
for 6 weeks
• 40 mg/m2 alternate day for 6 weeks
• then taper dose over the next 3 months
• total of 6 months therapy
Poland
(courtesy of Ryzard Grenda)
Turkey
(courtesy of A Güven)
• Use prednisolone
• 2001 questionnaire (22 centres) revealed
– 17/22 centres gave 2mg/kg initially
– 12/22 this was given as a b.d. regimen
– 19/22 gave 4 weeks, remainder 6 weeks
– Then 15/22 gave same dose on alternate days for
4 weeks
Turkey
(courtesy of A Güven)
• Following this, tapering regimen used in 15/22
• Initial steroid therapy lasted 4m in 14/22 centres
PREDNOS
NIHR funded (£780K)
225 children with newly
presenting SSNS
ISKDC regimen
Total 8 weeks steroids
Then placebo to 16 weeks
Prednisolone 60mg/m2/d 4w
Then alternate days 60mg/m2 2w
50mg/m2 2w
40mg/m2 2w
30mg/m2 2w
20mg/m2 2w
10mg/m2 2w
Total 16 weeks steroids
Pilot study
• Funded by KRUK and KRAF (now KKR)
• Adopted by MCRN (post commencement)
• Endorsed by BAPN and RCPCH
Pilot study
• Aim: to show that national paediatric nephrology
trials involving DGH paediatricians can be
successfully conducted
• Successful in building a collaborative trial network
• Recruited principal investigators in 37 sites,
• 26 fully set up
• 18 had recruited by end of study
• Another 13 sites actively interested
• Adopted by MCRN
Patients recruited
• 55 children (33 boys)
• Mean age 5.5 years
• Ethnicity
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White (UK + other) 39
South Asian 12
Mixed 2
Other 2
Relapse rate
• Pilot data remains blinded
• 12 month relapse rate 36/50
– 72% (95% CI 58%-83%)
• Relapses were treated with ISKDC prednisolone
regimen
• Additional treatment of relapsing disease:
– levamisole (3 patients)
– cyclophosphamide (1 patient)
– methylprednisolone (1 patient)
Safety reporting
• No SUSARS
• 3 SAEs
– Trapped finger requiring stitching in theatre
– Abdominal pain requiring hospitalization
– Viral induced wheezing requiring hospitalization
Pilot study feedback
• 10/55 patients/families surveyed
– all happy to have participated
– information sheets clearly written
– happy with study visit schedule
– high satisfaction with pharmacy arrangements
• all patients received complete course of study drug in
labelled blister packs couriered to family home
PREDNOS
• Primary end point
– Time to first relapse
• Secondary end points
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Frequently relapsing and steroid dependent disease
Incidence of relapse
Frequency and severity of adverse effects
Total use of prednisolone over study period
Use of other immunosuppressive therapies
Behavioural change
Cost effectiveness
Early clinical course and randomisation
• Initial therapy with prednisolone 60mg/m2 (max
80mg) daily
• Recommend use of non-soluble prednisolone
tablets – crushers provided
• Aim to begin consent process once clear child is
entering remission
– Needs to be consented and randomised in time to allow
delivery of study medicines by Day 29
Study visit schedule
• Study visits at:
– Weeks: 4 (start of randomised treatment), 8, 12, 16
– Months: 5, 6, 8, 10, 12, 18, 24, 30, 36, 42 and 48
• Achenbach Child Behaviour Checklist and QALY
(PedsQL and Child Health Utility-9D) questionnaires
at:
– Week 4
– Months: 4,12, 24, 36 and 48
Study drug
• Dispensed by Birmingham Children’s Hospital Clinical
Trials Pharmacy
– Entire 12 week course of trial therapy dispensed in blister
pack
– Delivered to family home in time for commencement on
day 29
– Matching placebo used thus maintaining double blinding
of study
PREDNOS
• We will carefully collect adverse effect data,
including important data on behavioural change
– Achenbach Child Behaviour Checklist
Power calculations
• Primary analysis will based on a log-rank test of time to
relapse
• Anticipated that relapse rate in control group will be 60% at 1
year
• To detect an absolute difference of 20% in relapse rate, from
60% to 40% at 1 year, with 80% power at 2p=0.05 will require
100 relapses
• Given the expected relapse rates we anticipate needing 200
patients in total
• If allow for 10% dropout, then this will require recruitment of
224 patients (112 per arm)
Health economic analysis
Health Economists: Dr Emma Frew and Dr Billingsley Kaambwa
from the 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)
Costs and Outcomes
Costs
• Treatment costs (medicines,
management, side-effects, treatment
complications)
• Consultation and follow-up costs
(routine tests such as blood tests and
urianalysis, outpatient and inpatient
visits)
• Long term treatment costs (care
for long term side effects).
Outcomes
• Euro-QoL (EQ-5D) used to
construct QALYs.
• PedsQL
• Achenbach Child Behaviour
Checklist (ACBC)
Mechanistic studies
• A single 10ml sample of blood will be collected for
DNA extraction
– GWAS to look for possible genetic loci associated with
steroid sensitive nephrotic syndrome
• Kleta / Bockenhauer
UCL
– DNA methylation studies
• Ray / Lennon
Manchester BRC
PREDNOS sites
PREDNOS recruitment
PREDNOS – contact information
• General Trial Website:
http://www.bctu.bham.ac.uk/PREDNOS
• Secure Trial Website for Randomisation and Online Data
Entry: https://www.trials.bham.ac.uk/PREDNOS
• Email: [email protected]
• Tel: +44 (0)121 415 9130
• Fax: +44 (0)121 415 9135
• Postal Address: PREDNOS Trial Office, Birmingham Clinical
Trials Unit, Robert Aitken Institute, University of Birmingham,
Edgbaston, Birmingham B15 2TT