ISRCTN - ISRCTN10900733: Short course daily prednisolone therapy at the time of upper respiratory tract infection in children with relapsing steroid sensitive nephrotic syndrome: The PREDNOS 2 study

Plain English Summary

Background and study aims
Steroid-sensitive nephrotic syndrome (SSNS) is the most common kidney disease of childhood. Large amounts of protein are leaked into the urine resulting in generalised oedema (swelling). It is treated with high-dose oral prednisolone, a steroid drug which is effective, though associated with a number of serious side effects. Following successful initial treatment, 70-80% of children develop relapses where leakage of protein into the urine recurs. These are associated with a risk of significant complications. Relapse of nephrotic syndrome is treated with a further course of high-dose prednisolone, further increasing the risk of side effects. Children are kept off school, resulting in educational impairment and parental absence from work. Around 50% of children suffer frequent relapses (four or more per year). In this situation, attempts are made to reduce prednisolone exposure using other more potent drugs such as ciclosporin and cyclophosphamide, which are associated with other significant side effects. It is therefore logical to attempt to reduce the frequency of relapses. There is known to be a strong link between viral upper respiratory tract infection (URTI, the common cold) and the development of relapse of nephrotic syndrome. Three previous small studies have suggested that the use of a short course of daily prednisolone at the time of URTI reduces the rate of disease relapse. This study aims to find out whether the use of such therapy effectively and safely reduces the rate of relapse in a large population of UK children.

Who can participate?
Participants aged over 1 year and less than 19 years will be eligible if they have relapsing SSNS, defined as having experienced two or more relapses in the previous 12 months.

What does the study involve?
We will randomly allocate 300 children with relapsing SSNS to receive either 6 days of daily prednisolone or continue unchanged on their existing therapy (the current standard of care) each time they develop a URTI over a 12-month period. We will assess the frequency of URTI-related relapse of nephrotic syndrome in both groups and look carefully for side effects of treatment. The 300 participants will be recruited from over 100 UK hospitals.

What are the possible benefits and risks of participating?
Participants will receive a 6-day course of prednisolone each and every time they develop an URTI over the 12-month study period. There is the risk that this course of action will increase overall steroid exposure without reducing relapse rate. We will be monitoring patients every 3 months and will carefully document side effects, including impact on behaviour. Those children who experience steroid toxicity during the course of the study will have their background immunosuppressive treatment enhanced in an attempt to reduce relapse frequency. There will be no additional study visits for the purposes of the study alone. The three monthly visits are in keeping with routine care in children with relapsing nephrotic syndrome.

Where is the study run from?
Birmingham Clinical Trials Unit (UK).

When is the study starting and how long is it expected to run for?
Recruitment will begin in early 2013 and continue for a 2-year period. Each subject will be followed-up every 3 months over a period of 1 year which is in keeping with routine clinical practice. The study will run for a total of 4 years.

Who is funding the study?
The National Institute for Health Research (NIHR) Health Technology Assessment programme.

Who is the main contact?
Dr Nicholas Webb (Chief Investigator)
Nicholas.Webb@cmft.nhs.uk

Trial website

http://www.birmingham.ac.uk/prednos2

Contact information

Type

Scientific

Primary contact

Miss Emma Barsoum

ORCID ID

Contact details

Birmingham Clinical Trials Unit
Division of Medical Sciences
Robert Aitken Institute
Edgbaston
Birmingham
B15 2TT
United Kingdom
prednos2@trials.bham.ac.uk

Additional identifiers

EudraCT number

2012-003476-39

ClinicalTrials.gov number

Protocol/serial number

13410

Study information

Scientific title

Short course daily prednisolone therapy at the time of upper respiratory tract infection in children with relapsing steroid sensitive nephrotic syndrome: The PREDNOS 2 study

Acronym

PREDNOS 2

Study hypothesis

Steroid sensitive nephrotic syndrome (SSNS) is the commonest kidney disease of childhood. Large amounts of protein are leaked into the urine resulting in generalised oedema (swelling). Treatment is with high dose oral prednisolone, a steroid drug which is effective, though associated with a number of serious side effects. Following successful initial treatment, 70-80% of children develop relapses where leakage of protein into the urine recurs. These are associated with a risk of significant complications. Treatment of relapse of nephrotic syndrome is with a further course of high dose prednisolone, further increasing the risk of sideeffects. Children are kept off school, resulting in educational impairment and parental absence from work. Around 50% of children suffer frequent relapses (4 or more per year). In this situation, attempts are made to reduce prednisolone exposure using other more potent drugs e.g. ciclosporin and cyclophosphamide, which are associated with other significant side effects. It is therefore logical to attempt to reduce the frequency of relapses.

There is known to be a strong link between viral upper respiratory tract infection (URTI the common cold) and the development of relapse of nephrotic syndrome. Three previous smalll studies have suggested that the use of a short course of daily prednisolone at the time of URTI reduces the rate of disease relapse. The PREDNOS 2 study aims to determine whether the use of such therapy effectively and safely reduces the rate of relapse in a large population of UKchildren. We will randomise 300 children with relapsing SSNS to receive either 6 days of daily prednisolone or continue unchanged on their existing therapy (the current standard of care) each time they develop a URTI over a 12 month period. We will assess the incidence of URTI related relapse of nephrotic syndrome in both study arms and look carefully for side effects of treatment.

More details can be found at: http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=13410

More details can be found at http://www.hta.ac.uk/project/2941.asp

Ethics approval

North West GM Central Research Ethics Committee (REC), Ref. No: 12/NW/0766 approval pending

Study design

Double blind randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Not specified

Trial type

Treatment

Patient information sheet

Patient information material can be foudn at http://www.birmingham.ac.uk/research/activity/mds/trials/bctu/trials/renal/prednos2/investigators/documentation.aspx

Condition

Steroid sensitive nephrotic syndrome

Intervention

Randomised to receive either 6 days of daily prednisolone or continue unchanged on their existing therapy (the current standard of care) each time they develop a URTI over a 12 month period.

Intervention type

Drug

Phase

Not Applicable

Drug names

Prednisolone

Primary outcome measures

URTI-related relapse of nephrotic syndrome following first URTI during 12 month follow-up period. Relapse is defined as Albustix positive proteinuria (+++ or greater) for 3 consecutive days or the presence of generalised oedema plus 3+ proteinuria. URTI-related relapse is defined as a relapse occurring within 14 days of the development of an URTI. First URTI refers to the first URTI which occurs within the 12 month study follow up period. Relapse will be assess at each clinic visit which will be every three months for a period of one year in keeping with routine clinical practice.

Secondary outcome measures

1. Rate of URTI-related relapse of nephrotic syndrome (relapses per year)
2. Rate of relapse (URTI-related and non URTI-related) of nephrotic syndrome (relapses per year)
3. Cumulative dose of prednisolone (mg/kg and mg/m2) received over the 12 month study period
4. Incidence of SAEs
5. Incidence of adverse effects of prednisolone including assessment of behaviour using the Achenbach Child Behaviour Checklist
6. Incidence of escalation of background immunosuppressive therapy (e.g. addition of ciclosporin, tacrolimus, cyclophosphamide etc.)
7. Incidence of reduction of background immunosuppressive therapy (i.e. cessation of long term maintenance prednisolone therapy)
8. Quality of life using the CHU-9D, EQ-5D and PedsQL
9. Cost per relapse of nephrotic syndrome
10. Cost per QALY gained

Overall trial start date

01/11/2012

Overall trial end date

01/10/2016

Reason abandoned

Eligibility

Participant inclusion criteria

Subjects aged over 1 year and less than 19 years will be eligible for inclusion if they have relapsing SSNS, defined as having experienced 2 or more relapses in the preceding 12 months. This will include the following groups:
1. Subjects on no longterm immunosuppressive therapy
2. Subjects receiving long term maintenance prednisolone therapy at a dose of up to and including 15mg/m2 on alternate days. Note that this is the maximum dose at the time of recruitment if children subsequently receive a higher dose e.g. after relapse, they can remain in the study
3. Subjects receiving long term maintenance prednisolone therapy at a dose of up to and including 15mg/m2 on alternate days in conjunction with other immunosuppressive therapies, including levamisole, ciclosporin, tacrolimus, MMF, mycophenolate sodium and azathioprine
4. Subjects receiving longterm immunosuppressive therapies, including levamisole, ciclosporin, tacrolimus, MMF, mycophenolate sodium and azathioprine without long term maintenance prednisolone therapy.
5. Subjects who have previously received a course of oral or intravenous cyclophosphamide:
5.1. Must have experienced two relapses in the 12 months prior to randomisation (in keeping with all other subjects)
5.2. Must have experienced at least one of these relapses following completion of cyclophosphamide therapy
5.3. Must be at least 3 months post completion of oral or intravenous cyclophosphamide therapy
6. Subjects who have previously received a single dose or course of intravenous rituximab:
6.1. Must have experienced two relapses in the 12 months prior to randomisation (in keeping with all other subjects)
6.2. Must have experienced at least one of these relapses following completion of rituximab therapy
6.3. Must be at least 3 months post completion of intravenous rituximab therapy
7. Parents and (where age appropriate) subject understand the definition of URTI and the need to commence study drug once this definition has been met
8. Written informed consent obtained from the subjects parents/guardians and written assent obtained from subject (where age appropriate). Subjects aged 16 years and above will provide their own written informed consent.

Participant type

Patient

Age group

Child

Gender

Both

Target number of participants

Planned Sample Size: 300; UK Sample Size: 300

Participant exclusion criteria

1. Subjects with steroid resistant nephrotic syndrome
2. Subjects receiving, or within 3 months of completing a course of oral or intravenous cyclophosphamide
3. Subjects receiving, or within 3 months of receiving a course of rituximab
4. Subjects on daily prednisolone therapy at time of recruitment
5. Subjects on a long term maintenance prednisolone dose of greater than 15mg/m2 on alternate days at time of recruitment
6. Subjects with a documented history of significant nonadherence with medical therapy
7. Subjects who will be transferred from paediatric to adult services during the 12 month study period
8. Subjects unable to take prednisolone tablets, even in crushed form
9. Known allergy to prednisolone

Recruitment start date

01/11/2012

Recruitment end date

01/10/2016

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Birmingham Clinical Trials Unit
Birmingham
B15 2TT
United Kingdom

Sponsor information

Organisation

University of Birmingham (UK)

Sponsor type

University/education

Website

Funders

Funder type

Government

Funder name

NIHR Health Technology Assessment Programme - HTA (UK) 11/129/261

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data