Clinical Trial Results:
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.
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Summary
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EudraCT number |
2012-003476-39 |
Trial protocol |
GB |
Global end of trial date |
10 Sep 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
21 Apr 2022
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First version publication date |
21 Apr 2022
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Other versions |
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Summary report(s) |
PREDNOS 2 HTA Report PREDNOS 2 JAMA publication |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
RG_12-188
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Additional study identifiers
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ISRCTN number |
ISRCTN10900733 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
University of Birmingham Sponsor Reference: RG_12-188, NIHR HTA Grant Reference No.: 11/129/261, IRAS Project Code: 111990, CTA No.: 21761/0281/001-0001, REC Reference No.: 12/NW/0766 | ||
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Sponsors
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Sponsor organisation name |
Manchester University NHS Foundation Trust
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Sponsor organisation address |
Oxford Rd, Manchester, United Kingdom, M13 9WL
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Public contact |
Dr Martin Christian, Nottingham Children’s Hospital, Martin.Christian@nuh.nhs.uk
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Scientific contact |
Dr Martin Christian, Nottingham Children’s Hospital, Martin.Christian@nuh.nhs.uk
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Sponsor organisation name |
University of Birmingham
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Sponsor organisation address |
Edgbaston, Birmingham, United Kingdom, B15 2TT
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Public contact |
Dr Martin Christian, Nottingham Children's Hospital, Martin.Christian@nuh.nhs.uk
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Scientific contact |
Dr Martin Christian, Nottingham Children's Hospital, Martin.Christian@nuh.nhs.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
25 Sep 2020
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Sep 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
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.
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Protection of trial subjects |
Research participants received a six day course of oral prednisolone each and every time they developed an URTI over the 12 month study period, which met the strict criteria laid down in the study protocol. The aim of this was to try and prevent the development of URTI-related relapse, necessitating the commencement of high dose daily prednisolone therapy. There was the risk that this course of action could increase overall steroid exposure without reducing relapse rate. We monitored patients every three months and carefully documented steroid-related adverse events, including impact on behaviour. Those children who experienced steroid toxicity during the course of the study had their background immunosuppressive therapy enhanced in an attempt to reduce relapse frequency.
There were no additional study visits for the purposes of the study alone. The three monthly visits were in keeping with routine care in children with relapsing nephrotic syndrome.
A single blood test was collected for the purposes of DNA studies. Where possible, this was collected at the time of venepuncture for routine clinical purposes. We ensured that patient discomfort was minimised through the use of topical anaesthetic creams, ethyl chloride spray, distraction therapy etc. in accordance with the individual child’s preference. The volume of blood to be sampled (10ml) did not pose any risk re development of hypovolaemia or anaemia.
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Background therapy |
Subjects were eligible if they were on any of the following four background therapies • Subjects on no long-term immunosuppressive therapy; • 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; • 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; • Subjects receiving long-term immunosuppressive therapies, including levamisole, ciclosporin, tacrolimus, MMF, mycophenolate sodium and azathioprine without long term maintenance prednisolone therapy. | ||
Evidence for comparator |
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. The PREDNOS 2 study determined whether the use of such therapy effectively and safely reduced the rate of relapse in a large population of UK children. Children were randomised with relapsing SSNS to receive either 6 days of daily prednisolone or placebo tablets (and so continue unchanged on their existing therapy, the current standard of care) each time they develop a URTI over a 12 month period. | ||
Actual start date of recruitment |
19 Mar 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 365
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Worldwide total number of subjects |
365
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
315
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Adolescents (12-17 years) |
50
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The trial was performed from Feb 1, 2013, to Jan 31, 2020, in 122 UK paediatric departments, consisting of 13 specialized paediatric nephrology and 109 general paediatric units. In the UK most children with SSNS are cared for by general paediatricians and only those with a more complicated disease course are seen by paediatric nephrologist. | |||||||||||||||
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Pre-assignment
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Screening details |
Participants were screened using the eligibility criteria as specified in the protocol. Formal screening logs were requested and in keeping with other studies they were not well kept. An estimate of approximately 1/3 of eligible patients entered the PREDNOS 2 trial. | |||||||||||||||
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Period 1
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Period 1 title |
Baseline period (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||||||||
Blinding implementation details |
All those involved in treating the participant, the participant and their parents/guardians were masked as to the randomised treatment allocation. Once the participant had been randomised, the central pharmacy at the Birmingham Children’s Hospital dispensed the PREDNOS trial medication by post to the participants home. Only delegated staff at pharmacy could view the treatment allocation, via a secure login, to dispatch the pots of trial treatment.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Active | |||||||||||||||
Arm description |
Daily prednisolone 15mg/m2 for a total of 6 days commenced once criteria for URTI have been met. | |||||||||||||||
Arm type |
Active comparator | |||||||||||||||
Investigational medicinal product name |
Prednisolone
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Investigational medicinal product code |
ATC CODE: H02A B06
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects who are receiving a long term maintenance prednisolone dose of up to and including 15mg/m2 on alternate days (including those not on maintenance prednisolone therapy) at the time of development of URTI will receive the following;
Active treatment arm - prednisolone 15mg/m2 daily for a total of six days, through the use of additional prednisolone study drug tablets. Subjects who are receiving a prednisolone dose of greater than 15mg/m2 on alternate days at the time of development of URTI will receive the following; Active treatment arm - prednisolone at alternate daily dose given daily for a total of six days, through the use of additional prednisolone study drug tablets. Once the six day course of study drug is complete, the subject will revert to their previous long term maintenance prednisolone dose (or no prednisolone if previously not receiving this). This will be repeated each and every time the subject develops an URTI meeting the designated criteria over the 12 months.
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Arm title
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Placebo | |||||||||||||||
Arm description |
Daily placebo 15mg/m2 for a total of 6 days commenced once criteria for URTI have been met. | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
N/A
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Daily placebo for a total of 6 days commenced once criteria for URTI have been met. Subjects who are receiving a long term maintenance prednisolone dose of up to and including 15mg/m2 on alternate days (including those not on maintenance prednisolone therapy) at the time of development of URTI will receive – No change to therapy through the use of placebo study drug tablets for a total of six days. Subjects who are receiving a prednisolone dose of greater than 15mg/m2 on alternate days at the time of development of URTI will receive; No change to therapy through the use of placebo study drug tablets for a total of six days. Once the six day course of study drug is complete, the subject will revert to their previous long term maintenance prednisolone dose (or no prednisolone if previously not receiving this). This will be repeated each and every time the subject develops an URTI meeting the designated criteria over the 12 month study period.
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Baseline characteristics reporting groups
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Reporting group title |
Active
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Reporting group description |
Daily prednisolone 15mg/m2 for a total of 6 days commenced once criteria for URTI have been met. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Daily placebo 15mg/m2 for a total of 6 days commenced once criteria for URTI have been met. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Modified Intention to Treat Population Active
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Subject analysis set type |
Modified intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
A total of 365 children with relapsing steroid-sensitive nephrotic syndrome were randomised (1 : 1) according to a minimisation algorithm based on background treatment. Eighty children completed 12 months of follow-up without an upper respiratory tract infection. Thirty-two children were withdrawn from the trial (14 prior to an upper respiratory tract infection), leaving a modified intention-to-treat analysis population of 271 children (134 and 137 children in the prednisolone and placebo arms, respectively).
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Subject analysis set title |
Modified Intention to Treat Population Placebo
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Subject analysis set type |
Modified intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
A total of 365 children with relapsing steroid-sensitive nephrotic syndrome were randomised (1 : 1) according to a minimisation algorithm based on background treatment. Eighty children completed 12 months of follow-up without an upper respiratory tract infection. Thirty-two children were withdrawn from the trial (14 prior to an upper respiratory tract infection), leaving a modified intention-to-treat analysis population of 271 children (134 and 137 children in the prednisolone and placebo arms, respectively).
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End points reporting groups
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Reporting group title |
Active
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Reporting group description |
Daily prednisolone 15mg/m2 for a total of 6 days commenced once criteria for URTI have been met. | ||
Reporting group title |
Placebo
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Reporting group description |
Daily placebo 15mg/m2 for a total of 6 days commenced once criteria for URTI have been met. | ||
Subject analysis set title |
Modified Intention to Treat Population Active
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
A total of 365 children with relapsing steroid-sensitive nephrotic syndrome were randomised (1 : 1) according to a minimisation algorithm based on background treatment. Eighty children completed 12 months of follow-up without an upper respiratory tract infection. Thirty-two children were withdrawn from the trial (14 prior to an upper respiratory tract infection), leaving a modified intention-to-treat analysis population of 271 children (134 and 137 children in the prednisolone and placebo arms, respectively).
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Subject analysis set title |
Modified Intention to Treat Population Placebo
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
A total of 365 children with relapsing steroid-sensitive nephrotic syndrome were randomised (1 : 1) according to a minimisation algorithm based on background treatment. Eighty children completed 12 months of follow-up without an upper respiratory tract infection. Thirty-two children were withdrawn from the trial (14 prior to an upper respiratory tract infection), leaving a modified intention-to-treat analysis population of 271 children (134 and 137 children in the prednisolone and placebo arms, respectively).
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End point title |
Proportion of patients experiencing an URTI related relapse | |||||||||||||||
End point description |
All outcome analyses were carried out on the modified ITT population of 271 children and excluded the 80 children who completed 12 months of follow-up without having had an URTI and the 14 children who were withdrawn without having had an URTI. The median time from randomisation to first URTI was 61 (IQR 21–126) days in the intervention arm and 54 (IQR 23–98) days in the placebo arm. There were 384 URTIs and 82 URRs in the intervention arm and 407 URTIs and 82 URRs in the placebo arm. One patient in the placebo arm had an URTI, but no information was provided on whether or not they had a URR and so their data were classed as missing. Three patients in the intervention arm and five patients in the placebo arm had URTIs but withdrew before the 12-month follow-up and did not report any URR for any time points for which they provided data. These patients were excluded from the primary analysis, but were included in a sensitivity analysis.
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End point type |
Primary
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End point timeframe |
Time to URTI and then any URTI related relapse within the 12 month assessment period.
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Statistical analysis title |
Proportion of patients experiencing an URR | |||||||||||||||
Statistical analysis description |
Proportion of patients experiencing an URTI-Related Relapse (URR)
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Comparison groups |
Modified Intention to Treat Population Active v Modified Intention to Treat Population Placebo
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Number of subjects included in analysis |
271
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 0.7 | |||||||||||||||
Method |
Binomial Model with Identity LinkFuntion | |||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||
Point estimate |
-0.024
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
-0.14 | |||||||||||||||
upper limit |
0.09 | |||||||||||||||
Variability estimate |
Standard error of the mean
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End point title |
URTI-related relapse rate | ||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Time to URTI and then time to URTI related relapse in the 12 month study period.
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End point title |
Proportion of patients experiencing any relapse | |||||||||||||||
End point description |
Proportion of patients experiencing any relapse (URTI and non-URTI related)
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End point type |
Secondary
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End point timeframe |
Time to relapse in the 12 month study period
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End point title |
Relapse rate | ||||||||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Time to relapse in the 12 month study period
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Proportion of patients who had escalation of background immunosuppressant therapy | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Escalation of therapy in the 12 month study period.
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End point title |
Proportion of patients who had reduction of background immunosuppressant therapy | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Reduction in 12 month study period
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End point title |
Cumulative prednisolone dose | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Cumulative dose in 12 month study period
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Adverse events information
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Timeframe for reporting adverse events |
Occurring over the 12 month study period and up to 3 months post treatment.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
3.0
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
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Reporting group title |
Prednisolone
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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20 Feb 2014 |
Protocol release V1.2
The protocol has been amended to reflect the Chief Investigator’s title change from a Doctor to Professor.
Membership of the Trial Steering Committee information has been updated
Prof Timothy Barrett has been removed from the Data Monitoring Committee.
A decision has been made by the Chief Investigator to change the wording in the exclusion criteria due to confusion at some centres regarding the background prednisolone dose the patient should be on at the time of randomisation. The exclusion criteria regarding subjects on ‘a long term maintenance prednisolone dose of greater than 15mg/m2 on alternate days at time of recruitment’ will be changed to subjects on a ‘prednisolone dose of greater than 15mg/m2 on alternate days at time of recruitment’.The PREDNOS 2 study trial schema wording has been corrected to show patient’s in the active treatment arm will have ‘ prednisolone administered daily for 6 days commenced within 24 hours of the criteria for an URTI being met’, in place of ‘prednisolone administered daily for 6 days commenced within 24 hours of onset of first URTI’.
The definition of a relapse has been made consistent throughout the protocol.
The study visit schedule has been amended to state a blood sample is required from all patients in the study, including those who previously participated in the blood sample for the PREDNOS study (giving a blood sample is optional).
The Statistical Analysis Section has been updated with further details. There have been no changes to the planned analyses but the explanation of the analyses has been expanded upon.
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09 Jun 2015 |
Release of protocol V1.3
Protocol Amendment:
• The protocol has been amended to reflect the increase in recruitment period from 2 to 3 years.
• The total study duration has increased from 4 to 5 years.
• Section 4.7 regarding the commencement of study drug has been amended to state ‘parents will be asked to contact their local study site before or within 24 hours of commencing study drug’.
• Other minor and administrative amendments.
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16 Jun 2017 |
Release of protocol V2.0
• Sample size increased from 300 patients to 360 patients.
• Increase in recruitment period from 3 years to 5 years and 1 month.
• Total study duration has increased from 5 years to 7 years and 1 month.
• Primary outcome measure has been refined to ‘First URTI-related relapse of nephrotic syndrome during the 12 month follow-up’.
• The RSI wording has been amended to state section 4.8 of the Wockhardt UK Ltd SmPC dated 31st March 2003 is the current RSI for the study.
• Parents/patients are instructed to contact Birmingham Children’s Hospital pharmacy to confirm receipt of study medication. Pharmacy are instructed to document when the parents/patients confirm receipt of the study medication.
• In Section 4.7 of the protocol, further instruction is provided on the use of the Advice Letter to Parents/Patients and a reminder that any contact between the site and parents/patients should be recorded in the medical notes.
• In Section 4.12 the study visit schedule has been amended to include tablet count details on the PREDNOS 2 Case Report Forms (CRFs) at each assessment visit.
• Section 4.16 has been amended to state the investigator must check and sign the Randomisation Notepad to confirm that the eligibility criteria have been met.
• In Section 4.20 further details on how to record the use of patient diaries has been added.
• Section 4.22, information on the completion of CRFs and questionnaires, and source data has been amended.
• Section 4.25 and Appendix 3 amended to reflect changes to the emergency unblinding process.
• Section 4.28 amended to reflect the changes to the sample size from 300 to 360 patients.
• Section 4.29 updated to reflect refinement to the primary outcome measure and statistical analysis.
• Section 5.0 Safety Assessment and Report includes a change to expectedness assessment, which should be carried out by the Chief Investigator and not the local investigator |
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03 Oct 2018 |
Release of protocol V3.0
• Prof Nicholas Webb has been replaced by Dr Martin Christian as Chief Investigator, and the associated contact details have been updated.
• The protocol has been amended to reflect the increase in recruitment period from 5 years and 1 month to 5 years and 11 months.
• The total study duration has increased from 7 years and 1 month to 7 years and 10 months. Please note – the apparent difference in extension times for recruitment period vs whole study duration is actually due to a miscalculation. The first patient was recruited after 5 months of set up when 6 months had initially been allowed for and subsequent extensions used the assumed 6 months of set up to calculate extension times (this was only spotted whilst preparing this amendment).
• The protocol has been updated to reflect both the General Data Protection Regulation 2018 and the Data Protection Act 2018.
• Updated sponsor trust name to reflect trust merger.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| A larger number of children than expected did not have an upper respiratory tract infection and the sample size attrition rate was adjusted accordingly during the trial. | |||
