Clinical Trial Results:
Open-label, long-term follow-up of safety and biochemical disease control of Infacort® in neonates, infants and children with congenital adrenal hyperplasia and adrenal insufficiency previously enrolled in the Infacort 003 study.
Summary
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EudraCT number |
2015-000458-40 |
Trial protocol |
DE |
Global end of trial date |
10 Aug 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
14 Feb 2019
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First version publication date |
14 Feb 2019
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Other versions |
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 |
Infacort 004
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02733367 | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Diurnal Limited
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Sponsor organisation address |
Cardiff Medicentre, Heath Park, Cardiff, United Kingdom, CF14 4UJ
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Public contact |
Dena Digweed, Diurnal Limited, +44 (0) 2920 682 069, info@diurnal.co.uk
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Scientific contact |
Dena Digweed, Diurnal Limited, +44 (0) 2920 682 069, info@diurnal.co.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 |
20 Nov 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
10 Aug 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Aug 2018
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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 |
The primary objective of the trial was to gather data on the long-term safety of Infacort in subjects who completed study Infacort 003.
The secondary objective was to gather data on the effects of Infacort.
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Protection of trial subjects |
Before enrolment, every subject (both parents/carers) received full oral and written information about the nature, purpose, expected advantages and possible risks of the study. The parents/carers agreed to participation in the study by signing the informed consent form. They were given an opportunity to enquire about details of the study. After a sufficient period of time (at least 24 hours) for the individual’s consideration and decision, comprehension and consent were documented on the consent form by the dated signature of both the subject’s parents/carers and the Investigator. Children aged 3 to 6 years were informed about their involvement in the study in the presence of their parents/carers.
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Background therapy |
Not applicable for this study. | ||
Evidence for comparator |
Not applicable for this study. | ||
Actual start date of recruitment |
04 Mar 2016
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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 |
Germany: 18
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Worldwide total number of subjects |
18
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EEA total number of subjects |
18
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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) |
6
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Children (2-11 years) |
12
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Adolescents (12-17 years) |
0
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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 |
Subjects recruited were those who had satisfactorily completed study Infacort 003 and agreed to participate in study Infacort 004. The investigator ensured that all subjects who were treated in study Infacort 003 were invited to participate. | ||||||||||
Pre-assignment
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Screening details |
Subject selection was confirmed by checking through all protocol inclusion and exclusion criteria at the initial visit for this study. | ||||||||||
Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||
Blinding implementation details |
Not applicable for this study.
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Arms
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Arm title
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Infacort | ||||||||||
Arm description |
This was a non-randomised, open-label, single-group study; all subjects who participated received Infacort. One subject was initially withdrawn from the study, but subsequently re-enrolled. | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Infacort
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Investigational medicinal product code |
INF
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Other name |
Infacort is now authorised in the European Union as Alkindi (EU/1/17/1260)
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Pharmaceutical forms |
Granules
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Routes of administration |
Oral use
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Dosage and administration details |
Infacort consists of immediate release granules, in dose strengths of 0.5mg, 1mg, 2mg and 5mg hydrocortisone, filled in a hard capsule; the capsule is a storage carrier and is not for consumption.
The granules were administered orally; either directly onto the top, and towards the back, of the child’s tongue; or indirectly onto the top and towards the back of the child’s tongue using a spoon; or the granules were sprinkled onto a spoonful of yoghurt, fruit purees (e.g. apple sauce) or fruit mousses immediately before being administered.
The granules could also be washed down with water, breast milk, formula milk or whole milk following administration.
Subjects received the usual clinically appropriate dose as determined by the Investigator, which was administered according to usual clinical practice – generally 3 or 4 times a day.
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial (overall period)
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Reporting group description |
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End points reporting groups
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Reporting group title |
Infacort
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Reporting group description |
This was a non-randomised, open-label, single-group study; all subjects who participated received Infacort. One subject was initially withdrawn from the study, but subsequently re-enrolled. |
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End point title |
Nature and occurrence of adverse events [1] | ||||||||||||||||||||
End point description |
The primary endpoint was the nature and occurrence of serious adverse events (SAEs) and adverse events (AEs) observed throughout the study. AEs were recorded from the time of the first intake of Infacort until the final visit.
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End point type |
Primary
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End point timeframe |
Assessed throughout the duration of the study.
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoint was the nature and occurrence of SAEs and AEs observed throughout the study; thus only descriptive statistical methods were used in the analyses of the data. |
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No statistical analyses for this end point |
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End point title |
Growth Velocity SDS | ||||||||||||
End point description |
Body height/length (cm) was obtained at each visit by specially trained paediatric endocrine nurses or physicians using standard calibrated auxological methods.
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End point type |
Other pre-specified
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End point timeframe |
Growth velocity standard deviation score (SDS) at visit 6 (11th month) and visit 10 (23rd month).
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No statistical analyses for this end point |
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End point title |
Cortisol levels - blood spot analysis | ||||||||||||
End point description |
The dried blood spots were analysed for multi-steroids, including cortisol (all subjects). Blood spot absolute laboratory values for the safety population are presented.
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End point type |
Other pre-specified
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End point timeframe |
A dried blood spot sample was collected at the initial and final visits, every month for the first 2 months of the study and thereafter every 6 months.
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events were recorded from the time of the first intake of Infacort in this study until the final study visit.
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Adverse event reporting additional description |
Details of any adverse events were collected, including date of onset, end date, frequency, severity, seriousness, relationship to Infacort, action taken, and outcome. Any adverse event was followed, whenever possible, until it returned to the baseline condition or became stable with no further change expected.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.0
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Reporting groups
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Reporting group title |
Infacort (safety population)
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Reporting group description |
Safety population (all subjects who received one complete or partial dose of Infacort). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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25 Jul 2016 |
Protocol amendment 1 - the following changes to the protocol were included in this amendment:
Interim data analyses were expected to be required for regulatory review as part of any Marketing Authorisation Applications. As such a statement to this effect was added to the statistical methods section of the synopsis and in Section 13.
In addition to the Infacort granules being administered directly onto the top, and towards the back, of the child’s tongue, it was added that the granules could also be sprinkled onto yoghurt, fruit purees (e.g. apple sauce) or fruit mousses immediately before being administered to the child. The granules could also be washed down with water, breast milk, formula milk or whole milk following administration. This information was added to Section 10.2.1 of the protocol.
In Section 8.5 (Previous and Concomitant Medication/Treatment) the protocol incorrectly stated that the trade names of the medications should be provided. This was amended to specify that generic names should be stated.
The timing of the blood spot samples was clarified to state that these should be taken in the morning wherever possible, since this is usually the time of poor control.
The statistical analysis section was updated to confirm that the change from baseline at each visit for continuous and categorical data would only be conducted if appropriate.
Section 10.2.2 of the protocol (Packaging and Labelling) was updated to state that Infacort capsules would be supplied in either blister packs or bottles. |
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20 Jul 2017 |
Protocol amendment 2 - the following changes to the protocol were included in this amendment:
It was confirmed that AEs, whether or not they are considered serious, leading to the application of sick day rules and use of sick day medication and which lead to any medical intervention either sought or required, such as at a hospital/clinic, are to be considered to be AEs of special interest. In addition, any occurrence of adrenal crisis must be recorded as an AE of special interest.
In some cases, whilst the subject is cared for at the study site for the purposes of the study, it may be necessary for the Investigator to visit the subject at their local hospital. A detailed procedure for this scenario has been added as an appendix to the protocol.
The wording around administration of the granules was amended to say that the granules can be sprinkled onto a spoonful of yoghurt, fruit purees (e.g. apple sauce) or fruit mousses rather than using the term 'mixed'.
A footnote was added stating that at the time of submission of this amendment (protocol version 4.0), Infacort is the subject of an ongoing Marketing Authorisation Application procedure and that for clarity, the end of study visits for each subject will occur after Infacort is commercially available locally.
It was added that if a visit needs to be postponed for more than 10 days, then the subject should attend for the visit before the period of absence for safety and drug supply reasons. Subsequent visits will then be scheduled at regular intervals from the revised early visit date.
Testing of hydrocortisone acetate in the blood spot analyses was removed since this is no longer analysed.
It was decided that the secondary endpoint of growth velocity would not be used, but instead the standard deviation score for height and weight would be calculated for each subject using an age- and gender-matched healthy German reference cohort. This change was implemented throughout the protocol. |
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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. | |||
This study was designed as a safety study to evaluate the long-term use of Infacort in routine clinical practice. Efficacy results should be viewed as exploratory and interpreted with care. | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/30058902 |