Clinical Trial Results:
Mindex: The efficacy and safety of very low dose dexamethasone used to facilitate the extubation of ventilator dependent preterm babies who are at high risk of bronchopulmonary dysplasia
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Summary
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EudraCT number |
2015-005342-63 |
Trial protocol |
GB |
Global end of trial date |
24 Jun 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
10 May 2019
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First version publication date |
10 May 2019
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Other versions |
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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 |
UoL001206
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Additional study identifiers
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ISRCTN number |
ISRCTN81191607 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University of Liverpool / Liverpool Joint Research Office
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Sponsor organisation address |
2nd Floor Block D Waterhouse Building, 3 Brownlow Street, Liverpool, United Kingdom, L69 3GL
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Public contact |
NPEU Clinical Trials Unit, National Perinatal Epidemiology Unit, +44 01865289737, minidex@npeu.ox.ac.uk
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Scientific contact |
NPEU Clinical Trials Unit, National Perinatal Epidemiology Unit, +44 01865289737, minidex@npeu.ox.ac.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 |
04 Sep 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
26 Apr 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
24 Jun 2018
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The primary objective is to determine if treatment with very low dose dexamethasone facilitates the extubation of ventilator dependent preterm babies of less than 30 weeks' gestation who are at high risk of developing BPD.
The main outcome measure is the time from randomisation to first extubation, when the baby remains extubated for more than 24 hours.
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Protection of trial subjects |
Safety data was reviewed by the DMC which, if appropriate, make recommendations regarding continuation of the trial or modification of the trial protocol. The Trial Steering Committee (TSC) will have ultimate responsibility for deciding whether the trial should be stopped on safety grounds.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Aug 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 |
United Kingdom: 22
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Worldwide total number of subjects |
22
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EEA total number of subjects |
22
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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 |
22
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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) |
0
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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 |
The trial recruitment took place in 11 tertiary neonatal units across the United Kingdom. Recruitment stopped on the 14th April 2018 after 22 babies had been randomised to the trial over a period of 9 months. This was a decision made by the funder due to poor recruitment. | |||||||||
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Pre-assignment
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Screening details |
330 babies were screened and 44 were eligible for the trial. 22 babies were not enrolled for the following reasons: 9 due to clinician decision, 11 due to parent(s) declining consent and 2 for unknown reasons. | |||||||||
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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 |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||
Blinding implementation details |
Dexamethasone (Hospira, dexamethasone 3.3 mg/ml solution for injection) was supplied as a clear sterile solution at a concentration of 3.3 mg per 1 ml in 2 ml vials. Cartons containing 14 single-use vials were provided.
Placebo was supplied as a clear sterile solution of 0.9% saline solution for injection. Cartons identical to those for dexamethasone, each containing 14 identical single-use vials were provided.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Dexamethasone | |||||||||
Arm description |
very low dose dexamethasone (50 mcg/kg /day for 13 doses) | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Dexamethasone (Hospira, dexamethasone 3.3 mg/ml solution for injection)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Nasogastric use , Intravenous use, Oral use
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Dosage and administration details |
Doses of 50 mcg/kg (0.015 ml/kg of 3.3 mg/ml solution) of dexamethasone will be administered daily on days 1 to 10 after randomisation (10 doses) then alternate days on days 12, 14 and 16, making a total of 13 doses.
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Arm title
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Placebo | |||||||||
Arm description |
matched placebo | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use, Nasogastric use , Oral use
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Dosage and administration details |
Placebo will be supplied as a clear sterile solution of 0.9% saline solution for injection.
Cartons identical to those for dexamethasone, each containing 14 identical single-use vials will be provided. Volume of IMP to be withdrawn from the vial will be calculated following the calculations for dexamethasone dosing and then diluted with dextrose or normal saline for administration.
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Baseline characteristics reporting groups
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Reporting group title |
Dexamethasone
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Reporting group description |
very low dose dexamethasone (50 mcg/kg /day for 13 doses) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
matched placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Dexamethasone
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Reporting group description |
very low dose dexamethasone (50 mcg/kg /day for 13 doses) | ||
Reporting group title |
Placebo
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Reporting group description |
matched placebo | ||
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End point title |
Time to first extubation (if extubated for >24 hours) after first IMP dose [1] | |||||||||||||||
End point description |
Time to event analysis
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End point type |
Primary
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End point timeframe |
Up to 16 days post randomisation
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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: As the trial was stopped early, no comparative analysis was performed due to the small number of participants recruited. Only descriptive statistics are reported. |
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| Notes [2] - Subjects extubated for >24 hours by day 16 [3] - Subjects extubated >24 hours by day 16 |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Time to first extubation after first IMP dose | |||||||||||||||
End point description |
Time-to-event analysis
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End point type |
Secondary
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End point timeframe |
Up to 16 days post-randomisation
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| Notes [4] - Subjects extubated by day 16 [5] - Subjects extubated by day 16 |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Extubation by day 7 (if extubated for >24 hours) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Day 7 after first IMP dose
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| Notes [6] - Subjects not discontinued by Day 7 [7] - Subjects not discontinued by Day 7 |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Extubation by day 7 (whether or not for more than 24 hours) | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Day 7 after first IMP dose
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| Notes [8] - Subjects not discontinued by Day 7 [9] - Subjects not discontinued by Day 7 |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Alive at 36 weeks' PMA or discharge if sooner | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
36 weeks' PMA or discharge if sooner
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Total duration of invasive ventilation through ET | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
36 weeks' PMA or discharge if sooner
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Total duration of non-invasive respiratory support nasal CPAP, nasal ventilation or high flow oxygen therapy | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
36 weeks' PMA or discharge if sooner
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Total duration of supplemental oxygen | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
36 weeks' PMA or discharge if sooner
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Open-label treatment with corticosteroids received after randomisation (cumulative dose) | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
36 weeks' PMA or discharge if sooner
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Diuretics received for >48 hours after randomisation | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
36 weeks' PMA or discharge if sooner
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
BPD assessment at 36 weeks' PMA or discharge if sooner | |||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
At 36 weeks' PMA or discharge if sooner
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| No statistical analyses for this end point | ||||||||||||||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
Until 36 weeks post menstrual age
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
Not applicable | |||||||||||||||||||||||||||||||||
Dictionary version |
n/a
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Reporting groups
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Reporting group title |
Dexamethasone
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Reporting group description |
very low dose dexamethasone (50 mcg/kg /day for 13 doses) | |||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
matched placebo | |||||||||||||||||||||||||||||||||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Non-serious adverse events are not reported for this population. |
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| Frequency threshold for reporting non-serious adverse events: 2% | ||||||||||||||||||||||||||||||||||
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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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01 Sep 2016 |
[Protocol v2.0 15/08/2016]
Exclusion criteria edited for clarity: removal of the word ‘concurrent’ and ‘previous’ from exclusion criteria 1, 4 and 5.
Secondary objectives updated to clarify recording at 36 weeks +/- 2 weeks or at discharge home if earlier.
Typos/Removed ET abbreviation and replaced with ‘endotracheal tube’/Consistency of phrasing: ’36 weeks (or discharge home if sooner)’ (Across the protocol).
Clarification that ‘existing diuretic therapy’ is for the 24 hours prior to randomisation.
Error in criteria for stopping trial medications – ‘48’ hours changed to ‘72’ hours.
Clarification that the IMP can be administered orally as per the MHRA approved IMP labels (Section 5.5).
All IMP stock will be stored on the neonatal unit rather than having separate stocks at pharmacy and on the neonatal unit (Section 5.5).
Changed ‘Trial Solution Request Form’ to ‘Pack Allocation Form’ to reflect change in name of document.
Addition of liver failure, left ventricular hypertrophy and hydrocephalus to foreseeable adverse events as recommended by the Chief Investigator and Clinical Lead. Removal of chronic lung disease as a separate foreseeable adverse event as this is considered the same as bronchopulmonary dysplasia. Changed ‘focal’ to ‘gastro’ for consistency (Section 6.4).
Clarification of the process for reporting SAEs (Section 6.5).
Oxygen reduction test flow diagram updated (Appendix 2).
Signature section for the Chief Investigator and the Statistician have been removed. These signatures are now documented separately and stored in the Trial Master File (front page). |
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26 Oct 2017 |
[Protocol v4.0 04/10/2017]
Change of Trial Statistician to Louise Linsell.
‘Changes to the inflammatory cytokine profile’ now listed as an exploratory outcome rather than secondary outcome (as requested by the Sponsor’s GCP expert).
Addition of text to section 4.6 to provide further detail about the storage and analysis of blood and ET secretion microsamples (as requested by the Sponsor’s GCP expert).
Further clarity of the circumstances in which trial medications should be stopped.
Further clarity on the recording of open-label corticosteroids.
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12 Mar 2018 |
[Protocol v5.0 14/02/2018]
Correction of abbreviations.
Clarification of outcomes: time to first extubation after first IMP dose and extubation by day 7 (this refers to 7 completed days after first IMP dose).
Correction of typos and minor grammatical errors.
Increase in number of sites to ≤25.
Clarification of timing of completion of Diary of Care and cytokine sampling.
Addition of text regarding cytokine profiling, as requested by the laboratory team responsible for this aspect of the trial.
Removal of ‘continuation of a treatment course of antibiotic therapy beyond 72 hours duration’ for stopping trial medication.
Addition of text clarifying that study medication should be stopped if treatment is required which would be contra-indicated with use of steroids in the opinion of the treating clinical team
Clarification of censoring of babies and exclusions from analyses
Removal of ‘temporarily’ discontinued, as babies will only be permanently discontinued
Removal of text regarding adjustment of effect estimates and exploratory analysis
Change of risk ratios from 99 to 95% CI
Clarification that the ‘28 days’ for assessing BPD and suitability for an oxygen reduction test should be considered cumulative
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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. | |||
| None reported | |||
