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    Clinical Trial Results:
    A Phase 3 open-label study of Infacort® in neonates, infants and children less than 6 years of age with adrenal insufficiency.

    Summary
    EudraCT number
    		 2014-002265-30
    Trial protocol
    		 DE  
    Global end of trial date
    20 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Dec 2016
    First version publication date
    22 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Infacort003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Diurnal Limited
    Sponsor organisation address
    Cardiff Medicentre, Heath Park, Cardiff, United Kingdom, CF14 4UJ
    Public contact
    David English, Diurnal Limited, 44 2920682069, davidenglish@diurnal.co.uk
    Scientific contact
    David English, Diurnal Limited, 44 2920682069, davidenglish@diurnal.co.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001283-PIP01-12
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    20 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate significant absorption of hydrocortisone from the Infacort® preparation.
    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 trial. The parents/carers agreed to participation in the trial 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 1 night) 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/treating doctor. Children aged 3 to 6 years were informed about their involvement in the study in the presence of their parents/carers. Both the subject information and the subject consent forms were prepared in duplicate. One of each form was kept by the Investigator, and the other was given to the subject or their parents/carers. All information sheets and consent forms were provided in German, the country in which the study was conducted. Since only one dose of the subject’s usual IRHC was replaced with Infacort® and the dose used was the same as the IRHC dose the subject was receiving before the study, the risk of study participation was considered to be minimal. Children usually take their medication every 8 hours so the maximum sampling period up to 8 hours after the Infacort® dose would not delay the subject’s usual dosing pattern. Further risk minimisation was provided by treating older children (who are more robust and less prone to hypoglycaemia due to steroid deficiency) before the younger children, and proceeding to the younger children only after a satisfactory assessment of all safety data by the IDMC.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Mar 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Ethical reason, Regulatory reason, Scientific research
    Long term follow-up duration
    		 30 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    24
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    6
    Infants and toddlers (28 days-23 months)
    6
    Children (2-11 years)
    12
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 • 12 subjects aged ≥2 and <6 years were studied in Cohort 1. • 6 subjects ≥28 days and <2 years were studied in Cohort 2. • 6 subjects <28 days were studied in the third cohort. All subjects were recruited to a single centre site in Germany. Subjects could be recruited remotely, but needed to visit the site in order to participate.

    Pre-assignment
    Screening details
    		 A total of 24 subjects were studied in 3 cohorts (as agreed in the PIP): • 12 subjects aged ≥2 and <6 years were studied in Cohort 1. • 6 subjects ≥28 days and <2 years were studied in Cohort 2. • 6 subjects <28 days were studied in the third cohort.

    Period 1
    Period 1 title
    Cohort 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Arm title
    		 Subjects aged 2 - <6 years
    Arm description
    		 The study consisted of 3 consecutive parts. Cohort 1 included 12 subjects aged between 2 and <6 years. No safety concerns emerged after review of this cohort, so 6 subjects aged 28 days to <2 years were enrolled (Cohort 2). No safety concerns were raised after a review of accumulated data so 6 neonates aged from birth to <28 days were enrolled (Cohort 3). The decision to continue after each cohort was based on the recommendation of the IDMC.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Infacort
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Administration of Infacort® took place approximately 8 hours following the subject’s prior hydrocortisone dose. The subject had to fast for at least 2 hours (45 minutes for children below 1 year of age) before the dose and were asked not to eat until after the sampling at 60 minutes (30 minutes below 1 year of age). Details of meals (e.g. time of eating and content of meal) were recorded in the CRF. The Infacort® capsule was opened and the entire contents (i.e. drug granules) were administered either: 1. Directly onto the top, and towards the back of the child’s tongue, by the study nurse/Investigator and washed down immediately with fluid (water, breast milk, formula milk, juice). 2. Indirectly onto the top, and towards the back of the child’s tongue, by the study nurse/Investigator using a spoon and washed down immediately with fluid (water, breast milk, formula milk, juice). The time, dose, and any other details were recorded in the CRF.

    Number of subjects in period 1 [1]
    		Subjects aged 2 - <6 years
    Started
    12
    Completed
    12
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The study consisted of three consecutive cohorts. Cohort 1 included 12 subjects aged between 2 and < 6 years. As no safety concerns emerged, 6 subjects aged 28 days to <2 years were enrolled (Cohort 2). A review of accumulated data was then undertaken and again, no safety concerns emerged, so 6 neonates aged from birth to <28 days were enrolled (Cohort 3). The decision to continue after each cohort was based on the recommendation of an Independent Data Monitoring Committee.
    Period 2
    Period 2 title
    Cohort 2
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Arm title
    		 Subjects aged 28 days to <2 years
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Infacort
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Administration of Infacort® took place approximately 8 hours following the subject’s prior hydrocortisone dose. The subject had to fast for at least 2 hours (45 minutes for children below 1 year of age) before the dose and were asked not to eat until after the sampling at 60 minutes (30 minutes below 1 year of age). Details of meals (e.g. time of eating and content of meal) were recorded in the CRF. The Infacort® capsule was opened and the entire contents (i.e. drug granules) were administered either: 1. Directly onto the top, and towards the back of the child’s tongue, by the study nurse/Investigator and washed down immediately with fluid (water, breast milk, formula milk, juice). 2. Indirectly onto the top, and towards the back of the child’s tongue, by the study nurse/Investigator using a spoon and washed down immediately with fluid (water, breast milk, formula milk, juice). The time, dose, and any other details were recorded in the CRF.

    Number of subjects in period 2 [2]
    		Subjects aged 28 days to <2 years
    Started
    6
    Completed
    6
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The study consisted of three consecutive cohorts. Cohort 1 included 12 subjects aged between 2 and < 6 years. As no safety concerns emerged, 6 subjects aged 28 days to <2 years were enrolled (Cohort 2). A review of accumulated data was then undertaken and again, no safety concerns emerged, so 6 neonates aged from birth to <28 days were enrolled (Cohort 3). The decision to continue after each cohort was based on the recommendation of an Independent Data Monitoring Committee.
    Period 3
    Period 3 title
    Cohort 3
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Arm title
    		 Subjects aged <28 days
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Infacort
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Administration of Infacort® took place approximately 8 hours following the subject’s prior hydrocortisone dose. The subject had to fast for at least 2 hours (45 minutes for children below 1 year of age) before the dose and were asked not to eat until after the sampling at 60 minutes (30 minutes below 1 year of age). Details of meals (e.g. time of eating and content of meal) were recorded in the CRF. The Infacort® capsule was opened and the entire contents (i.e. drug granules) were administered either: 1. Directly onto the top, and towards the back of the child’s tongue, by the study nurse/Investigator and washed down immediately with fluid (water, breast milk, formula milk, juice). 2. Indirectly onto the top, and towards the back of the child’s tongue, by the study nurse/Investigator using a spoon and washed down immediately with fluid (water, breast milk, formula milk, juice). The time, dose, and any other details were recorded in the CRF.

    Number of subjects in period 3
    		Subjects aged <28 days
    Started
    6
    Completed
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Subjects aged 2 - <6 years
    Reporting group description
    		 The study consisted of 3 consecutive parts. Cohort 1 included 12 subjects aged between 2 and <6 years. No safety concerns emerged after review of this cohort, so 6 subjects aged 28 days to <2 years were enrolled (Cohort 2). No safety concerns were raised after a review of accumulated data so 6 neonates aged from birth to <28 days were enrolled (Cohort 3). The decision to continue after each cohort was based on the recommendation of the IDMC.

    Reporting group values
    		 Subjects aged 2 - <6 years Total
    Number of subjects
    		 12 12
    Age categorical
    Units: Subjects
        Children (2 to <6 years)
    		 12 12
    Gender categorical
    Units: Subjects
        Female
    		 5 5
        Male
    		 7 7

    End points

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    End points reporting groups
    Reporting group title
    Subjects aged 2 - <6 years
    Reporting group description
    		 The study consisted of 3 consecutive parts. Cohort 1 included 12 subjects aged between 2 and <6 years. No safety concerns emerged after review of this cohort, so 6 subjects aged 28 days to <2 years were enrolled (Cohort 2). No safety concerns were raised after a review of accumulated data so 6 neonates aged from birth to <28 days were enrolled (Cohort 3). The decision to continue after each cohort was based on the recommendation of the IDMC.
    Reporting group title
    Subjects aged 28 days to <2 years
    Reporting group description
    		 -
    Reporting group title
    Subjects aged <28 days
    Reporting group description
    		 -

    Primary: Maximum levels of serum cortisol concentration up to 240 minutes after intake of study drug as determined by the central laboratory.

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    End point title
    		 Maximum levels of serum cortisol concentration up to 240 minutes after intake of study drug as determined by the central laboratory.
    End point description
    The objective of this endpoint is to demonstrate significant absorption of hydrocortisone from the Infacort preparation.
    End point type
    Primary
    End point timeframe
    Up to 240 minutes post-administration with Infacort
    End point values
    		 Subjects aged 2 - <6 years Subjects aged 28 days to <2 years Subjects aged <28 days
    Number of subjects analysed
    12
    6
    6
    Units: P-value
        number (not applicable)
    0.0005
    0.0313
    0.0313
    Statistical analysis title
    		 Primary efficacy analysis
    Statistical analysis description
    At the maximum cortisol level (i.e. at Cmax) a statistically significant increase was seen in cortisol levels compared to baseline for all cohorts combined (p<0.0001). Thus the primary endpoint of the study was met. A statistically significant difference compared to baseline was seen in Cohort 1 (p=0.0005), but for Cohorts 2 and 3, although all subjects showed an increase in cortisol, the difference from baseline was not statistically significant (p=0.0313 at the 1% level).
    Comparison groups
    Subjects aged 28 days to <2 years v Subjects aged <28 days v Subjects aged 2 - <6 years
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.0001
    Method
    		 Sign test
    Confidence interval

    Secondary: Serum cortisol concentration up to 6 hours after intake of study drug as determined by the central laboratory

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    End point title
    		 Serum cortisol concentration up to 6 hours after intake of study drug as determined by the central laboratory
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 6 hours post-administration of Infacort
    End point values
    		 Subjects aged 2 - <6 years Subjects aged 28 days to <2 years Subjects aged <28 days
    Number of subjects analysed
    12
    4
    5
    Units: P-value
        number (not applicable)
    0.00001
    0.4654
    0.0905
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were recorded from the time of first intake of Infacort® until Visit 4.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    All subjects
    Reporting group description
    		 All 24 subjects were included within the AE reporting group for the study (Also referred to as the "safety population")

    Serious adverse events
    		 All subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 24 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 24 (33.33%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Vomiting
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Possetting (infantile spitting up)
    Additional description: Considered to be a form of reflux rather than vomiting, hence coding separately.
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Hyperhidrosis
    Additional description: Excessive sweating
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Aug 2015
    The protocol was amended to allow the following changes: • Collection of full date of birth. Changes in important parameters that affect disposition of molecules such as hydrocortisone are age-related. These parameters most importantly include absorption, volume of distribution & clearance. As an example, paracetomol (acetaminophen) clearance (L/hr) increases from 2.02 L/hr at 1 month of age to 4.09 L/hr at 1 year of age and to 14.27 L/hr at 16 years of age (Krasniak et al., 2014). Therefore, collection of year of birth only in subjects is insufficient to enable accurate interpretation of results. Section 13 of the Parent Information Sheet has been amended accordingly. Originally, the protocol allowed for full date of birth in Section 8.4 but was inconsistent with respect to Section 15.8. The informed consent form however did not allow for collection of the full date of birth. • Change to the method of Investigational Medicinal Product (IMP) administration. In Cohort 1 the Investigator administered the IMP in accordance with parent/carer preference and usual clinical practice. The amended protocol now reflects the actual methods of IMP administration adopted during Cohort 1. • Change to the storage temperature of serum blood samples. The change to the storage temperature of serum blood samples is necessary to reflect freezer availability in the study site sample processing facility. • Provision for direct blood sampling if cannulation is not considered suitable by the Investigator. In the younger subjects (Cohorts 2 & 3) it might not be appropriate to insert a cannula due to the small size of the subject’s veins. In this event a small needle will be used for direct venous blood sampling. This will result in a maximum of 2 venous punctures at each timepoint.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None.
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