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    Clinical Trial Results:
    Confirmatory validation of oral macimorelin as a Growth Hormone (GH) Stimulation Test (ST) for the diagnosis of Adult Growth Hormone Deficiency (AGHD) in comparison with the Insulin Tolerance Test (ITT)

    Summary
    EudraCT number
    2015-002337-22
    Trial protocol
    GB   AT   DE   PL   IT  
    Global end of trial date
    29 Nov 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Dec 2017
    First version publication date
    15 Dec 2017
    Other versions
    Summary report(s)
    AEZS-130-052 Synopsis to E3 Clinical Trial Report

    Trial information

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    Trial identification
    Sponsor protocol code
    AEZS-130-052
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02558829
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    IND number: 073196
    Sponsors
    Sponsor organisation name
    Aeterna Zentaris GmbH
    Sponsor organisation address
    Weismuellerstr. 50, Frankfurt am Main, Germany, 60314
    Public contact
    Clinical trial information desk, Aeterna Zentaris GmbH, +49 69426023472, clinical.trials@aezsinc.com
    Scientific contact
    Clinical trial information desk, Aeterna Zentaris GmbH, +49 69426023472, clinical.trials@aezsinc.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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
    18 Jan 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To validate the use of single dose oral macimorelin for the dagnosis of AGHD ('macimorelin GHST'), using the Insulin Tolerance Test (ITT) as comparator (non-reference standard) GHST.
    Protection of trial subjects
    The following was applied: selection of trial subjects according to in- and exclusion critieria as defined in the trial protocol; exclusion of subjects e.g., with conditions contraindicated for the conduct of an ITT. Monitoring of subjects by qualified trial site personnel during the conduct of both Growth Hormone Stimulation Tests (GHSTs). Collection of data related to concomitant medication, medical history, adverse events (AEs). Establishment of a Data Review Committee (DRC): the evaluation of “agreement” in the test outcome of investigational and comparator assay required that in a given subject both assays had been performed and that no critical deviations from the planned test procedure occurred in either assay. Also, the agreement either could not have been determined due to lack of data or would have been questionable with regard to data quality. Therefore, a Data Review Committee (DRC) reviewed the assay performance prior to availability of the data on the stimulated growth hormone levels and qualified a test as “evaluable” or “non-evaluable”.
    Background therapy
    Not applicable
    Evidence for comparator
    The Insulin Tolerance Test (ITT) is considered as a 'Gold Standard' for diagnosing AGHD
    Actual start date of recruitment
    15 Sep 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 49
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 21
    Country: Number of subjects enrolled
    Serbia: 21
    Country: Number of subjects enrolled
    United States: 37
    Country: Number of subjects enrolled
    Italy: 1
    Worldwide total number of subjects
    157
    EEA total number of subjects
    99
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    154
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study centers: 30 sites in 9 countries were initiated, i.e. 25 sites in Europe (Austria, Germany, Spain, France, Italy, Poland, Serbia, and UK) with 21 of them becoming active, and 5 sites in the USA. Study period: First subject randomized: 03-Dec-2015, Last subject completed: 29-Nov-2016

    Pre-assignment
    Screening details
    Screening occurred at D-28 to D-1 (D=Day). Screening procedures included written informed consent procedure, data on vital signs, ECG, clinical laboratory, physical examination, medical history (incl. review for known risk factors for AGHD), prior-/concomitant medication, check of eligibility criteria incl. pre-defined in-and exclusion criteria.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Blinding for growth hormone (GH) values: serum concentrations of GH for a given subject were provided by the central laboratory to the investigator only after the serum samples for both tests were available and appropriateness of the test performance had been adjudicated by a Data Review Committee (DRC). Adjudications were performed before release of the stimulated GH concentrations from the central laboratory to rule out potential bias if the GHST outcome was known at the time of DRC review.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    GHST Sequence A
    Arm description
    1st Macimorelin-GHST, 2nd Insulin Tolerance Test. Drug: Macimorelin macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose Other Names: Macimorelin-GHST (MAC) Drug: Insulin Insulin, 0.10 U/kg (0.15 U/kg if BMI > 30 kg/m2), intravenous injection, single dose Other Names: Insulin Tolerance Test (ITT)
    Arm type
    Experimental

    Investigational medicinal product name
    macimorelin
    Investigational medicinal product code
    AEZS-130
    Other name
    macimorelin Growth Hormone Stimulation Test (GHST), macimorelin GHST, MAC
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose

    Arm title
    GHST Sequence B
    Arm description
    1st Insulin Tolerance Test (ITT), 2nd Macimorelin-GHST (MAC) Drug: Macimorelin macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose Other Names: • Macimorelin-GHST (MAC) Drug: Insulin Insulin, 0.10 U/kg (0.15 U/kg if BMI > 30 kg/m2), intravenous injection, single dose Other Names: • Insulin Tolerance Test (ITT)
    Arm type
    Experimental

    Investigational medicinal product name
    insulin
    Investigational medicinal product code
    Other name
    Insulin Tolerance Test; ITT
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Insulin, 0.10 U/kg (0.15 U/kg if BMI > 30 kg/m2), intravenous injection, single dose. An additional insulin bolus of 0.05 U/kg was to be administered if glucose did not show a value of less than 2.2 mmol/L (40 mg/dL) AND symptomatic hypoglycemia (e.g., diaphoresis, confusion, sensation of warmth, weakness, or fatigue) had not been achieved within 45 minutes after the initial insulin dose.

    Number of subjects in period 1
    GHST Sequence A GHST Sequence B
    Started
    81
    76
    Completed
    74
    66
    Not completed
    7
    10
         Protocol deviation
    7
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    - Safety Population (SAF): included all subjects who received at least 1 dose of the study drug (N=157). - modified Intent-to-Treat (mITT) Population: is the primary analysis population and included all randomized subjects in whom both GHSTs of the cross-over were evaluable (N=140). Primary objective: to validate the use of single dose oral macimorelin for the diagnosis of AGHD (‘macimorelin GHST’), using the insulin tolerance test as comparator GHST. The sequential order of the GHSTs for the suspected AGHD subjects was determined by stratified randomization by Group; healthy control subjects (Group D) were tested in the same sequence as the matched Group A subjects. The macimorelin-GHST (‘MAC’) and the ITT of the core study were to be performed 7 days to 1 month apart. Serum concentrations of growth hormone were measured at pre-defined time points before and after GHST administration of macimorelin or insulin.

    Reporting group values
    Overall trial Total
    Number of subjects
    157 157
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    40.7 ± 13.1 -
    Gender categorical
    Units: Subjects
        Female
    64 64
        Male
    93 93
    BMI
    Body Mass Index
    Units: kg/m²
        arithmetic mean (standard deviation)
    28.0 ± 4.8 -
    Subject analysis sets

    Subject analysis set title
    Group A - SAF
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    High likelihood of growth hormone deficiency (GHD): •Structural hypothalamic or pituitary lesions and low insulin-like growth factor 1 (IGF-1), and/or •Three or more pituitary hormone deficiencies (PHD) and low IGF-1, or •Childhood onset GHD with structural lesions and low IGF-1.

    Subject analysis set title
    Group B - SAF
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Intermediate likelihood of GHD: • Eligible subjects not qualifying for either high or low likelihood (Group A/C)

    Subject analysis set title
    Group C -SAF
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Low likelihood of GHD: •One risk factor for GHD only, such as history of distant traumatic brain injury (TBI) or one PHD only with otherwise normal pituitary function or •Isolated idiopathic childhood onset GHD without additional pituitary deficits

    Subject analysis set title
    Group D - SAF
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Healthy control: Healthy subjects matching Group A subjects by sex, age, body mass index (BMI), and estrogen status (females only).

    Subject analysis set title
    Positive Agreement of MAC with ITT
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Percent positive agreement of MAC with ITT

    Subject analysis set title
    Negative agreement of MAC with ITT
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Percent negative agreement of MAC with ITT

    Subject analysis set title
    Sensitivity of MAC
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Group A and Group D subjects

    Subject analysis set title
    Specificity of MAC
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Group A and Group D subjects

    Subject analysis set title
    Positive Agreement MAC core and MAC repeatability
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Protocol Amendment 1: had been issued for selected sites in Europe to obtain exploratory data on the repeatability of the MAC in a subset of subjects that had completed the core study. Primary efficacy variable: comparison of peak GH levels following repeated treatments with macimorelin. MAC repeatability was evaluated for overall agreement only. Pre-defined MAC cut-off point GH: 2.8 ng/mL. Data presented: percent positive agreement of MAC core study with MAC repeatability extension.

    Subject analysis set title
    Negative Agreement MAC core and MAC repeatability
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Protocol Amendment 1: had been issued for selected sites in Europe to obtain exploratory data on the repeatability of the MAC in a subset of subjects that had completed the core study. Primary efficacy variable: comparison of peak GH levels following repeated treatments with macimorelin. MAC repeatability was evaluated for overall agreement only. Pre-defined MAC cut-off point GH: 2.8 ng/mL. Data presented: percent negative agreement of MAC core study with MAC repeatability extension.

    Subject analysis sets values
    Group A - SAF Group B - SAF Group C -SAF Group D - SAF Positive Agreement of MAC with ITT Negative agreement of MAC with ITT Sensitivity of MAC Specificity of MAC Positive Agreement MAC core and MAC repeatability Negative Agreement MAC core and MAC repeatability
    Number of subjects
    42
    42
    44
    29
    140
    140
    63
    63
    34
    34
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    42.3 ± 15.0
    45.8 ± 11.8
    34.9 ± 10.5
    40.0 ± 12.4
    ±
    ±
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    17
    24
    9
    14
        Male
    25
    18
    35
    15
    BMI
    Body Mass Index
    Units: kg/m²
        arithmetic mean (standard deviation)
    27.6 ± 4.6
    29.8 ± 4.5
    27.9 ± 5.7
    26.1 ± 3.2
    ±
    ±
    ±
    ±
    ±
    ±

    End points

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    End points reporting groups
    Reporting group title
    GHST Sequence A
    Reporting group description
    1st Macimorelin-GHST, 2nd Insulin Tolerance Test. Drug: Macimorelin macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose Other Names: Macimorelin-GHST (MAC) Drug: Insulin Insulin, 0.10 U/kg (0.15 U/kg if BMI > 30 kg/m2), intravenous injection, single dose Other Names: Insulin Tolerance Test (ITT)

    Reporting group title
    GHST Sequence B
    Reporting group description
    1st Insulin Tolerance Test (ITT), 2nd Macimorelin-GHST (MAC) Drug: Macimorelin macimorelin acetate, 0.5 mg/kg body weight, drinking solution, single dose Other Names: • Macimorelin-GHST (MAC) Drug: Insulin Insulin, 0.10 U/kg (0.15 U/kg if BMI > 30 kg/m2), intravenous injection, single dose Other Names: • Insulin Tolerance Test (ITT)

    Subject analysis set title
    Group A - SAF
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    High likelihood of growth hormone deficiency (GHD): •Structural hypothalamic or pituitary lesions and low insulin-like growth factor 1 (IGF-1), and/or •Three or more pituitary hormone deficiencies (PHD) and low IGF-1, or •Childhood onset GHD with structural lesions and low IGF-1.

    Subject analysis set title
    Group B - SAF
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Intermediate likelihood of GHD: • Eligible subjects not qualifying for either high or low likelihood (Group A/C)

    Subject analysis set title
    Group C -SAF
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Low likelihood of GHD: •One risk factor for GHD only, such as history of distant traumatic brain injury (TBI) or one PHD only with otherwise normal pituitary function or •Isolated idiopathic childhood onset GHD without additional pituitary deficits

    Subject analysis set title
    Group D - SAF
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Healthy control: Healthy subjects matching Group A subjects by sex, age, body mass index (BMI), and estrogen status (females only).

    Subject analysis set title
    Positive Agreement of MAC with ITT
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Percent positive agreement of MAC with ITT

    Subject analysis set title
    Negative agreement of MAC with ITT
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Percent negative agreement of MAC with ITT

    Subject analysis set title
    Sensitivity of MAC
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Group A and Group D subjects

    Subject analysis set title
    Specificity of MAC
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Group A and Group D subjects

    Subject analysis set title
    Positive Agreement MAC core and MAC repeatability
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Protocol Amendment 1: had been issued for selected sites in Europe to obtain exploratory data on the repeatability of the MAC in a subset of subjects that had completed the core study. Primary efficacy variable: comparison of peak GH levels following repeated treatments with macimorelin. MAC repeatability was evaluated for overall agreement only. Pre-defined MAC cut-off point GH: 2.8 ng/mL. Data presented: percent positive agreement of MAC core study with MAC repeatability extension.

    Subject analysis set title
    Negative Agreement MAC core and MAC repeatability
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Protocol Amendment 1: had been issued for selected sites in Europe to obtain exploratory data on the repeatability of the MAC in a subset of subjects that had completed the core study. Primary efficacy variable: comparison of peak GH levels following repeated treatments with macimorelin. MAC repeatability was evaluated for overall agreement only. Pre-defined MAC cut-off point GH: 2.8 ng/mL. Data presented: percent negative agreement of MAC core study with MAC repeatability extension.

    Primary: Percent Positive/ Percent Negative Agreement of Macimorelin-GHST (MAC) With ITT

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    End point title
    Percent Positive/ Percent Negative Agreement of Macimorelin-GHST (MAC) With ITT [1]
    End point description
    Percent positive agreement (upper limit for crossover interval between both GHSTs); percent negative agreement of Macimorelin-GHST (MAC) with ITT. Pre-defined cut-off point for the Macimorelin GHST (MAC): GH 2.8 ng/mL; cut-off point for the ITT: GH 5.1 mg/mL. Percent positive and negative agreement are defined as co-primary outcome measures. The probability for a "Negative Agreement" equals the sum of the probability of both tests being correct (negative test results for both tests for subjects with "true non-AGHD") and the probability of both tests being wrong (negative test results for both tests for subjects with "true AGHD").
    End point type
    Primary
    End point timeframe
    8-28 days (time frame between two GHSTs)
    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: A short statistical analysis description is provided in the End point definition. No statistical testing for a p-value was performed in this test validation study. Therefore, no p-value related information can be entered in the Statistical Analysis section - but without entering a value here, an error message occurs. Furthermore, the trial has a cross-over design: unfortunately, a wrong number of subjects is automatically calculated (280 instead of 140 subjects).
    End point values
    Positive Agreement of MAC with ITT Negative agreement of MAC with ITT
    Number of subjects analysed
    140 [2]
    140 [3]
    Units: percent
        number (confidence interval 95%)
    74.32 (62.84 to 83.78)
    93.94 (85.20 to 98.32)
    Notes
    [2] - modified Intention-to-Treat (mITT)
    [3] - modified Intention-to-Treat (mITT)
    No statistical analyses for this end point

    Secondary: Sensitivity and Specificity of the MAC, GH: 2.8 ng/mL

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    End point title
    Sensitivity and Specificity of the MAC, GH: 2.8 ng/mL
    End point description
    Exploratory evaluation of sensitivity and specificity of the MAC based on GH Peak Levels in Group A and Group D subjects.
    End point type
    Secondary
    End point timeframe
    90 minutes
    End point values
    Sensitivity of MAC Specificity of MAC
    Number of subjects analysed
    63 [4]
    63 [5]
    Units: percent
        number (not applicable)
    87
    96
    Notes
    [4] - Group A and Group D subjects
    [5] - Group A and Group D subjects
    No statistical analyses for this end point

    Other pre-specified: Overall Agreement MAC Core Study and MAC Repeatability Extension

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    End point title
    Overall Agreement MAC Core Study and MAC Repeatability Extension
    End point description
    Amendment no 1 (repeatability extension) had been issued for selected sites in Europe to obtain exploratory data on the repeatability of the MAC in a subset of subjects that had completed the core study. Primary efficacy variable: comparison of peak GH levels following repeated treatments with macimorelin. MAC repeatability was evaluated for overall agreement only. Pre-defined MAC cut-off point GH: 2.8 ng/mL.
    End point type
    Other pre-specified
    End point timeframe
    90 minutes
    End point values
    Positive Agreement MAC core and MAC repeatability Negative Agreement MAC core and MAC repeatability
    Number of subjects analysed
    34 [6]
    34 [7]
    Units: percent
        number (confidence interval 95%)
    88.89 (65.29 to 98.62)
    100.00 (79.41 to 100.00)
    Notes
    [6] - All subjects included in the mITT analysis who also participated in the repeatability extension.
    [7] - All subjects included in the mITT analysis who also participated in the repeatability extension.
    No statistical analyses for this end point

    Post-hoc: Agreement between MAC and ITT at MAC cut-off point 5.1 ng/mL

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    End point title
    Agreement between MAC and ITT at MAC cut-off point 5.1 ng/mL
    End point description
    After this study was found not to have met one of two co-primary endpoints of the confirmatory efficacy analyses, encouraging preliminary results from exploratory analysis suggesting superior performance of the MAC if evaluated at a higher GH cut-off point were discussed with the FDA. It was considered acceptable by the Agency, to include results from exploratory analyses supporting the validity of the MAC at a recommended GH cut-off point. The exploratory analyses applied the same methodology as used for the planned primary efficacy analyses (incl. agreement between MAC and ITT, estimated sensitivity and specificity for both GHSTs, explored in hierarchical testing). A value of 5.1 ng/mL was finally concluded to be the recommended optimal GH cut-off point for the MAC, with collection of blood samples for GH measurements 45 and 60 minutes after intake of the macimorelin test dose.
    End point type
    Post-hoc
    End point timeframe
    28 days
    End point values
    Positive Agreement of MAC with ITT Negative agreement of MAC with ITT
    Number of subjects analysed
    139 [8]
    139 [9]
    Units: percent
        number (confidence interval 95%)
    83.78 (73.39 to 91.33)
    90.77 (80.98 to 96.54)
    Notes
    [8] - Exclusion of data from one subject with suspected non-compliance or dosing error from the mITT.
    [9] - Exclusion of data from one subject with suspected non-compliance or dosing error from the mITT.
    No statistical analyses for this end point

    Post-hoc: Sensitivity and Specificity of the MAC, cut-off GH: 5.1 ng/mL

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    End point title
    Sensitivity and Specificity of the MAC, cut-off GH: 5.1 ng/mL
    End point description
    Within exploratory post-hoc analyses to determine an optimal GH cut-off point, the same values for sensitivity and specificity in the subset of Group A and Group D subjects were obtained for the recommended new GH cut-off point of 5.1 ng/mL as for the planned analyses at the value of 2.8 ng/mL.
    End point type
    Post-hoc
    End point timeframe
    90 minutes
    End point values
    Sensitivity of MAC Specificity of MAC
    Number of subjects analysed
    63 [10]
    63 [11]
    Units: percent
        number (not applicable)
    92
    96
    Notes
    [10] - Assuming Group A as 'true' AGHD subjects and Group D as 'true' AGHD negative subjects.
    [11] - Assuming Group A as 'true' AGHD subjects and Group D subjects as 'true' AGHD negative subjects.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the trial, i.e. over a period of ca. 15 months, the subjects were questioned and/or examined by the Investigators or his/her designee for evidence of adverse events. Per subject, the time frame for collection of such data was up to 70 days.
    Adverse event reporting additional description
    GHST emergent adverse events (TEAEs): various untoward effects were anticipated to be associated with the GHSTs. For the ITT, this included signs and symptoms associated with the hypoglycemia, which is prerequisite for an appropriate ITT performance. All untowards effects during or after a GHST were documented as an AE.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Macimorelin GHST (MAC) SAF population
    Reporting group description
    Macimorelin GHST (MAC): combined safety data from core study and repeatability extension (Amendment 1, European sites only)). All subjects with at least one macimorelin GHST performed: N=154 (subjects in the repeatability extension: N=34) All subjects valid for safety (SAF) analysis: N=157 (three subjects were exposed to the ITT only).

    Reporting group title
    ITT, SAF Population
    Reporting group description
    Insulin Tolerance Test (ITT) All subjects with at least one ITT performed: N=157 All subjects valid for safety (SAF) analysis: N=157

    Serious adverse events
    Macimorelin GHST (MAC) SAF population ITT, SAF Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 154 (0.65%)
    1 / 157 (0.64%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Upper limp fracture
    Additional description: The patient had underwent an ITT on July 5 and the macimorelin GHST on July 12, 2016. On July 13, the patient fell of a ladder accidentally and broke his left arm. Causality reported: unrelated to study treatment.
         subjects affected / exposed
    1 / 154 (0.65%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Macimorelin GHST (MAC) SAF population ITT, SAF Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 154 (25.32%)
    151 / 157 (96.18%)
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 154 (0.65%)
    17 / 157 (10.83%)
         occurrences all number
    1
    18
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 154 (3.90%)
    43 / 157 (27.39%)
         occurrences all number
    7
    48
    Dysgeusia
         subjects affected / exposed
    7 / 154 (4.55%)
    5 / 157 (3.18%)
         occurrences all number
    7
    7
    Headache
         subjects affected / exposed
    6 / 154 (3.90%)
    15 / 157 (9.55%)
         occurrences all number
    6
    16
    Somnolence
         subjects affected / exposed
    1 / 154 (0.65%)
    57 / 157 (36.31%)
         occurrences all number
    1
    62
    Tremor
         subjects affected / exposed
    1 / 154 (0.65%)
    25 / 157 (15.92%)
         occurrences all number
    1
    28
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 154 (3.90%)
    43 / 157 (27.39%)
         occurrences all number
    6
    49
    Hunger
         subjects affected / exposed
    5 / 154 (3.25%)
    46 / 157 (29.30%)
         occurrences all number
    5
    51
    Asthenia
         subjects affected / exposed
    1 / 154 (0.65%)
    30 / 157 (19.11%)
         occurrences all number
    1
    32
    Chills
         subjects affected / exposed
    1 / 154 (0.65%)
    9 / 157 (5.73%)
         occurrences all number
    1
    12
    Feeling cold
         subjects affected / exposed
    1 / 154 (0.65%)
    6 / 157 (3.82%)
         occurrences all number
    1
    6
    Feeling hot
         subjects affected / exposed
    2 / 154 (1.30%)
    44 / 157 (28.03%)
         occurrences all number
    2
    50
    Thirst
         subjects affected / exposed
    1 / 154 (0.65%)
    12 / 157 (7.64%)
         occurrences all number
    1
    13
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    5 / 154 (3.25%)
    21 / 157 (13.38%)
         occurrences all number
    5
    22
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    2 / 154 (1.30%)
    105 / 157 (66.88%)
         occurrences all number
    2
    120

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Sep 2015
    Amendment 1 - Repeatability Extension This amendment implements a suggestion from a Scientific Advice Procedure with EMA (Procedure No. EMEA/H/SA/FU1/2015/SME/III) on the planned Phase III Trial of macimorelin. In the Final Advice Letter (EMA/CHMP/SAWP/295316/2015, dated 21 May 2015), the Scientific Advice Working Party (SAWP) suggested to assess the reproducibility of the macimorelin GHST, and a “three-way cross-over with two repeat macimorelin tests and one ITT per participant” was suggested, leaving open the choice of other trial design option. The amendment describes the performance of a second macimorelin GHST in subjects that have completed the trial procedures according to the core protocol AEZS-130-052 (furtheron referred to as “core trial”) and was implemented at selected trial sites in Europe. A subset of 30 participants who have completed the core trial, 10 subjects each from Group A, B, and C (subjects with high, intermediate, and low AGHD likelihood, respectively) was planned to be retested with macimorelin. No healthy control subjects (Group D) were retested, as a sufficient number of “true test-negative” subjects was included in the retested Group B and C subjects to assess the repeatability of the macimorelin GHST in subjects without AGHD. The additional macimorelin GHST was performed at or after the End-of-trial visit of the core trial to minimize the impact of the amendment on the analysis and reporting of the core trial.
    18 Feb 2016
    Amendment 2 was implemented in a Protocol Version 2. The main reason for this Amendment 2 was a refinement of the rules for the inclusion of GHST results in the primary analysis and an extension in the scope of the Data Review Committee (DRC). Like the new task of verifying an investigator’s Group assignment of a trial subject, the adjudication of the GHST performance by the DRC had to be done before GH concentration data were available to prevent bias in the qualification of a GHST as “evaluable” or “not evaluable”. However, if potentially critical deviations in a GHST procedure would lead to the conservative adjudication of a GHST as “not evaluable”, subsequently available GH concentration data would re-qualify a GHST as “evaluable”. Under specific conditions, missing values would reasonably be imputed and also allow to re-qualify a GHST as “evaluable”, so that the repetition of that GHST would finally not be needed and justifiable. Additional changes related to clarifications of DRC-related procedures, IMP dosage, and three exclusion criteria, as well as the affiliation of the coordinating investigator. Amendment 2 was based on clinical trial protocol version 1.0 and CTP version 2.0 was applicable for all sites participating in the trial. Amendment 2 did not affect Amendment 1 (‘Exploratory evaluation of the repeatability of the macimorelin GHST’) that remained in place unchanged at all sites participating in that trial extension. For trial sites in France, Amendment 2 replaced the local amendment 1 (19-Nov-2015) which covered Change 4 of Amendment 2. For trial sites in Germany, Amendment 2 replaced a note to file (17-Dec-2015) which covered the clarification provided in Change 7 of Amendment 2.

    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 reported
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