| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diagnosis of growth hormone deficiency in pediatric subjects |
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| E.1.1.1 | Medical condition in easily understood language |
| Suspect of lacking growth hormone in children |
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| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To determine the diagnostic efficacy of macimorelin in diagnosing suspected growth hormone deficiency (GHD) in pediatric subjects assuming the outcome of GHD status adjudication by the external adjudication committee as the “true” GHD status. |
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| E.2.2 | Secondary objectives of the trial |
• To assess the agreement of the macimorelin growth hormone stimulation test (GHST) with the outcome of arginine and clonidine GHSTs used in the growth hormone deficiency (GHD) diagnosis in pediatric subjects with suspected GHD;
• To investigate the pharmacodynamics (PD) of macimorelin measured by growth hormone (GH) release and time of the peak concentration;
• To investigate the pharmacokinetics (PK) of macimorelin measured by macimorelin concentration;
• To investigate test-retest reliability;
• To investigate the safety and tolerability of macimorelin as a GHST.
• To investigate on the difference in time parents took off work for macimorelin GHST compared to the standard GHSTs
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects are eligible to be included in the trial only if all of the following criteria apply:
1. Informed consent of subject, parent(s) or legally acceptable representative (LAR) of subject and child assent, if appropriate, must be obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial.
2. Male and female pediatric subjects from 2 to less than 18 years of age at the time of signing informed consent.
3. Indication for the performance of growth hormone stimulation test.
4. Presence of a height measurement minimum 6 and maximum 18 months prior to screening.
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| E.4 | Principal exclusion criteria |
Subjects are excluded from the trial if any of the following criteria apply:
Lack of suitability for the trial:
1. Established diagnosis of a disease that is sufficient to explain growth deficiency or metabolic disorders that are also associated with short stature (e.g., Turner syndrome, skeletal dysplasia’s, celiac disease, etc.).
2. Ongoing growth hormone therapy.
3. Presence of hypothyroidism and/or adrenal insufficiency without adequate and stable replacement therapy treatment for at least 30 days prior to first GHST.
4. Treatment with drugs directly affecting the pituitary secretion of somatotropin (e.g., somatostatin analogues, clonidine, levodopa and dopamine agonists) or provoking the release of somatostatin (antimuscarinic agents e.g., atropine).
5. Medical history of ongoing clinically symptomatic psychiatric disorders.
6. 2nd or 3rd degree atrioventricular-block, prolongation of the QRS complex over 120 milliseconds, prolongation of the QTc interval over 450 milliseconds, or any
other clinically significant abnormal electrocardiogram results at the screening
ECG as judged by the investigator.
7. Previous participation in this trial. Participation is defined as signed informed consent.
8. Participation in any clinical trial of an approved or non-approved investigational medicinal product within 30 days before screening.
Safety concerns:
9. Known or suspected hypersensitivity to trial product(s) or related products;
10. Any disorder, which in the investigator’s opinion might jeopardize subject’s safety or compliance with the protocol.
11. Concomitant treatment with any drugs that might prolong QT/QTc
Note: A subject who receives such treatment will not be a candidate for this study, if his/her condition does not allow for a treatment-free period of at least 5 elimination half-lives of the drug that might prolong QT/QTc before the GHST;
12. Elevation of laboratory parameters indicating hepatic or renal dysfunction or damage (AST, ALT, GGT > 2.5 x ULN; creatinine or bilirubin > 1.5x ULN);
13. Current active malignancy other than non-melanoma skin cancer;
14. Female of child-bearing potential and not using an adequate contraceptive method (adequate contraceptive measures as required by local regulation or practice).
15. Male of reproductive age who or whose partner(s) is not using an adequate contraceptive method (adequate contraceptive measures as required by local regulation or practice).
Administrative reasons:
16. Lack of ability or willingness to give informed consent by the subject and/or his/her legal representative;
17. Anticipated non-availability for trial visits/procedures.
Amendment for Germany:
18. Prepubertal boys >11 years and in prepubertal girls >10 years who would need to undergo sex steroid priming before a GHST. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Area under the Receiver Operator Characteristic curve (ROC AUC) based on GH concentration during growth hormone stimulation test (GHST) following macimorelin administration.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Derived from Cmax GH measurements collected in the time frame from 0 to 90 minutes after initial macimorelin GHST (visit 2 (day 0)) and GH adjudication status performed by the adjudication committee after visit 4 (between day 11 and day 58)). |
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| E.5.2 | Secondary end point(s) |
CONFIRMATORY SECONDARY ENDPOINTS
• Sensitivity for the macimorelin GHST
• Specificity for the macimorelin GHST
• Overall agreement between the outcome of the macimorelin GHST and the combined outcome from the 2 standard GHSTs
SUPPORTIVE SECONDARY ENDPOINTS
• Overall agreement between the outcome of the macimorelin GHST and the outcome from each of the 2 standard GHSTs
• Negative predictive value (NPV) and positive predictive value (PPV) for the macimorelin GHST
• Positive agreement and negative agreement between the outcome of the macimorelin GHST and the 2 standard GHSTs
• Overall agreement between the outcome of the first macimorelin GHST and the second macimorelin GHST
PHARMACOKINETICS (PK)
Based on concentration-time profiles of macimorelin: Cmax, Tmax.
PHARMACODYNAMICS (PD)
Based on concentration-time profiles of GH: Cmax GH, Tmax GH.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Sensitivity and Specificity, NPV and PPV for macimorelin GHST: Cmax GH measurements collected in the time frame from 0 to 90 minutes after initial macimorelin GHST (visit 2 (day 0)) and GH adjudication status performed by the adjudication committee after visit 4 (between day 11 and day 58)).
Overall, Positive and Negative agreement between macimorelin GHST and the 2 standard GHSTs: Visit 4 (between day 11 and day 58)
Overall agreement between first and second macimorelin GHST: Visit 5 (between day 19 and day 87)
PK, PD: Cmax and Tmax from 0 to 90 min after a single dose of macimorelin exposure Visit 2 (day 0)
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Georgia |
| Russian Federation |
| Serbia |
| Ukraine |
| United States |
| Czechia |
| Germany |
| Italy |
| Poland |
| Romania |
| Slovenia |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| Last-Subject-Last-Visit (LSLV) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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