E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diagnosis of Adult Growth Hormone Deficiency (AGHD) |
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E.1.1.1 | Medical condition in easily understood language |
Diagnosis of lacking growth hormone in adults |
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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 | No |
E.2 Objective of the trial |
E.2.1 | 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. |
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E.2.2 | Secondary objectives of the trial |
To characterize the safety profile of single dose oral macimorelin in suspected AGHD subjects |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female, aged between 18 and 65 years.
2. Suspected growth hormone deficiency (GHD), based on either of the following:
- structural hypothalamic or pituitary disease, or
- surgery or irradiation in these areas, or
- head trauma as an adult, or
- evidence of other pituitary hormone deficiencies, or
- idiopathic childhood onset GHD (without known hypothalamic or pituitary lesion or injury).
OR (recruitment at dedicated trial sites only)
3. Group D: Healthy* control
Subject matching a Group A subject by
- sex, age (+/- 5 years), BMI (+/- 2 kg/m2), and estrogen status** (women only);
* ‘healthy’ comprising:
- history of normal growth and development,
- serum prolactin concentration within normal range limits,
- history of regular, age-appropriate menses in females
- serum testosterone concentration within normal range limits for males.
** matching for ‘estrogen status’:
- Group A subjects below 50 years and on oral estrogen therapy will be matched to control subjects who are also taking estrogen (as an oral contraceptive or for replacement); the route of estrogen administration (e.g. oral vs transdermal) must also be matched.
- Group A subjects 50 years or older and with untreated estrogen deficiency will be matched to female control subjects who are not receiving estrogen. |
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E.4 | Principal exclusion criteria |
Lack of suitability for the trial:
1. GH therapy within 1 month prior to anticipated first GHST within this trial (within 3 months in case of long-acting GH formulation).
Note: A patient with ongoing GH therapy will not be a candidate for this trial, if a corresponding treatment-free interval is not medically justifiable.
2. GHST within 7 days prior to the anticipated first test day within the trial.
3. Subjects with a medical history and clinical signs of a not adequately
treated thyroid dysfunction or subjects who had a change in thyroid therapy within 30 days prior to anticipated first test day within the trial.
4. Untreated hypogonadism or not on a stable substitution treatment within 30 days prior to anticipated first test day within the trial.
Note: Postmenopausal status will not be considered as an exclusion.
5. 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 (atropine).
6. Concomitant use of a CYP3A4 inducer (e.g., carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's Wort).
7. Medical history of ongoing clinically symptomatic severe psychiatric disorders.
8. Parkinson’s disease.
9. Cushing disease or patients on supraphysiologic glucocorticoid therapy within 30 days prior to the anticipated first test day within the trial.
10. Type 1 diabetes or untreated or poorly controlled Type 2 diabetes, as defined by HbA1c > 8%.
11. Body mass index (BMI) ≥ 40.0 kg/m2.
12. Participation in a trial with any investigational drug within 30 days prior to trial entry.
13. Vigorous physical exercise within 24 hours prior to each GHST within this trial.
Safety concerns:
14. Known hypersensitivity to macimorelin or insulin, or any of the constituents of either preparation.
15. Clinically significant cardiovascular or cerebrovascular disease.
16. Prolonged ECG QT interval, defined as QTc > 500 msec.
17. Concomitant treatment with any drugs that might prolong QT/QTc (see list of drugs at http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm (registration required), a copy of which is included in the Investigator’s File).
Note: A patient who receives such treatment will not be a candidate for this trial, 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.
18. Elevation of laboratory parameters indicating hepatic or renal dysfunction or damage (ASAT, ALAT , GGT > 2.5 x ULN; creatinine, or bilirubin > 1.5x ULN).
19. Medical history of seizure disorders.
20. Known immunosuppression.
21. Current active malignancy other than non-melanoma skin cancer.
22. Breastfeeding or positive urine pregnancy test (for women of childbearing potential only).
23. Women of childbearing age without contraception, such as hormonal contraception or use of condom and spermicides or use of diaphragm and spermicides or Intra Uterine Device (IUD).
Administrative reasons:
24. Lack of ability or willingness to give informed consent.
25. Anticipated non-availability for trial visits/procedures. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Co-Primary efficacy variables will be 'Percent Negative Agreement' and 'Percent Positive Agreement' when using predefined cut-points of both GHSTs. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation of the Primary endpoints will be performed at two timepoints (i.e. during two separate visits per Growth Hormone Stimulation Test): For Test 1 on Day 1, for Test 2 on D8-28 (i.e. on one day within a time period from Day8 to Day28) |
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E.5.2 | Secondary end point(s) |
Secondary efficacy criteria will be 'Percent Overall Agreement' and estimated sensitivity and specificity of both GHSTs when using predefined cut-points of both GHSTs.
Safety:
Adverse events, clinical laboratory and 12-lead ECG.
Other:
Test acceptance/Preference by Trial subjects and investigators.
Preliminary PK: Tmax and Cmax of macimorelin Plasma concentrations in the sampling period.
Preliminary PK/PD: Tmax for macimorelin vs Tmax for GH; Cmax for macimorelin vs Cmax for GH. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluation of the secondary endpoints will be:
- efficacy related at two timepoints (i.e. during two separate visits per Growth Hormone Stimulation Test), as mentioned in Section E.5.1.1: For Test 1 on Day 1, for Test 2 on D8-28 (i.e. on one day within a time period from Day8 to Day28)
- safety related at four timepoints, i.e. at all four visits of this Trial (Screening visit, Test 1, Test 2, End-of-Trial visit) |
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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 | No |
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 | Yes |
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 | 24 |
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 |
Austria |
France |
Germany |
Italy |
Poland |
Serbia |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
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 | 1 |