| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult Growth Hormone Deficiency (AGHD) |
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| E.1.1.1 | Medical condition in easily understood language |
| Lack of growth hormone in the body |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10056438 |
| E.1.2 | Term | Growth hormone deficiency |
| E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
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| 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 evaluate the efficacy of once-weekly lonapegsomatropin compared to placebo at 38 weeks in adults with growth hormone deficiency (GHD). |
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| E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety and tolerability of once-weekly lonapegsomatropin in adults with GHD.
2. To evaluate the pharmacokinetics (PK) of once-weekly lonapegsomatropin in adults with GHD.
3. To evaluate the pharmacodynamics (PD) of once-weekly lonapegsomatropin in adults with GHD. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age between 23 and 80 years, inclusive, at screening.
2. AGHD Diagnosis Criteria
For adult-onset AGHD: documented history of structural hypothalamic-pituitary disease, hypothalamic-pituitary surgery, cranial irradiation, 1-4 non-GH pituitary hormone deficiencies, a proven genetic cause of GHD, or traumatic brain injury (TBI).
Subjects with childhood-onset GHD must have had GH axis re assessed at final height.
In subjects with TBI as a cause of GHD, GHD must be confirmed by GH stimulation testing performed at least 12 months after the injury.
For all subjects, documentation of test results must be available before randomization. Stimulation test protocols and results are subject to review and approval by the Medical Monitor.
A. For all countries except Japan: Subjects must satisfy at least one of the following criteria:
a. Insulin tolerance test: peak GH ≤5 ng/mL
b. Glucagon stimulation test according to body mass index (BMI)
i. BMI ≤30 kg/m2: peak GH ≤3 ng/mL
ii. BMI >30 kg/m2: peak GH ≤1 ng/mL
c. Three or four pituitary axis deficiencies (ie, adrenal, thyroid, gonadal, and/or vasopressin; not including GH) with IGF-1 SDS ≤ -2.0 at screening as measured by central laboratory,
d. Macimorelin test: peak GH ≤2.8 ng/mL
e. Growth hormone-releasing hormone (GHRH) + arginine test according to BMI:
i. BMI <25 kg/m2, peak GH <11 ng/mL
ii. BMI ≥25–≤30 kg/m2, peak GH <8 ng/mL
iii. BMI >30 kg/m2, peak GH <4 ng/mL
B. For Japan only: Subjects with GHD and deficiency of at least one non-GH pituitary hormone need to satisfy one of the following GH stimulation tests. Subjects with GHD and without additional non-GH pituitary hormone deficiency with or without evidence of intracranial structure disorder need to satisfy at least 2 of the following stimulation tests:
a. Insulin tolerance test: peak GH ≤1.8 ng/mL
b. Glucagon test: peak GH ≤1.8 ng/mL
c. Growth Hormone-Releasing Peptide-2 (GHRP-2) tolerance test: peak GH ≤9 ng/mL
3. IGF-1 SDS ≤ -1.0 at screening as measured by central laboratory.
4. hGH treatment-naïve or no exposure to hGH therapy or GH secretagogue for at least 12 months prior to screening.
5. For subjects on hormone replacement therapies for any hormone deficiencies other than GH (eg, adrenal, thyroid, estrogen, testosterone) must be on adequate and stable doses for ≥6 weeks prior to and throughout screening.
6. For subjects not on glucocorticoid replacement therapy, documentation of adequate adrenal function at screening defined as: morning (6:00-10:00AM) serum cortisol >15.0 microg/dL (measured at central laboratory) and/or Adrenocorticotrophic Hormone (ACTH) stimulation test or ITT with serum cortisol >18.0 microg/dL at or within 90 days prior to screening.
7. For males not on testosterone replacement therapy: morning (6:00 10:00AM) total testosterone within normal limits for age as measured by the central laboratory at screening.
8. On a stable diet and exercise regime at screening with no intention to modify diet or exercise pattern during the trial, ie, no weight reduction program intended during the trial or within the last 90 days prior to or through screening.
9. No plans to undergo bariatric surgery during the trial.
10. Fundoscopy at screening without signs/symptoms of intracranial hypertension or diabetic retinopathy stage 2 / moderate or above or any other retinal disease contraindicated to growth hormone therapy. For subjects with a diagnosis of diabetes mellitus at screening, this must be documented with a fundus photograph.
11. Able and willing to provide a written Informed Consent Form (ICF) and authorization for protected health information (PHI) disclosure in accordance with Good Clinical Practice (GCP)
12. Serum fT4 in the normal range at screening as measured by central laboratory.
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| E.4 | Principal exclusion criteria |
1. Known Prader-Willi Syndrome and/or other genetic diseases that may have an impact on an endpoint
2. Diabetes mellitus at screening if any of the following criteria are met:
a. Poorly controlled diabetes, defined as HbA1c >7.5% at screening according to central laboratory
b. Diabetes mellitus (defined as HbA1c ≥6.5% and/or fasting plasma glucose ≥126 mg/dL and/or plasma glucose ≥200 mg/dL two hours after oral glucose tolerance test) diagnosed <26 weeks prior to screening
c. Change in diabetes regimen (includes dose adjustment) within <90 days prior and throughout screening
d. Use of any diabetes drugs other than metformin and/or DPP 4 inhibitors for a cumulative duration of greater than 4 weeks within 12 months prior to screening
e. Diabetes-related complications at screening (ie, nephropathy as judged by the investigator, neuropathy requiring pharmacological treatment, retinopathy stage 2 / moderate and above within 90 days prior to screening or during screening)
3. Active malignant disease or history of malignancy. Exceptions to this exclusion criterion:
a. Resection of in situ carcinoma of the cervix uteri
b. Complete eradication of squamous cell or basal cell carcinoma of the skin
c. Subjects with GHD attributed to treatment of intracranial malignant tumors or leukemia, provided that a recurrence-free survival period of at least 5 years prior to screening is documented in the subject’s file based on a Magnetic Resonance Imaging (MRI) result for intracranial malignant tumors
4. Evidence of growth of pituitary adenoma or other benign intracranial tumor within the last 12 months before screening.
5. Subjects with acromegaly without remission / with documented remission less than 24 months prior to screening.
6. Subjects with Cushing’s disease without remission / with documented remission less than 24 months prior to screening.
7. Subjects with prior cranial irradiation or hypothalamic-pituitary surgery: the procedure took place less than 12 months prior to screening.
8. Any disease or condition that, in the judgement of the investigator, may make the subject unlikely to comply with the requirements of the trial or any condition that presents undue risk from the investigational product or procedures.
9. Participation in another interventional clinical trial involving an investigational compound within 26 weeks prior to screening or in parallel to this trial. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in trunk percent fat (as assessed by dual-energy x ray absorptiometry [DXA]) at Week 38. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Change from baseline in trunk fat mass at Week 38 (as assessed by DXA).
• Change from baseline in total body lean mass at Week 38 (as assessed by DXA).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| 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 |
| Australia |
| Canada |
| Israel |
| Japan |
| New Zealand |
| United States |
| France |
| Poland |
| Bulgaria |
| Netherlands |
| Romania |
| Spain |
| Germany |
| Greece |
| Italy |
| Armenia |
| Belarus |
| Denmark |
| Georgia |
| Russian Federation |
| Slovakia |
| Turkey |
| Ukraine |
| United Kingdom |
| Serbia |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 22 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 24 |
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