| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Growth hormone deficiency (GHD) in prepubertal children |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lack of growth hormone in the body |
|
| 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 |
|
| 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 and compare the annualized height velocity (HV) of prepubertal children with growth failure due to GHD treated with weekly TransCon hGH to that of a commercially available daily human growth hormone (hGH) formulation at 52 weeks. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety of weekly TransCon hGH administered over 52 weeks compared to daily hGH
• To evaluate and compare the annualized HV over 52 weeks of weekly TransCon hGH to daily hGH
• To evaluate and compare the change in height SDS over 52 weeks of weekly TransCon hGH to daily hGH
• To evaluate serum IGF-1 and IGFBP-3 and IGF-1 SDS and IGFBP-3 SDS; and the normalization of IGF-1 SDS over 52 weeks of weekly TransCon hGH or daily hGH
• To describe the pharmacokinetic/pharmacodynamic (PK/PD) profile of TransCon hGH, hGH, IGF-1, IGF-1 SDS, IGFBP-3, IGFBP-3 SDS and polyethylene glycol (PEG) administered as a weekly injection (PK/PD subset; TransCon hGH cohort only)
• To compare the maximum value of concentration (Cmax) for hGH of TransCon hGH to the anticipated Cmax of daily hGH
• To determine the incidence of anti-hGH antibodies for both treatments, and treatment emergent anti-PEG antibodies for TransCon hGH over 52 weeks |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Prepubertal children with GHD (either isolated or as part of a multiple pituitary hormone deficiency) in Tanner stage 1 aged:
• Boys: 3-12 years, inclusive
• Girls: 3-11 years, inclusive
2) Impaired HT defined as at least 2.0 standard deviations (SD) below the mean height for chronological age and sex
(HT SDS ≤-2.0) according to the 2000 CDC Growth Charts for the United States Methods and Development or, after approval by the Medical Expert, at least 1.5 SD below the mid-parental height
3) BMI within ±2.0 SD of the mean BMI for chronological age and sex according to 2000 CDC standards, or BMI within ±2.0 SD of the mean BMI for bone age and sex
4) Diagnosis of GHD confirmed by 2 different GH stimulation tests, defined as a peak GH level of ≤10 ng/mL, determined with a validated assay. One or 2 well documented historical tests (with properly recorded sampling times and results as well as documented euthyroid status of the subject) performed within approximately 6 months prior to Screening can be accepted to replace 1 or both GH stimulation tests. The highest GH level determines eligibility. For subjects with known panhypopituitarism (eg, subjects who are deficient in TSH and/or ACTH post cranial radiation or born with ≥ 2 pituitary hormone deficiencies in addition to GH), GH stimulation tests may not be required.
5) Bone age (BA) at least 6 months less than chronological age (X-ray may have been taken within approximately 6 months prior to Screening, the X-ray or digital image should be sent to the central reader).
6) Baseline IGF-1 level of at least 1.0 SD below the mean IGF-1 level standardized for age and sex (IGF-1 SDS ≤-1.0) according to the central laboratory reference values.
7) Normal fundoscopy at Screening (without signs/symptoms of intracranial hypertension).
8) Children with multiple hormonal deficiencies must be on stable replacement therapy (stable dose and normal blood hormone levels) for other hypothalamo-pituitary axes for approximately
3 months. Thyroid replacement therapy for thyroid hormone deficiency must be instituted approximately 6 months (and be stable for approximately 3 months) prior to Screening. Temporary adjustment of glucocorticoid replacement therapy, as appropriate, is acceptable.
9) Normal 46 XX karyotype for girls (results prior to Screening may be accepted).
10) Written, signed informed consent of the parent(s) or legal guardian(s) of the subject and written assent of the subject (if the subject is able to read, understand, and sign). |
|
| E.4 | Principal exclusion criteria |
1) Children with a body weight below 12 kg
2) Prior exposure to recombinant hGH or IGF-1 therapy
3) Children with past or present intracranial tumor growth as confirmed by a sellar MRI scan (with contrast dye recommended) at Screening (MRI results from up to approximately 6 months prior to Screening may be accepted)
4) Children born small for gestational age (SGA) (ie, birth weight ≤-2.0 SD for gestational age, with or without a birth length ≤-2.0 SD for gestational age)
5) Malnutrition, defined as:
• Serum albumin level below the lower limit of normal (LLN) according to the reference ranges of the central laboratory, and
• Serum iron below the LLN according to the reference ranges of the central laboratory, and
• body mass index (BMI) ≤-2.0 SD for age and sex
6) Children with psychosocial dwarfism
7) Children with idiopathic short stature
8) Other causes of short stature such as coeliac disease (confirmed by anti-transglutaminase antibodies test), hypothyroidism, or rickets
9) History or presence of malignant disease; any evidence of present tumor growth; children with GHD and clinically cured tumors may be eligible after consultation with the Medical Expert
10) Any clinically significant abnormality likely to affect growth or the ability to evaluate growth (eg, chronic diseases like renal insufficiency, spinal cord irradiation)
11) Subjects with poorly controlled diabetes mellitus (HbA1c ≥8.0%) or diabetic complications
12) Known chromosomal abnormalities and other named medical syndromes known to impact growth (eg, Turner syndrome, Laron syndrome, Noonan syndrome, Prader-Willi syndrome, Russell- Silver syndrome, SHOX mutations/deletions and skeletal dysplasias) with the exception of septo-optic dysplasia
13) Closed epiphyses
14) Tanner stage >1 (scant pubic hair alone does not exclude the subject)
15) Concomitant administration of other treatments that may have an effect on growth such as anabolic steroids with the exception of hormone replacement therapies (thyroxine, hydrocortisone, desmopressin)
16) Children requiring glucocorticoid therapy (eg, asthma) who are taking a dose of greater than 400 μg/d of inhaled budesonide or equivalents for longer than 1 month during a calendar year
(Note: Approximately equivalent doses: fluticasone: 264 μg/d; beclomethasone: 504 μg/d; flunisolide 1,000 μg/d; triamcinolone: 1,000 μg/d; mometasone: 211 μg/d; ciclesonide 264 μg/d)
17) Major medical conditions and/or presence of contraindication to hGH treatment
18) Known or suspected HIV-positive subject
19) Known hypersensitivity to the components of the study drug
20) The subject and/or the parent/legal guardian are likely to be non-compliant with respect to trial conduct
21) Participation in any other trial of an investigational agent within 3 months prior to Screening
22) Any other reason that in the opinion of the investigator would prevent the subject from completing participation or following the trial schedule |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy endpoints:
Primary efficacy endpoint: Annualized HV at 52 weeks for weekly TransCon hGH and daily hGH treatment groups
Safety endpoints:
• Incidence of AEs
• Local tolerability (assessed by the subject, the parents/legal guardians and the
investigator)
• Incidence of anti-hGH antibodies including neutralizing antibodies as needed (both cohorts) and incidence of treatment-emergent anti-PEG antibody formation (in TransCon hGH subjects)
• IGF-1 levels and IGF-1 SDS
• Parameters of glucose metabolism (fasting glucose and insulin level, HbA1c)
and lipid parameters
• Hormone levels: thyroid status and morning cortisol
• All other hematology and biochemistry blood parameters
• ECG
• Results of the physical examinations, vital sign measurements
• Bone age at 52 weeks |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
• Annualized HV for the TransCon hGH and the daily hGH treatment group over 52 weeks
• Change in HT SDS over 52 weeks for the TransCon hGH and the daily hGH treatment group
• Serum IGF-1 and IGFBP-3 levels and IGF-1 SDS and IGFBP-3 SDS; and normalization of IGF-1 SDS over 52 weeks for the TransCon hGH and the daily hGH treatment group
Pharmacokinetic and pharmacodynamic endpoints:
Subset of at least 8 TransCon hGH treated subjects after 13 weeks of treatment:
• PK profile of TransCon hGH over 1 week
• PK profile of hGH over 1 week
• PK profile of PEG over 1 week
• PD profile of IGF-1 and IGFBP-3 over 1 week
• PD profile of IGF-1 SDS and IGFBP-3 SDS over 1 week
• C max for hGH of TransCon hGH |
|
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Genotropin (somatropin [rDNA origin] Powder and Solvent for Solution for Injection |
|
| 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 | 25 |
| 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 |
| Armenia |
| Australia |
| Azerbaijan |
| Belarus |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Egypt |
| France |
| Georgia |
| Germany |
| Greece |
| Italy |
| Kazakhstan |
| Kyrgyzstan |
| Lebanon |
| Lithuania |
| New Zealand |
| Poland |
| Romania |
| Russian Federation |
| South Africa |
| Spain |
| Sweden |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
| Jordan |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
