E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pre-Pubertal Children with Idiopathic Growth Hormone Deficiency and with poor response after one year of treatment. |
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E.1.1.1 | Medical condition in easily understood language |
Young children with lack of Growth hormone and not responding well to Growth hormone treatment. |
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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 | 13.1 |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate a superior efficacy on height velocity (HV) of treatment with a combination of flexible rhIGF-1 dose and 0.035 mg/kg/day of rhGH, as compared to treatment with 0.035 mg/kg/day of rhGH only, after one year of treatment in pre-pubertal children with IGHD, showing a poor response to rhGH treatment during the first treatment year. |
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E.2.2 | Secondary objectives of the trial |
• To assess:
- effect on HV, delta height SDS, HV SDS of flexible rhIGF-1 dose and fixed rhGH dose combination therapy vs. fixed rhGH dose therapy
- safety of flexible rhIGF-1 dose and fixed rhGH dose combination vs. fixed rhGH dose therapy
- effect on serum concentrations of GH and IGF-1 and their binding proteins during flexible rhIGF-1 dose and fixed rhGH dose combination therapy vs. fixed rhGH dose therapy
- effect on serum concentrations of IGF-1 and GH, IGF-1 SDS before and 2 to 6 hours after IMP injection(s)
- effect on change of IGF-1 SDS
- effect on pubertal status
- change in bone age
• To identify prognostic factors of therapeutic response to flexible rhIGF-1 dose and fixed rhGH combination therapy, based on historical data (pre rhGH treatment and at study start), on GH stimulation tests, IGF-1, auxology and diagnosis
• To assess changes in fasting metabolic parameters
• To assess changes in anti-GH and anti-IGF-1 antibodies |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Treatment with rhGH at a minimum starting dose of 0.025 mg/kg/day (without dose reduction) to a maximum dose of 0.035 mg/kg/day for at least 12 months and a maximum of 18 months based on the diagnosis of IGHD with a pre-treatment GH stimulation test/spontaneous maximum of GH < 10µg/L
• First year of rhGH treatment resulting in height gain < 0.5 SDS
• Chronological age from 3 to 9 years inclusive for girls, from 3 to 10 years inclusive for boys
• Pre-pubertal: Tanner stage 1 (Girls: Tanner B1, Boys: Testis ≤ 3ml)
• Parent(s)/guardian(s) have provided written informed consent |
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E.4 | Principal exclusion criteria |
• Evidence (more than 20% rhGH injections missed) or suspicion of poor compliance during the first year of rhGH treatment
• Hypothalamic-pituitary tumours or malformations diagnosed or treated prior to screening
• Any history of cancer and/or evidence of any active malignancy or intracranial tumours
• Co-morbidity known to affect linear growth including, but not limited to, skeletal dysplasia
• Chronic illness including but not limited to diabetes, inborn errors of metabolism, osteochondrodystrophy, disorders of genitourinary, cardiopulmonary, gastrointestinal, or central nervous system
• Any named syndrome known to be associated with short stature but not limited to Prader-Willi syndrome, Russel Silver syndrome, etc.
• Neurological disease and mental disabilities that may interfere with compliance [Attention Deficit Hyperactivity Disorders (ADHD), autism, Asperger]
• Ongoing drug treatment known to alter growth, including but not limited to high dose glucocorticoids
• Multiple hormonal deficiencies except hypothyroidism if corrected and well controlled
• Clinically significant abnormal findings at previous fundoscopy or echocardiogram, that could be worsened by rhGH and/or rhIGF-1 administration
• Significant abnormality in clinical screening laboratories, as determined by the Investigator
• Syndromes that predispose the subject to cancer (e.g. Fanconi syndrome, Bloom syndrome, ataxia telangectasia)
• Active seizure disorders, defined as one or more seizures per month irrespective of anticonvulsant therapy
• Known allergy or hypersensitivity to any components of NutropinAq® (somatropin) or Increlex® (mecasermin)
• Acute critical illness due to complications following open heart or abdominal surgery, multiple accidental traumas or acute respiratory failure
• Any current or previous exposure to therapeutic spinal irradiation
• Prior bone marrow transplantation
• Evidence of clinical malnutrition or growth deficit attributable to emotional deprivation
• Participation in a clinical trial within the last 12 weeks
• Any social or medical condition that, in the opinion of the Investigator, would be detrimental to either the subject or the study |
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E.5 End points |
E.5.1 | Primary end point(s) |
Difference in mean HV between the two treatment groups after 1 year of treatment. A difference of ≥ 1.5 cm/year is considered to be clinically relevant. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline (Visit 2) to week 52 (Visit 8). |
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E.5.2 | Secondary end point(s) |
1) Difference in mean HV
2) Difference in delta height SDS
3) Difference in mean HV SDS
4) Change in serum concentration of GH, IGF-1 and IGFBP-3
5) Change in:
- serum concentration of IGF-1 and GH
- IGF-1 SDS
before and 2 to 6 hours after IMP injection(s).
6) Change in IGF-1 SDS
7) Change in serum concentration of Growth Hormone Binding Protein (GHBP) and ALS
8) Change in pubertal status
9) Change in bone age
10) Identification of prognostic factors of therapeutic response, based on historical data (pre rhGH treatment and at study start), on GH stimulation tests, IGF-1, auxology and diagnosis
11) Change in fasting metabolic parameters: Insulin, IGFBP-1, glycosylated haemoglobin and lipid profile over the course of treatment |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) from baseline to 26 and 39 weeks
2) after 13, 26, 39, and 52 weeks
3) from baseline to 26, 39, and 52 weeks
4) from baseline to 2, 4, 13, 26, 39, and 52 weeks
5) before and 2 to 6 hours after first dose administered at Day 1 (baseline visit), 2 weeks and 52 weeks.
6) from Day 1 (baseline visit) to 2, 4, 13, 26, 39, and 52 weeks (based on the 2 to 6 hours sampling result)
7) from Day 1 (baseline visit) to 52 weeks
8) from screening to Day 1 (baseline visit), 4, 13, 26, 39, and 52 weeks
9) from screening to 52 weeks
10) historical data
11) from baseline to 2 and 52 weeks |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
Prospective and multi-centre |
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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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 49 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |