E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Children with Idiopathic Short Stature (ISS) at puberty onset. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10040600 |
E.1.2 | Term | Short stature |
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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 |
The primary objective of this study is:
To test the hypothesis that combined treatment with 0.05 mg/kg/day of somatropin (0.35 mg/kg/week) until adult height is reached and 11.25 mg of leuprorelin every three months for three years (or for a minimum two years and up to a chronological age of 13 years for girls and 15 years for boys, whichever occurs first) in pubertal children with idiopathic short stature results in a greater adult height, expressed in standard deviation score (SDS), than treatment with 0.05 mg/kg/day of somatropin alone (0.35 mg/kg/week) until adult height is reached.
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are :
-To compare the annual height velocity, height SDS and gain in height velocity and height SDS between the two groups
-To compare the difference between adult height SDS and target height SDS between the two groups.
-To compare the difference between adult height SDS and baseline predicted height SDS between the two groups.
-To compare the difference between adult height SDS and baseline height SDS between the two groups.
-To compare the proportion of children with normal adult height SDS between the two groups.
-To compare the annual progression of bone age between the two groups.
-To compare the safety profiles between the two study groups.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Male or female children with ISS defined as height ≤ –2.5 SDS for age and gender (according to national references) or predicted adult height ≤ –2.5 SDS at study entry based on the Bayley-Pinneau method, with a bone age reading by the central reader.
2.A chronological age ≥ 8 years and < 12 years and 3 months for girls (before the 12th birthday), and ≥ 9 years and < 14 years and 3 months for boys.
3.A bone age ≤ 12.0 years for girls and ≤ 14.0 years for boys based on a central reading of an X-ray of the left hand and wrist taken at the screening visit (V0).
4.Pubertal stage B2 and B3 for girls based on the Tanner method, as determined by clinical examination at the screening visit (V0).
5.Pubertal stage G2 and G3 for boys based on the Tanner method or a testicular length ≥ 30 mm and < 40 mm or a testicular volume ≥ 4 ml and < 12 ml, as determined by clinical examination at the screening visit (V0).
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E.4 | Principal exclusion criteria |
1.Growth hormone deficiency (GHD) based on two GH stimulation tests performed in the 3 years before the screening visit resulting in both GH values ≤ 20 mIU/L (depending on the conversion factor, usually: 10 ng/ml). Note: one stimulation test with a GH peak value > 20 mIU/L (depending on the conversion factor, usually: 10 ng/ml) is sufficient to eliminate a GHD.
2.Chromosomal abnormality diagnosed locally on a karyotype. For girls, the karyotype, to eliminate a Turner syndrome, is mandatory.
3.Small for gestational age (SGA): defined as length and/or weight at birth < –2 SDS versus normal gestational age height and weight measurements (Usher and McLean standards). Patients will not be excluded due to an unknown birth weight or length.
4.Has reached menarche (had her first menstrual period).
7.Have been currently or previously treated with any drug that may directly influence growth, such as somatropin, growth hormone releasing hormone or GnRH agonists, anabolic steroids, or aromatase inhibitors. This includes the previous completion or withdrawal from this study or any other study investigating any of these treatments.
8.Have any significant concomitant disease that is likely to interfere with growth or with the study, or is a known contraindication to GH treatment (malignancy, intra-cranial tumor, chronic disease such as insulin-dependent diabetes mellitus, chronic infectious disease, chronic renal insufficiency, chronic heart failure, chronic hepatic disease, chronic pulmonary disease, active rheumatological disease, psychosis, neurofibromatosis, McCune Albright syndrome, dysmorphic syndromes such as Russell-Silver syndrome, Leri-Weill syndrome, achondroplasia, etc.) Hypothyroidism correctly substituted with thyroid hormone replacement treatment is not an exclusion criterion.
9.Have any known contraindication to GnRHa treatment (known hypersensitivity to GnRH, to GnRH agonists or to one of its ingredients) or presents genital bleeding of undetermined cause.
10.Receiving systemic or inhaled glucocorticoid therapy (more than ten days of treatment during the past three months) or receiving any other drug that is likely to directly interfere with growth (see classes of prohibited drugs in the appendix of protocol). A hypothyroidism correctly substituted with thyroid hormone replacement treatment is not an exclusion criterion.
11.Presenting with a lumbar spine BMD < –2 SDS (Z-score) assessed by DXA carried out at the screening visit and centrally assessed.
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E.5 End points |
E.5.1 | Primary end point(s) |
Gain in adult height SDS at last visit in patients with combined treatment (Humatrope and Enantone) compared to treatment with Humatrope alone. |
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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 | Yes |
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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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 |
Somatropin+ leuprorelin versus somatropin alone |
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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 | 31 |
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 | Information not present in EudraCT |
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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It is provided in the protocol: visit when adult height is achieved. |
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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 | 8 |
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 | 8 |