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    Summary
    EudraCT Number:2016-001145-11
    Sponsor's Protocol Code Number:TransCon_hGH_CT-301
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-01-10
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2016-001145-11
    A.3Full title of the trial
    A multicenter, Phase 3, randomized, open-label, active-controlled, parallel-group trial investigating the safety, tolerability, and efficacy of TransCon hGH administered once a week versus standard daily hGH replacement therapy over 52 weeks in prepubertal children with growth hormone deficiency (GHD)
    Sperimentazione di fase III multicentrica, randomizzata, in aperto, con controllo attivo e a gruppi paralleli volta a valutare la sicurezza, la tollerabilità e l’efficacia di TransCon hGH somministrato una volta alla settimana rispetto alla terapia di sostituzione standard con hGH somministrata una volta al giorno nell’arco di 52 settimane in bambini in età prepuberale con deficit dell'ormone della crescita (GHD)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A trial of TransCon hGH, a sustained-release recombinant human growth hormone product, for treatment of Growth Hormone Deficiency in prepubertal children
    Sperimentazione di TransCon hGH, ormone ricombinante della crescita umano a rilascio sostenuto, per il trattamento del deficit dell'ormone della crescita in bambini in età prepuberale
    A.4.1Sponsor's protocol code numberTransCon_hGH_CT-301
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAscendis Pharma Endocrinology Division A/S
    B.1.3.4CountryDenmark
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAscendis Pharma Endocrinology Division A/S
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAscendis Pharma A/S
    B.5.2Functional name of contact pointClinical Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressTuborg Boulevard 5
    B.5.3.2Town/ cityHellerup
    B.5.3.3Post code2900
    B.5.3.4CountryDenmark
    B.5.4Telephone number+4570 22 22 44
    B.5.6E-mailclinhelpdesk@ascendispharma.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTransCon hGH CT-301 (ACP-011) - 12,1mg
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTransCon hGH (ACP-011)
    D.3.9.2Current sponsor codeTransCon hGH (ACP-011)
    D.3.9.3Other descriptive nameTransiently PEGylated hGH prodrug
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12.1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name GENOTROPIN 12 mg powder and solvent for solution for injection.
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameGENOTROPIN 12 mg powder and solvent for solution for injection.
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSomatropin
    D.3.9.1CAS number 12629-01-5
    D.3.9.3Other descriptive namerecombinant DNA-derived human growth hormone
    D.3.9.4EV Substance CodeSUB20678
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name GENOTROPIN 12 mg powder and solvent for solution for injection.
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited
    D.2.1.2Country which granted the Marketing AuthorisationAustria
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameGENOTROPIN 12 mg powder and solvent for solution for injection.
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSomatropin
    D.3.9.1CAS number 12629-01-5
    D.3.9.3Other descriptive namerecombinant DNA-derived human growth hormone
    D.3.9.4EV Substance CodeSUB20678
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name GENOTROPIN 12 mg powder and solvent for solution for injection.
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited
    D.2.1.2Country which granted the Marketing AuthorisationLithuania
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameGENOTROPIN 12 mg powder and solvent for solution for injection.
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSomatropin
    D.3.9.1CAS number 12629-01-5
    D.3.9.3Other descriptive namerecombinant DNA-derived human growth hormone
    D.3.9.4EV Substance CodeSUB20678
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSterile Water for Injection
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSterile Water
    D.3.9.3Other descriptive nameSTERILISED WATER FOR INJECTIONS
    D.3.9.4EV Substance CodeSUB33365
    D.3.10 Strength
    D.3.10.1Concentration unit % percent
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Growth hormone deficiency (GHD) in prepubertal children
    Deficit dell'ormone della crescita (GHD), in bambini in età prepuberale
    E.1.1.1Medical condition in easily understood language
    Lack of growth hormone in the body
    Mancanza dell'ormone della crescita nel corpo
    E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level PT
    E.1.2Classification code 10056438
    E.1.2Term Growth hormone deficiency
    E.1.2System Organ Class 10014698 - Endocrine disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate and compare the annualized height velocity of prepubertal children with growth failure due to GHD treated with weekly TransCon hGH to that of a commercially available daily hGH formulation at 52 weeks.
    Valutare e comparare la velocità di crescita staturale annua dei bambini in età prepuberale con disturbi dell'accrescimento dovuti al deficit di GH curati settimanalmente con TransCon hGH, rispetto al gruppo curato con la formulazione di hGH disponibile in commercio a somministrazione giornaliera, a 52 settimane.
    E.2.2Secondary objectives of the trial
    Secondary:
    • To evaluate the safety of weekly TransCon hGH administered over 52 weeks compared to daily hGH
    • To evaluate and compare the annualized height velocity 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 the change in serum IGF-1 and IGFBP-3 and the change in 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 PK/PD profile of TransCon hGH, hGH, IGF-1, IGF-1 SDS, IGFBP-3, IGFBP-3 SDS and PEG administered as a weekly injection (PK/PD subset; TransCon hGH cohort only)
    • To compare the Cmax for hGH of TransCon hGH to the anticipated Cmax of daily hGH
    • To determine the incidence of anti-hGH antibodies for both treatments, andtreatment emergent anti-PEG antibodies for TransCon hGH over 52 weeks
    Valutare:
    •sicurezza TransCon hGH somministrato settiman per 52settimane rispetto hGH somminist giornalm
    •e confrontare velocità crescita staturale annua nelle 52settimane di somministraz settimanale di TransCon hGH rispetto a quella giornaliera di hGH
    •e confrontare variazione deviazione standard(DS) della crescita staturale nelle 52settimane di trattamento a somministraz settimanale di TransCon hGH rispetto a hGH giornaliero
    •variazione siero IGF-1 e IGFBP-3 e DS di IGF-1 e IGFBP-3, e normalizzaz DS di IGF-1 nelle 52settimane di somministraz settimanale di TransCon hGH e di hGH giornaliero
    •Descrivere il profilo PK/PD di TransCon hGH, hGH, IGF-1, la DS di IGF-1, IGFBP-3, la DS IGFBP-3 e il PEG somministr con iniezione settiman (sottopopolazione PK/PD; solo coorte TransCon hGH)
    •Confronto Cmax hGH di TransCon hGH con quella attesa di hGH giornaliera
    •Determinare incidenza anticorpi anti-hGH per i 2 trattamenti, e anticorpi anti-PEG trattamento per TransCon hGH nelle 52settimane
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Prepubertal children with GHD (either isolated or as part of a multiple pituitary hormone deficiency) in Tanner stage 1 aged:
    o Boys: 3-12 years, inclusive
    o Girls: 3-11 years, inclusive
    2) Impaired height (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
    3) BMI within ±2.0 SD of the mean BMI for chronological age and sex according to 2000 CDC standards
    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 6 months prior to Screening can be accepted to replace 1 or both GH stimulation tests. The highest GH level determines eligibility.
    5) Bone age (BA) at least 6 months less than chronological age (X-ray may have been taken within 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 at least 3 months. Thyroid replacement therapy for thyroid hormone deficiency must be instituted at least 6 months (and be stable for at least 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).
    1. Bambini in età prepuberale con GHD (isolato o parte di Deficit ormonale ipofisario multiplo) allo stadio 1 di Tanner, età:
    o Maschi: 3-12 anni, inclusi
    o Femmine: 3-11 anni, inclusi
    2. Deficit dell'altezza assoluta (HT) definita con una deviazione standard (DS) minima di 2.0 sotto l'altezza media per età cronologica e sesso (HT DS ≤-2,0) in base al "2000 CDC Growth Charts for the United States Methods and Development"
    3. BMI entro ± 2,0 SD della media BMI per età cronologica e sesso, secondo gli standard CDC 2000
    4. Diagnosi di GHD confermata da 2 differenti test di stimolazione del GH, definita da un picco del livello del GH ≤10 ng/mL, determinato con un test validato. Per sostituire 1 o entrambi i test di stimolazione del GH, potranno essere accettati uno o 2 esami precedenti ben documentati (con tempi di campionamento propriamente registrati e risultati dello stato tiroideo del soggetto ben documentati) effettuati nei 6 mesi precedenti lo screening. L'ammissibilità è data dal livello più alto di GH.
    5. Età ossea (BA) di almeno 6 mesi inferiore all'età cronologica (la radiografia potrà essere stata effettuata nei 6 mesi precedenti lo screening; la radiografia o l'immagine digitale deve essere inviata al lettore centrale).
    6. Livello baseline IGF-1 con una DS di almeno 1.0 al di sotto del livello medio IGF-1 standardizzato per età e sesso (IGF-1 SDS ≤-1.0) in base ai valori di riferimento del laboratorio centrale.
    7. Fundoscopia normale allo Screening (senza segni/sintomi di ipertensione endocranica).
    8. I bambini con carenze ormonali multiple devono seguire una terapia sostitutiva stabile (dose stabile e livelli di ormoni nel sangue nella norma) per gli altri assi ipotalamo- ipofisi, per almeno 3 mesi. La terapia sostitutiva per la carenza di ormone della tiroide deve essere cominciata almeno 6 mesi prima dello screening (e rimanere stabile per almeno 3 mesi). Se la terapia temporanea di sostituzione dei glucocorticoidi è adeguata, è accettabile.
    9. Cariotipo 46 XX normale per le ragazze (si accettano risultati precedenti allo screening).
    10. Consenso informato scritto e firmato dal/dai genitore/i o dal/dai tutore/i legale/i del soggetto e assenso scritto del soggetto (se il soggetto è in grado di leggere, comprendere e firmare).
    E.4Principal 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 6 months prior to Screening may be accepted)
    4) Children born small for gestational age (SGA) (ie, birth weight and/or birth length) ≤-2.0 SD for gestational age
    5) Malnutrition, defined as:
    o Serum albumin level below the lower limit of normal (LLN) according to the reference ranges of the central laboratory, and
    o Serum iron below the lower limit of normal (LLN) according to the reference ranges of the central laboratory, and
    o 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
    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 (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
    1) Bambini con un peso corporeo inferiore a 12 kg
    2) Precedente esposizione ad hGH ricombinante o a terapie con IGF-1
    3) Bambini con passata o presente crescita tumorale endocranica confermata da una risonanza magnetica della regione sellare (consigliato un mezzo di contrasto) al momento dello screening (si accettano risultati della MRI effettuata nei 6 mesi precedenti allo screening)
    4) Bambini nati piccoli per l'età gestazionale (SGA) (cioè, peso alla nascita e/o lunghezza alla nascita) ≤-2.0 SD per l'età gestazionale
    5) Malnutrizione, definita come:
    o Livello di albumina sierica al di sotto del limite inferiore della norma (LLN) secondo i valori di riferimento del laboratorio centrale, e
    o Ferro sierico al di sotto del limite inferiore della norma (LLN) secondo i valori di riferimento del laboratorio centrale, e
    o BMI ≤-2.0 SD per età e sesso
    6) Bambini con nanismo psicosociale
    7) I bambini con bassa statura idiopatica
    8) Altre cause di bassa statura come la celiachia (confermata dal test degli anticorpi ¬antitransglutaminasi), ipotiroidismo o rachitismo
    9) Storia o presenza di malattia maligna; qualsiasi evidenza di crescita di un tumore presente
    10) Qualsiasi anomalia clinicamente significativa che potrebbe influenzare la crescita o la possibilità di valutarla (per esempio malattie croniche come l'insufficienza renale o irradiazione del midollo spinale)
    11) Soggetti con diabete mellito scarsamente controllato (HbA1c> 8,0%) o complicazioni dovute al diabete
    12) Anomalie cromosomiche note e altre sindromi mediche note (ad esempio, sindrome di Turner, sindrome di Laron, sindrome di Noonan, sindrome di Prader-Willi, sindrome di Russell-Silver, mutazioni del gene SHOX/delezioni o displasie scheletriche), fatta eccezione per la displasia setto-ottica
    13) Chiusura delle epifisi
    14) Tanner stadio> 1 (la sola scarsità di peli pubici non escluderà il soggetto dallo studio)
    15) La somministrazione concomitante di altri trattamenti che possono avere un effetto sulla crescita, come gli steroidi anabolizzanti, ad eccezione di terapie di sostituzione ormonale (tiroxina, idrocortisone, desmopressina)
    16) Bambini che necessitano di terapia con glucocorticoidi (ad esempio, per l'asma), che assumono una dose superiore a 400 μg/d di budesonide per via inalatoria o equivalenti per più di 1 mese nel corso di un anno solare (Nota: Dosi approssimativamente equivalenti: fluticasone: 264 μg/die; beclometasone: 504 μg/die; flunisolide 1,000 μg/die; Triamcinolone: 1.000 μg/die; mometasone: 211 μg/die; ciclesonide 264 μg/die)
    17) Condizioni mediche gravi e/o presenza di controindicazioni al trattamento con hGH
    18) Nota o sospetta positività del soggetto all'HIV
    19) Ipersensibilità nota ai componenti del farmaco oggetto di studio
    20) Se è probabile che il soggetto e/o il genitore/ il tutore legale non rispetterà la condotta della sperimentazione
    21) La partecipazione a qualsiasi altra sperimentazione di un agente sperimentale nei 3 mesi precedenti allo screening
    22) Qualsiasi altra ragione che, a giudizio dello Sperimentatore, impedirebbe al soggetto di completare la partecipazione o di seguire il programma della sperimentazione
    E.5 End points
    E.5.1Primary 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

    Endpoint di efficacia:
    Endpoint di efficacia primario: Velocità di crescita staturale annua, a 52 settimane, con TransCon hGH settimanale e gruppi in trattamento con hGH quotidiano

    Endpoint di sicurezza:
    • Incidenza degli EA
    • Tollerabilità locale (valutata dal soggetto, dai genitori/tutori legali e dallo sperimentatore)
    • Incidenza di anticorpi anti-hGH, inclusi gli anticorpi neutralizzanti se necessario (per entrambe le coorti), e incidenza della formazione dell'anticorpo anti-PEG emergente dal trattamento (nei soggetti TransCon hGH)
    • Livelli di IGF-1 e DS di IGF-1
    • Parametri del metabolismo del glucosio (glicemia a digiuno e livello di insulina, HbA1c) e parametri lipidici
    • Livelli di ormone: stato della tiroide e cortisolo alla mattina
    • Tutti gli altri parametri ematologici e biochimici del sangue
    • ECG
    • Risultati degli esami fisici, misurazioni dei segni vitali
    • Età ossea a 52 settimane
    E.5.1.1Timepoint(s) of evaluation of this end point
    52 weeks
    52 settimane
    E.5.2Secondary 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
    • Change in serum IGF-1 and IGFBP-3 levels and change in 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
    • Cmax for hGH of TransCon hGH
    Endpoint di efficacia secondari:
    • Velocità di crescita staturale annua per il gruppo in trattamento con TransCon hGH e hGH giornaliero, nel corso di 52 settimane
    • Variazione nella DS della velocità di crescita staturale nel corso di 52 settimane per il gruppo in trattamento con TransCon hGH e giornaliero con hGH
    • Variazione dei livelli di siero IGF-1 e IGFBP-3 e cambiamento della DS di IGF-1 e della DS di IGFBP-3; normalizzazione della DS di IGF-1 nel corso di 52 settimane nel gruppo in trattamento con TransCon hGH e per il gruppo con trattamento giornaliero di hGH


    Endpoint farmacocinetico e farmacodinamico:
    Sottopopolazione di almeno 8 soggetti trattati con TransCon hGH dopo 13 settimane di trattamento:
    • Profilo PK di TransCon hGH nel corso di 1 settimana
    • Profilo PK di hGH nel corso di 1 settimana
    • Profilo PK di PEG nel corso di 1 settimana
    • Profilo PD di IGF-1 e IGFBP-3 nel corso di 1 settimana
    • Profilo PD di IGF-1 DS e DS di IGFBP-3 nel corso di 1 settimana
    • Cmax hGH di TransCon hGH
    E.5.2.1Timepoint(s) of evaluation of this end point
    52 weeks
    52 settimane
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Genotropin (somatropina [origine rDNA] Polvere e solvente per iniezione
    Genotropin (somatropin [rDNA origin] Powder and Solvent for Solution for Injection
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    Jordan
    Kazakhstan
    Kyrgyzstan
    Lebanon
    Lithuania
    New Zealand
    Poland
    Romania
    Russian Federation
    South Africa
    Spain
    Sweden
    Turkey
    Ukraine
    United Kingdom
    United States
    E.8.7Trial 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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 150
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 135
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 15
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patients are between 3-12 years old and therefore not able to give legal consent. Parents or legal guardian will sign the informed consent. Children will sign as well in case they are able to read, understand and sign.
    Soggetti tra 3-12 anni e pertanto non in grado dare consenso legale. I genitori o un rappresentante legale firmerà il modulo del consenso informato. Lo stesso faranno i bambini in grado di leggere, capire e firmare.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 150
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    All subjects who successfully complete this 52 week trial are invited to participate in an
    extension trial, for whom Visit 6 represents the first visit for the extension trial. This extension
    trial is to assess long-term safety and efficacy. Subjects on Genotropin treatment (Cohort 2) will
    switch over to TransCon hGH treatment.
    I soggetti saranno invitati a partecipare all'estensione della sperimentazione dopo il completamento del periodo iniziale di trattamento di 52 settimane. Lo scopo del periodo di estensione è quello di valutare la sicurezza e l'efficacia a lungo termine. I soggetti in trattamento con Genotropin (Coorte 2) saranno passati a trattamento con TransCon hGH per l'estensione dello studio.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-04-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-02-08
    P. End of Trial
    P.End of Trial StatusOngoing
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