A clinical study in paediatric patients with growth hormone deficiency to assess safety, tolerability, and efficacy of GX-H9

• Register: EUCTR
• Last refreshed on: 22 May 2017
• Main ID: EUCTR2015-001939-21-CZ
• Date of registration: 10/07/2015
• Prospective Registration: Yes
• Primary sponsor: Genexine, Inc.
• Public title: A clinical study in paediatric patients with growth hormone deficiency to assess safety, tolerability, and efficacy of GX-H9
• Scientific title: A phase 2, randomized, open-label, active controlled, dose finding study of the long-acting hybrid Fc fused recombinant human growth hormone (GX-H9) in paediatric patients with growth hormone deficiency
• Date of first enrolment: 14/10/2015
• Target sample size: 48
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-001939-21
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: yes Other specify the comparator: Genotropin Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belarus, Czech Republic, Egypt, Estonia, Greece, Hungary, Latvia, Lebanon, Lithuania, Poland, Romania, Russian Federation, Serbia, Slovakia, Spain, Tunisia, Turkey, Ukraine

Contacts

• Name: Clinical Trials Info
• Affiliation: Accelsiors CRO and Consultancy Services Ltd.

• Name: Clinical Trials Info
• Affiliation: Accelsiors CRO and Consultancy Services Ltd.

Key inclusion & exclusion criteria

Inclusion criteria:
1.Pre-pubertal children with either isolated GHD, or GH insufficiency as part of multiple pituitary hormone insufficiency, idiopathic or organic GH insufficiency (e.g., due to pituitary tumor, pituitary or brain surgery):
•Boys: 3 years = boy’s age = 11 years
•Girls: 3 years = girl’s age = 10 years
2.GHD confirmed by 2 different GH provocation tests with peak GH concentration below 10 ng/mL as described in consensus guidelines. Well documented historical GH provocation tests can be used for study eligibility providing that the tests are performed as defined in Appendix 2 (e.g. the same sampling time points). Data of each historical GH stimulation test will be reviewed by Medical Monitor and Sponsor in order to assess acceptance for the study;
3.Without prior exposure to any rhGH therapy;
4.Bone age (BA) is not older than chronological age and should not be greater than 9 years for girls and 10 years for boys;
5.Impaired height and height velocity defined as:
•Height (HT) of at least 2.0 standard deviations (SD) below the mean height for chronological age (CA) and gender according to the standards from Prader et. al 1989, (HT SDS = -2.0)
•Annualized height velocity (HV) of at least 1 SD below the mean HV for chronological age and gender according to the standards of Prader et al (1989). The interval between two height measurements should be at least 6 months (but not longer than 18 months) before inclusion.
6.All subjects must have at least one cranial imaging study [magnetic resonance imaging (MRI) or computed tomography (CT)] prior to randomization:
•To exclude intracranial causes of GHD in subjects without history of pituitary tumor [obtained within 6 months prior to informed consent signing, or
•Subjects with a previously treated pituitary tumor must have no tumor progression for at least the past year [obtained within 3 months prior to informed consent signing, compared with a previous MRI or CT performed at least 12 months earlier].
•If not performed within these specified time frames prior to informed consent signing, may be performed as a part of the screening procedures.
7.Body mass Index (BMI) must be within ±2 SD of mean BMI for the chronological age and sex according to the 2000 CDC standards;
8.Baseline IGF-1 level of at least 1 SD below the mean IGF-1 level standardized for age and sex (IGF-1 SDS= -1.0) according to the central laboratory reference values. One IGF-1 retest is allowed during the Screening period if first results were not higher than -0.85 SDS and if GH stimulation tests results and auxology parameters met eligibility criteria;
9.Children with normal fundoscopy (ophthalmoscopy) at screening (without signs/symptoms of intracranial hypertension as assessed by fundoscopy);
10.Children with multiple hormonal deficiencies must be on stable replacement therapies for other hypothalamo-pituitary-organ axes for at least 3 months and 6 months for thyroid replacement therapy prior to Screening. Temporary adjustment of glucocorticoid replacement therapy, as appropriate, is acceptable;
11.Normal 46 XX karyotype for girls;
12.Written informed consent of the parent or legal guardian of the subject and assent of the subject (if the subject can read);
13.Parent or legal guardian who is capable and willing to administer the study drug.
Are the trial subjects under 18? yes
Number of subjects for this age range: 48
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderl
Exclusion criteria:
1.History of radiation therapy or chemotherapy;
2.Malnourished children defined as:
•Serum albumin below the lower limit of normal (LLN) according to the reference ranges of central laboratory; and
•Serum iron below the lower limit of normal (LLN) according to the reference ranges of central laboratory; and
•BMI<-2 SD for age and sex;
3.Children with psychosocial dwarfism;
4.Children born small for gestational age (SGA-birth weight and/or birth length < -2 SD for gestational age according to the standards from Niklasson et al., 1991);
5.Presence of anti-hGH antibodies at screening;
6.Any clinically significant abnormality likely to affect growth or the ability to evaluate growth, such as, but not limited to, chronic diseases like renal insufficiency, spinal cord irradiation, etc.;
7.Subjects with diabetes mellitus;
8.Subjects with impaired fasting sugar (based on WHO; fasting blood sugar > 110mg/dl or 6.1 mmol/l) after repeated blood analysis;
9.Chromosomal abnormalities and medical syndromes (Turner’s syndrome, Laron syndrome, Noonan syndrome, Prader-Willi syndrome, Russell-Silver Syndrome, SHOX mutations/deletions and skeletal dysplasias), with the exception of septo-optic dysplasia;
10.Evidence of closed epiphyses;
11.Concomitant administration of other treatments that may have an effect on growth such as anabolic steroids and methylphenidate for attention deficit hyperactivity disorder (ADHD), with the exception of hormone replacement therapies [thyroxine, hydrocortisone, desmopressin (DDAVP)];
12.Children requiring glucocorticoid therapy, other than treated for hypothalamo-pituitary–adrenal insufficiency in replacement doses 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 (e.g. asthma);
13.Major medical conditions and/or presence of contraindication to rhGH treatment;
14.Has a history of positive serology results to HIV, HBV and/or HCV;
15.Subject who has a known or suspected hypersensitivity to rhGH;
16.Other causes of short stature such as coeliac disease, hypothyroidism and rickets;
17.The subject and/or the parent/legal guardian are likely to be non-compliant in respect to study conduct;
18.Subject who has received an investigational product, or has participated in a clinical study within 60 days before screening.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Hormonal diseases [C19]

Growth Hormone Deficiency (GHD) in pre-pubertal children
MedDRA version: 18.0 Level: PT Classification code 10056438 Term: Growth hormone deficiency System Organ Class: 10014698 - Endocrine disorders

Intervention(s)

Product Name: GX-H9
Pharmaceutical Form: Solution for injection
INN or Proposed INN: none
Current Sponsor code: GX-H9
Other descriptive name: hGH-hyFc, recombinant human growth hormone
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 30-

Trade Name: Genotropin®
Product Name: Genotropin®
Pharmaceutical Form: Powder and solvent for solution for injection
INN or Proposed INN: SOMATROPIN
CAS Number: 12629-01-5
Other descriptive name: recombinant DNA-derived human growth hormone
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 12-

Primary Outcome(s)

Main Objective: •To compare the safety, efficacy and tolerability of two weekly and one semi-monthly GX-H9 treatments to that of a commercially available standard daily recombinant human growth hormone (rhGH) formulation in pre-pubertal children with growth failure due to insufficient secretion of endogenous growth hormone.
•To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) profiles of 3 different doses of GX-H9 in pre-pubertal growth hormone deficient (GHD) children.
•To select the optimal dose(s) of GX-H9 for the subsequent phase 3 study on the basis of safety and efficacy.
•To evaluate immunogenicity of GX-H9.

Timepoint(s) of evaluation of this end point: Primary timepoints:
•Annual Height Velocity in SDS/year at 6 months
For PK/PD Endpoints:
After single and after the repeated doses (the steady state)
Safety timepoints:
Incidence of AEs: Screening (SCR), Single dose period (SDP), V1 to V10
anti-GX-H9 antibody formation: SDP, V1, V4, V5, V7, V8, V9, V10
Local injection site assessment: SDP, V1, to V9
IGF-1 level outside (above + 2 SDS): SCR, SDP, V1 to V9
Parameters of glucose metabolism
blood glucose, fasting insulin level:SCR,SDP, V1 to V9
HbA1c: SCR, V1, V3, V5, V6, V7, V8, V9
Thyroid status: SCR, V1, V3, V4, V5, V6, V7, V9
Lipid parameters: SCR, V1, V4 to V9
Cortisol levels: SCR, V9
All other hematology & biochemical parameters: SCR, SDP, V1, V4 to V9
Physical examination: SCR, V1 to V10
Vital signs: SCR, SDP, V1 to V10

Primary end point(s): EFFICACY ENDPOINTS
Primary Endpoint
•Annual Height Velocity in SDS/year at 6 months

SAFETY ENDPOINTS
•Incidence of adverse events;
•Incidence of anti-GX-H9 antibody formation (including characterization of the antibodies and neutralizing properties);
•Local injection site assessment;
•IGF-I levels outside (above) plus 2 SDS;
•Parameters of glucose metabolism: blood glucose, fasting insulin level, HbA1C;
•Thyroid status;
•Lipid parameters;
•Cortisol levels;
•All other hematology and biochemical parameters;
•Physical examination;
•Vital signs.

PK/PD ENDPOINTS
After single and after the repeated doses (the steady state)
•AUC,
•Cmax,
•Ctrough,
•Tmax,
•T1/2

Secondary Objective: Not applicable

Secondary Outcome(s)

Secondary end point(s): Secondary Endpoints (Auxology/Clinical/Biochemical)
•Height velocity at 3 and 12 months expressed in SDS;
•Change in height SDS at 3, 6 and 12 months (compared to Baseline value);
•Annualized height velocity at 3, 6 and 12 months expressed in cm/year;
•Change in height at 3, 6 and 12 months expressed in cm;
•Change in absolute IGF-I levels through visits;
•Change in IGF-I SDS through visits.

Other exploratory endpoints:
•Change in absolute IGFBP-3 levels through visits;
•Change in IGFBP-3 SDS through visits;
•Bone maturation after 12 months of treatment;
•Predicted adult height change from start to 12 months;
•Number of subjects needing at least one dose modification.

Timepoint(s) of evaluation of this end point: Secondary Endpoints (Auxology/Clinical/Biochemical)
•Height velocity at 3 and 12 months expressed in SDS;
•Change in delta height SDS at 3, 6 and 12 months (compared to Baseline value);
•Annualized height velocity at 3, 6 and 12 months expressed in cm/year;
•Change in height at 3, 6 and 12 months expressed in cm;
•Change in absolute IGF-I levels through visits;
•Change in IGF-I SDS through visits.

Other Exploratory Endpoints
•Change in absolute IGFBP-3 levels through visits;
•Change in IGFBP-3 SDS through visits;
•Bone maturation after 12 months of treatment;
•Predicted adult height change from start to 12 months;
•Number of subjects needing at least one dose modification.

Secondary ID(s)

GX-H9-003

2015-001939-21-HU

Source(s) of Monetary Support

Genexine, Inc.