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

• Register: EUCTR
• Last refreshed on: 4 May 2020
• Main ID: EUCTR2015-001939-21-PL
• Date of registration: 18/01/2016
• 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: 19/04/2016
• Target sample size: 56
• 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, Estonia, Greece, Hungary, Korea, Republic of, Latvia, Lebanon, Lithuania, Poland, Russian Federation, Serbia, Slovakia, 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) – it is highly recommended to take a photograph (if
equipment is available at the study center);
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: 56
F.1.2 Adults (18-6
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

Growth Hormone Deficiency (GHD) in pre-pubertal children
MedDRA version: 20.0 Level: PT Classification code 10056438 Term: Growth hormone deficiency System Organ Class: 10014698 - Endocrine disorders

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

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)

Primary end point(s): EFFICACY ENDPOINTS
Primary endpoints:
•Annualized Height Velocity in cm/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
Single Dose PK/PD Period
•After GX-H9 administration: Cmax, Ctrough, Tmax, T1/2, AUC;
•IGF-1 after GX-H9 administration: Cmax, Ctrough, Tmax, T1/2, AUC;
•IGF-1 after Genotropin® administration: plasma concentration.
2. Multiple Dose-Dose Finding Period
•After GX-H9 or Genotropin® repeated dose for 3 months : Cmax,
Ctrough, Tmax, T1/2, AUC, Rac - only for GX-H9;
•IGF-1 after GX-H9 or Genotropin® repeated dose for 3 months: Cmax,
Ctrough, Tmax, T1/2, AUC, Rac.
3. Throughout the Study Period
•PK/PD plasma concentration

Main Objective: To compare the safety, efficacy and tolerability of two weekly and one
every other week (EOW) 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 further clinical
development on the basis of safety and efficacy.
To evaluate immunogenicity of GX-H9.

Secondary Objective: Not applicable

Timepoint(s) of evaluation of this end point: Primary timepoints:Annualized Height Velocity in cm/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 PK/PD period(SDP),V1 to
V15
Incidence of anti-GX-H9 antibody
formation:SDP,V1,V4,V5,V7,V9,V10,V12,V14,V15
Local injection site assessment:SDP,V1 to V14
IGF-I levels outside (above) plus 2 SDS:SDP,V1 to V14
Blood glucose, fasting insulin level:SCR,SDP,V1 to V14
HbA1c:SCR,V1,V3,V5,V6,V7,V8,V9,V11 to V14
Thyroid status:SCR,V1,V3,V4,V5,V6,V7,V9,V11 to V14
Lipid parameters:SCR,V1,V4 to V7,V9,V12,V14
Cortisol levels:SCR,V9,V14
All other hematology and biochemical parameters:SCR,SDP,V1,V4 to
V7,V9,V12,V14
Physical examination:SCR,V1 to V14
Vital signs:SCR,SDP,V1-V14

Secondary Outcome(s)

Secondary end point(s): Secondary Endpoints (Auxology/Clinical/Biochemical)
•Annualized Height velocity at 3, 6, 12 and 24 months expressed in SDS;
•Change in height SDS at 3, 6, 12 and 24 months (compared to Baseline
value);
•Annualized height velocity at 3, 12 and 24 months expressed in
cm/year;
•Change in height at 3, 6, 12 and 24 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;
•Change in BMI SDS at 6, 12 and 24 months (compared to the baseline value);
•Change in annualized height velocity (AHV) at 6, 12 and 24 months (compared to the baseline value);
•Bone maturation after 12 and 24 months of treatment;
•Predicted adult height change from start to 12 and 24 months;
•Number of subjects needing at least one dose modification.

Timepoint(s) of evaluation of this end point: Secondary Endpoints
•Annualized Height velocity expressed in SDS (V5,V7,V9,V14);
•Change in height SDS (V5,V7,V9,V14);
•Annualized height velocity expressed in cm/year (V5,V9,V14);
•Change in height expressed in cm (V5,V7,V9,V14);
•Change in absolute IGF-I levels (Screening, SDP,V1 to V14);
•Change in IGF-I SDS (Screening, SDP,V1 to V14).
Other exploratory endpoints:
•Change in absolute IGFBP-3 levels (Screening, SDP,V1 to V14);
•Change in IGFBP-3 SDS (Screening, SDP,V1 to V14);
•Change in BMI SDS (V7,V9,V14);
•Change in annualized height velocity (V7,V9,V14);
•Bone maturation (V9,V14);
•Predicted adult height change (V9,V14);
•Number of subjects needing at least one protocol specified dose modification (SDP,V1 to V14).

Secondary ID(s)

2015-001939-21-HU

GX-H9-003

NCT03309891

Source(s) of Monetary Support

Genexine, Inc.

Ethics review

Status: Approved
Approval date: 25/01/2016
Contact: