An efficacy and safety study of weekly mod-4023 compared to daily genotropin® therapy in pre-pubertal children with growth hormone deficiency

• Register: EUCTR
• Last refreshed on: 30 June 2019
• Main ID: EUCTR2016-003874-42-GB
• Date of registration: 03/01/2017
• Prospective Registration: Yes
• Primary sponsor: OPKO Biologics Ltd.
• Public title: An efficacy and safety study of weekly mod-4023 compared to daily genotropin® therapy in pre-pubertal children with growth hormone deficiency
• Scientific title: A phase 3, open-label, randomized, multicenter, 12 months, efficacy and safety study of weekly mod-4023 compared to daily genotropin® therapy in pre-pubertal children with growth hormone deficiency - N/A
• Date of first enrolment: 04/09/2017
• Target sample size: 220
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003874-42
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Belarus, Bulgaria, Canada, Colombia, France, Georgia, Germany, Greece, India, Israel, Mexico, New Zealand, Poland, Romania, Russian Federation, Spain, Taiwan, Turkey, Ukraine, United Kingdom, United States

Contacts

• Name: Director of Clinical Affairs
• Affiliation: OPKO Biologics Ltd.

• Name: Director of Clinical Affairs
• Affiliation: OPKO Biologics Ltd.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Pre-pubertal children aged =3 years , and not yet 11 years for girls (10 years and 364 days) or not yet 12 years (11 years and 364 days) for boys, (on the date of ICF signature), with either isolated GHD, or GH insufficiency as part of multiple pituitary hormone deficiency.
2. Confirmed diagnosis of GHD by two different GH provocation tests defined as a peak plasma GH level of =10 ng/mL, determined by local or central laboratory using a validated assay . Global study MM may accept prior local laboratory results; subject to pre-approval and if the tests were conducted as recommended in the protocol
3. BA is not older than CA and should be < 10 for girls and < 11 for boys.
4. Without prior exposure to any recombinant hGH (r-hGH) therapy (naïve patients).
5. Impaired Ht velocity defined as:
• Annualized height velocity (HV) below the 25th percentile for CA (HV < -0.7 SDS) and gender according to the OPKO HV (Tanner, Prader and Hermanussen) calculator, provided
• The interval between 2 Ht measurements should be at least 6 months, but should not exceed, 18 months prior to inclusion.
6. Baseline IGF-1level of at least 1 standard deviation (SD) below the mean IGF-1 level standardized for age and sex (IGF-I SDS =-1) according to the central laboratory reference values. A single re-test will be allowed (subject to discussion with MM) if all other criteria are met.
7. Normal calculated glomerular filtration rate (GFR) based on updated “bedside” Schwartz formula for pediatric patients (calculation is recommended below):
Creatine Clearance Rate (CrCL) (mL/min/1.73 m2) =0.413 * *Ht / /serum creatine (Scr)
Ht: in cm;
Scr: in mg/dL;
8. Children with multiple hormonal deficiencies must be on stable replacement therapies (no change in dose) for other hypothalamo-pituitary organ axes for at least 3 months prior to ICF signing
9. Normal 46XX karyotype for girls.
10. Willing and able to provide written informed consent of the parent or legal guardian of the patient and written assent from pediatric patients (where applicable based on age and country regulation).


Inclusion into the LT-OLE: 11. Completion of the main study (12 months of treatment) with adequate compliance. 12. Willing and able to provide written informed consent of the parent or legal guardian of the patient and written assent from pediatric patients (where applicable based on age and country regulation). 13. Agreement to refrain from sexual activity during the LT-OLE i.e. observe complete sexual abstinence as the only acceptable contraceptive measure during the LT-OLE (for pubertal and post-pubertal patients).
Are the trial subjects under 18? yes
Number of subjects for this age range: 220
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Children with prior history of leukemia, lymphoma, sarcoma or any other forms of cancer.
2. History of radiation therapy or chemotherapy
3. Malnourished children defined as BMI < -2 SDS for age and sex
4. Children with psychosocial dwarfism
5. Children born small for gestational age (SGA – birth weight and/or birth length <-2 SDS for gestational age)
6. Presence of anti-hGH Ab at screening
7. Any clinically significant (CS) 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.
8. Types 1 and2 diabetic patients who, in the opinion of the investigator, are not receiving standard of care treatment, or are non-compliant with their prescribed treatment or who are in poor metabolic control(criteria for controlled diabetes are defined in Appendix F of the protocol).
9. Chromosomal abnormalities including Turner’s syndrome, Laron syndrome, Noonan syndrome, Prader-Willi syndrome, Russell-Silver syndrome, SHOX mutations/deletions and skeletal dysplasias.
10. Concomitant administration of other treatments that may have an effect on growth such as anabolic steroids, or sex steroids, with the exception of Attention-Deficit/Hyperactivity Disorder (ADHD) drugs or hormone replacement therapies (thyroxin, hydrocortisone, desmopressin [DDAVP]) ®]).
11. Children requiring glucocorticoid therapy (e.g. for asthma) that are taking chronically a dose greater than 400 µg/day of inhaled budesonide or equivalent
12. Major medical conditions and/or presence of contraindication to r-hGH treatment.
13. More than 1 closed epiphyses
14. Known or suspected Human Immunodeficiency Virus (HIV-)-positive patient, or patient with advanced diseases such as Acquired Immunodeficiency Syndrome (AIDS) or tuberculosis.
15. Drug, substance, or alcohol abuse.
16. Known hypersensitivity to the components of study medication.
17. Other causes of short stature such as celiac disease, uncontrolled primary hypothyroidism and rickets.
18. The patient and/or the parent/legal guardian are likely to be non-compliant in respect to study conduct.
19. Participation in any other study of an investigational agent within 30 days prior to ICF signature (including administration of investigational agent).
20. Study enrollment requirements have been met or the study has been closed by the Sponsor prior to the completion of screening process.

Exclusion during the LT-OLE: 21. Concomitant administration of other treatments that may have an effect on growth such as anabolic steroids, or sex steroids (other than for hormonal replacement), with the exception of ADHD drugs or hormone replacement therapies (thyroxin, hydrocortisone, testosterone, estrogen/progesterone, desmopressin [DDAVP®]) 22. Change in medical condition during the treatment period (such as, but not limited to, development of a serious inter-current critical illness, a severe adverse drug reaction, etc.) 23. Positive pregnancy test. 24. Unresolved drug related (MOD-4023 or Genotropin®) SAE from the treatment period as per MM judgement.


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

Health Condition(s) or Problem(s) studied

Growth hormone deficiency 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 Code: MOD-4023
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Somatrogon
CAS Number: 1663481-09-1
Current Sponsor code: MOD-4023
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

Product Code: MOD-4023
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Somatrogon
CAS Number: 1663481-09-1
Current Sponsor code: MOD-4023
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 50-

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: SOMATROPIN FOR INJECTION
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5.3-

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: SOMATROPIN FOR INJECTION
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 12-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Baseline and after 12 months of treatment
LT-OLE: At each 12-month interval

Secondary Objective: To evaluate the safety and tolerability of weekly MOD-4023 administration.

To demonstrate LT safety and efficacy of MOD-4023 in an OLE

Primary end point(s): Annual HV in cm/year

Main Objective: To demonstrate that weekly MOD-4023 administration is non-inferior to daily Genotropin administration

Secondary Outcome(s)

Secondary end point(s): Secondary efficacy endpoints (Auxology/Clinical):
• Annualized HV after 6 months of treatment
• Change in Ht SDS at 6 and 12 months, compared to baseline
• Change in bone maturation (BM) at the end of 12 months, compared to Baseline BA (calculated as BA/CA)
Secondary endpoints (Biochemical):
• Absolute IGF-1 levels on Day 4(-1) after MOD-4023 dosing across study visits
• IGF-1 SDS on day 4(-1) after MOD-4023 dosing across study visits
•IGFBP-3 levels and IGFBP-3 SDS on Day 4(-1) after MOD-4023 dosing across study visits
Additional Endpoints
•QoL endpoint measured by the QoLISSY core questionnaire at Baseline and month 12 in specific countries per Appendix L of the protocol.

LT-OLE Endpoints:
Safety Endpoints
• Incidence of AEs and SAEs;
• Incidence of anti-MOD-4023 Ab formation (including characterization of the Ab and neutralizing properties);
• Local injection site reaction assessment;
• Parameters of glucose metabolism: blood fasting glucose, fasting insulin level, HbA1c;
• Thyroid (endocrinology) status;
• Lipid profile;
• All other safety hematology, biochemical parameters and urinalysis;
• Physical examination;

• Fundoscopy results - if performed (normal/abnormal);
• Vital signs;
• ECG.
Auxology/Clinical Endpoints
• Annual HV in cm/year at each 12-month interval.
• Change in height SDS every 12 months (compared to the previous values).
• Change in bone maturation (BM) every 12 months, (compared to Week 52 BA (calculated as BA/CA) at completion of LT-OLE year 1 and to previous values from LT-OLE year 2 onwards).

Biochemical Endpoints
• IGF-1 and IGF-1 SDS levels on day 4 (-1) after MOD-4023 dosing across study visits.
• IGFBP-3 levels and IGFBP-3 SDS on day 4 (-1) after MOD-4023 dosing across study visits.

Timepoint(s) of evaluation of this end point: as above

Secondary ID(s)

CP-4-006

Source(s) of Monetary Support

OPKO Biologics Ltd.

Ethics review

Status: Approved
Approval date:
Contact: