Clinical trial NCT03874013: Safety and Efficacy Study of MOD-4023 to Treat Children With Growth Hormone Deficiency
Official title: A Phase 3, Open-Label, Randomized, Multicenter, 12-month, Efficacy and Safety Study of Weekly MOD-4023 Compared to Daily Genotropin® Therapy in Japanese Pre-pubertal Children With Growth Hormone Deficiency
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Growth Hormone Deficiency
Lead sponsor: OPKO Health, Inc.
Sponsor class: INDUSTRY
First posted: 2019-03-14
Enrollment: 44
Sex: ALL
Minimum age (years): 3
Maximum age (years): 11
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: Treatment of children with growth failure due to growth hormone deficiency (GHD).

Primary • To evaluate the efficacy and safety of weekly MOD-4023 administration compared to daily Genotropin® administration in Japanese pre-pubertal children with GHD.

Secondary

• To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) profiles of three different doses of MOD-4023 in Japanese pre-pubertal children with GHD.

Detailed description: This is a 12-month, open-label, randomized, active controlled, parallel group study comparing the efficacy and safety of weekly MOD-4023 to daily recombinant human growth hormone (r-hGH), Genotropin ®. Both drugs will be injected subcutaneously (SC) using a pen device.

After a 4 week Screening period, patients meeting all the entry criteria and none of the exclusion criteria, will be eligible to participate in the study.

Eligible patients will be randomized in a 1:1 ratio, to receive either:

• MOD-4023 (investigational treatment): weekly MOD-4023 SC injections for 12 months; initially over the first 6 weeks, MOD-4023 will be administered in 3 stepwise escalating doses (0.25 mg/kg/week, 0.48 mg/kg/week and 0.66 mg/kg/week), each for two weeks sequentially. For the remaining 46 weeks, patients will continue to receive MOD-4023 at a dose of 0.66 mg/kg/week.

Or

• Genotropin® (reference treatment): daily Genotropin® (0.025 mg/kg/day which is equivalent to 0.175 mg/kg/week, divided equally into 7 daily injections over a week) SC injection for 12 months.

After the 6-week PK/PD sampling period, the dose of MOD-4023 and Genotropin® will be adjusted every 3 months based on a patient's body weight. Doses may be decreased for safety reasons according to the pre-defined dose-adjustment criteria (which will be based on the severity of adverse events (AEs) or repeated, elevated levels of IGF-1 Standard Deviation Score (SDS)).

The key safety data will be reviewed by an independent and external Data and Safety Monitoring Board (DSMB). DSMB review will also include a review of the number or percentage of patients requiring dose reductions due to AEs. Following the completion of the12-month treatment period, eligible patients will be consented to enroll into an open-label long term extension (LTE) period, and an amendment to this study protocol will be submitted prior to the first patient completes the 12 months treatment period. Eligible Genotropin®-treated patients will be switched to a MOD-4023 dose of 0.66 mg/kg/week in the LTE. The LTE is planned to continue until MOD-4023 marketing registration in Japan.

Eligibility criteria: Inclusion Criteria:

1. Pre-pubertal child aged ≥ 3 years old, and not yet 10 years for girls (9 years and 364 days) or not yet 11 years for boys (10 years and 364 days), 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 2 different types of GH provocation tests (standardized on growth foundation data): defined as a peak serum GH level of ≤ 6.0 ng/mL or ≤ 16 ng/mL when conducting GHRP-2 provocation test.

   Prior local laboratory results will be accepted subject to pre-approval by the study medical monitor and if the tests were conducted as specified in the protocol.
3. Bone age (BA) is not older than chronological age and should be less than 10 for girls and less than 11 for boys.
4. Without prior exposure to any r-hGH therapy.
5. Height SD score ≤ -2.0 at screening
6. Impaired height velocity defined as:

   * Annualized height velocity (HV) below the 25th percentile for CA (HV \< -0.7 SDS) and gender according to the local primary care provider standard.
   * The interval between two height measurements should be at least 6 months, but should not exceed 18 months prior to inclusion.
7. BMI must be within ±2 SDS of mean BMI for the chronological age and sex.
8. Baseline IGF-1 level of at least 1 SDS below the mean IGF-1 level standardized for age and sex (IGF-1 SDS ≤ -1) according to the central laboratory reference values. A single re-test will be allowed (subject to discussion with the study medical monitor) if all other criteria are met.
9. Normal creatinine levels according to common practice reference ranges per age.
10. 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
11. Normal 46 XX karyotype for girls.
12. Willing and able to provide written informed consent of the parent or legal guardian of the patient and written assent from pediatric patients (when applicable based on age and Japan regulation).

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 suspected psychosocial dwarfism by the discretion of the investigator
5. Children born small for gestational age (SGA - birth weight and/or birth length \< -2 SDS for gestational age)
6. Presence of anti-hGH antibodies at screening
7. 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.
8. Children with diabetes mellitus
9. Chromosomal abnormalities including Turner's syndrome, Laron syndrome, Noonan syndrome, Prader-Willi syndrome, Russell-Silver syndrome, SHOX (short stature homeobox) mutations/deletions and skeletal dysplasia's, with the exception of septo-optic dysplasia.
10. Concomitant administration of other treatments that may have an effect on growth such as anabolic steroids, sex steroids, with the exception of 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/d of inhaled budesonide or equivalent as provided in Appendix J.
12. Major medical conditions and/or presence of contraindication to r-hGH treatment.
13. Known or suspected HIV-positive patient, or patient with advanced diseases such as AIDS or tuberculosis.
14. Drug substance or alcohol abuse.
15. Known hypersensitivity to the components of study medication.
16. Other causes of short stature such as celiac disease, uncontrolled primary hypothyroidism and rickets.
17. The patient and/or the parent/legal guardian are likely to be non-compliant in respect to study conduct.
18. Participation in any other clinical trial within 30 days prior to screening and throughout the entire study period (including administration of investigational agent).

Primary outcomes:
measure: Annual Height Velocity (HV) After 12 Months
timeFrame: 12 months
Secondary outcomes:
measure: Height Velocity at 6 Months
timeFrame: 6 months
measure: Change in Height Standard Deviation Score (SDS) Compared to Baseline After 12 Months
timeFrame: 12 months
measure: Change in Bone Maturation (BM) After 12 Months
timeFrame: 12 months
Other outcomes:
measure: Biochemical
timeFrame: Baseline, Visit 6 (Month 3), Visit 7 (Month 6), Visit 8 (Month 9) and Visit 9 (12 months)
Locations:
city: Nagakute
country: Japan
facility: Aichi Medical University Hospital
state: Aichi
city: Sakura
country: Japan
facility: Seirei Sakura Citizen Hospital
state: Chiba
city: Kitakyushu
country: Japan
facility: Hospital of the University of Occupational and Environmental Health
state: Fukuoka
city: Maebashi
country: Japan
facility: Gunma University Hospital
state: Gunma
city: Fukuyama
country: Japan
facility: Fukuyama City Hospital
state: Hiroshima
city: Kure
country: Japan
facility: National Hospital Organization Kure Medical Center & Chugoku Cancer Center
state: Hiroshima
city: Onomichi
country: Japan
facility: Onomichi General Hospital
state: Hiroshima
city: Asahikawa
country: Japan
facility: Hokkaido P.W.F.A.C. Asahikawa-Kosei General Hospital
state: Hokkaido
city: Asahikawa
country: Japan
facility: Asahikawa Medical University Hospital
state: Hokkaido
city: Sapporo
country: Japan
facility: KKR Sapporo Medical Center
state: Hokkaido
city: Kobe
country: Japan
facility: Kobe University Hospital
state: Hyogo
city: Kobe
country: Japan
facility: Takahashi Clinic
state: Hyogo
city: Takarazuka
country: Japan
facility: Takarazuka City Hospital
state: Hyogo
city: Kawasaki
country: Japan
facility: St. Marianna University School of Medicine Hospital
state: Kanagawa
city: Jōyō
country: Japan
facility: National Hospital Organization Minami Kyoto Hospital
state: Kyoto
city: Sendai
country: Japan
facility: East Japan Railway Company Sendai Branch Office JR Sendai Hospital
state: Miyagi
city: Sendai
country: Japan
facility: National University Corporation Tohoku University Tohoku University Hospital
state: Miyagi
city: Sendai
country: Japan
facility: Igarashi childrens clinic
state: Miyagi
city: Yufu
country: Japan
facility: Oita University Hospital
state: Oita
city: Izumi
country: Japan
facility: Osaka Women's and Children's Hospital
state: Osaka
city: Suita
country: Japan
facility: Osaka University Hospital
state: Osaka
city: Iruma-Gun
country: Japan
facility: Saitama Medical University Hospital
state: Saitama
city: Kawagoe
country: Japan
facility: Saitama Medical Center
state: Saitama
city: Izumo
country: Japan
facility: Shimane University Hospital
state: Shimane
city: Fuchū
country: Japan
facility: Tokyo Metropolitan Childrens Medical Center
state: Tokyo
city: Itabashi
country: Japan
facility: Teikyo University Hospital
state: Tokyo
city: Setagaya-Ku
country: Japan
facility: National Center for Child Health and Development
state: Tokyo
city: Shinjuku
country: Japan
facility: Keio University Hospital
state: Tokyo
city: Yonago
country: Japan
facility: Tottori University Hospital
state: Tottori
city: Akita
country: Japan
facility: Akita University Hospital
city: Fukuoka
country: Japan
facility: Fukuoka Children's Hospital
city: Gifu
country: Japan
facility: Gifu University Hospital
city: Hiroshima
country: Japan
facility: Hiroshima City Hospital Organization Hiroshima City Hiroshima Citizens Hospital
city: Kumamoto
country: Japan
facility: Kumamoto University Hospital
city: Miyazaki
country: Japan
facility: Miyazaki Prefectural Miyazaki Hospital
city: Nagano
country: Japan
facility: Arakawa Children's Clinic
city: Nara
country: Japan
facility: Nara Prefecture General Medical Center
city: Niigata
country: Japan
facility: Niigata University Medical & Dental Hospital
city: Okayama
country: Japan
facility: Okayama Saiseikai General Hospital Outpatient Center
city: Okayama
country: Japan
facility: National Hospital Organization Okayama Medical Center
city: Osaka
country: Japan
facility: Osaka City General Hospital
city: Osaka
country: Japan
facility: Osaka City University Hospital
city: Saitama
country: Japan
facility: Saitama Childrens Medical Center
city: Saitama
country: Japan
facility: Saitama City Hospital
city: Shizuoka
country: Japan
facility: Shizuoka Childrens Hospital
city: Tokyo
country: Japan
facility: Toranomon Hospital
Study officials:
affiliation: National Center for Child Health and Development
name: Reiko Horikawa, M.D, Ph. D.
role: PRINCIPAL_INVESTIGATOR
References: