Evaluating the Efficacy and Safety of GB08 Injection in Pediatric Patients With Growth Hormone Deficiency

A Phase II/III, Seamless, Multicenter, Randomized, Open-Label, Positive-Comparator Controlled Clinical Trial to Evaluate the Efficacy and Safety of GB08 Injection in Pediatric Patients With Growth Hormone Deficiency

This study aims to evaluate the efficacy and safety of GB08 injection compared to Norditropin NordiFlex in pediatric patients with growth hormone deficiency (PGHD). It seeks to resolve the following questions:

• 1: Does GB08 injection demonstrate comparable efficacy in treating PGHD at 24 weeks compared to Norditropin NordiFlex?
• 2: Which dose (0.4 mg/kg, 0.8 mg/kg, and 1.2 mg/kg) of GB08 injection best balances efficacy and safety in treating PGHD at 24 weeks?
• 3: Does GB08 injection maintain its efficacy in treating PGHD at 52 weeks compared to Norditropin NordiFlex? To achieve these, GB08 injection will be compared to Norditropin NordiFlex to see if it provides a more effective or safer treatment option for PGHD.

This is a Phase II/III, Seamless, Multicenter, Randomized, Open-Label, Positive-Comparator Controlled Clinical Trial with two stages. Stage 1 answers questions #1 and #2 by comparing the efficacy and safety of GB08 injection and Norditropin NordiFlex intervention among PGHD at 24 weeks. It involves four groups (n=16 each): GB08 0.4 mg/kg, GB08 0.8 mg/kg, GB08 1.2 mg/kg, and Norditropin NordiFlex 0.035 mg/kg. GB08 and Norditropin NordiFlex will be administered once weekly and once daily, respectively. The primary outcome measurement is annualized height velocity (AHV) at 24 weeks. Other measurements include growth hormone levels, safety parameters, immunogenicity markers, and pharmacokinetic/pharmacodynamic profiles.

The optimal GB08 dose will be further investigated in Stage 2, which answers question #3. At this stage, PGHD patients will randomly receive either GB08 injection or Norditropin NordiFlex intervention for 52 weeks (n=102 for each). After that, the efficacy and safety of GB08 will also be detected.

This is a multicenter, randomized, open-label, positive-controlled Phase II/III seamless design clinical study evaluating the efficacy and safety of GB08 injection in pediatric patients with growth hormone deficiency (PGHD). It aims to compare the efficacy and safety of GB08 injection with Norditropin NordiFlex in PGHD patients, thereby benefiting this population. This study involves two parts: Phase II and Phase III.

Phase II: Identifying the Optimal Dose This part assesses the efficacy and safety of three doses of GB08 in treating PGHD to recommend the optimal dose for the phase III.

Eligible patients with PGHD will be randomly divided into four groups (n=16 per group) and stratified by GH peak value (≤5 μg/L and >5 μg/L). They will receive GB08 0.4 mg/kg, GB08 0.8 mg/kg, GB08 1.2 mg/kg, or Norditropin NordiFlex 0.035 mg/kg (positive control) treatment for 24 weeks with another 28 weeks of follow-up. GB08 and Norditropin NordiFlex therapy will be provided once weekly and once daily, respectively. All participants will have blood samples collected for pharmacokinetics (GB08 groups only), pharmacodynamics, immunogenicity, and safety and efficacy assessments, as well as records of concomitant medications/treatments and adverse events. The primary outcome measurement is the annualized height velocity (AHV) at 24 weeks among the four groups. The optimal GB08 dose will be identified based on the 24-week data.

Phase III: The 52-week efficacy and safety of GB08 injection compared to Norditropin NordiFlex This part aims to evaluate the efficacy of GB08 injection compared to Norditropin NordiFlex in PGHD patients at 52 weeks.

It contains a treatment group (GB08 injection) and a control group (Norditropin NordiFlex), each with 102 participants. Accordingly, they will receive GB08 or Norditropin NordiFlex intervention for 52 weeks. The dose of GB08 will be determined by Phase II. Stratified randomization will be based on age (<6 years vs. ≥6 years), gender (male vs. female), and GH peak value (≤ 5 ug/L, 5-7 ug/L, >7 ug/L). The treatment period will last for 52 weeks with a 2-week follow-up. The primary endpoint measurement is the efficacy of GB08 injection at the 52nd week compared to Norditropin NordiFlex.

Inclusion Criteria:

1. Diagnosed with Growth Hormone Deficiency (GHD) based on medical history, clinical symptoms and signs, GH stimulation tests, and imaging studies. The participant must meet the following:

1. Absolute height 2 standard deviations (SD) below the mean height of children of the same age and sex, according to the standardized growth curves for children and adolescents in China (0-18 years old) published in 2009.
2. Annualized height velocity (AHV) ≤ 5.0 cm/year, calculated from measurement of 6 to 18 months before screening.
3. GH peak ≤ 10 ng/ml proved by two different GH stimulation tests within a year before screening.
4. Bone age lagging at least 1 year behind actual age (bone age assessment within the past 6 months before screening), with girls < 10 years old and boys < 11 years old.

2. Aging > 3 years and ≤ 10 years (girls) or ≤ 11 years (boys) based on birth date; Tanner stage I (testicular volume < 4 ml for boys and no palpable breast tissue for girls) 3. Uniform short stature with normal intellectual development. 4. IGF-1 levels below the mean for children and adolescents of the same age and sex, at least 1 SD below (IGF-1 SDS ≤ -1.0).

5. Body mass index (BMI) within ±2 SD of the mean BMI for children and adolescents of the same age and sex.

6. For subjects with GHD as part of multiple pituitary hormone deficiencies, must be stable for ≥1 month, as determined by the investigator.

7. Guardians understand and sign the Informed Consent Form (ICF). If the participant is ≥8 years old, they must also sign the ICF. For participants <8 years old who can express consent, their consent must be recorded.

Exclusion Criteria:

1. History of systematic growth-promoting therapy, including growth hormone and sex hormones.
2. Severe allergic constitution or known allergy to growth hormone or its excipients, such as mannitol, lysine, or sodium chloride.
3. Closed epiphyses.
4. Other types of growth disorders such as idiopathic short stature, Turner syndrome, Noonan syndrome, Prader-Willi syndrome, and Russell-Silver syndrome.
5. Short stature due to other causes, such as intrauterine growth restriction, familial short stature, thyroid hormone deficiency, adrenal insufficiency, antidiuretic hormone deficiency, celiac disease, rickets, psychological factors, chronic kidney disease, infections, or trauma.
6. Any clinically significant abnormalities that may affect growth or growth assessment; subjects with liver or kidney dysfunction (ALT > 1.5 times upper limit of normal, creatinine > upper limit of normal), chronic diseases (malnutrition, fasting blood glucose ≥ 126 mg/dL or HbA1c ≥ 6.5%), diabetes, severe cardiac, pulmonary, hematological, or systemic infections, immunodeficiency, psychiatric disorders, or congenital malformations.
7. Infectious diseases, such as hepatitis B, hepatitis C, AIDS, syphilis, or tuberculosis (HBV surface antigen-positive subjects must undergo HBV DNA testing; HCV antibody-positive subjects must undergo HCV RNA testing; if HBV DNA or HCV RNA > detection limit, they are excluded).
8. Use of corticosteroids or other steroids within the past 12 months, such as long-term steroid use for asthma.
9. History of pituitary or hypothalamic tumors, or other intracranial tumors on MRI; history of leukemia, lymphoma, or other malignancies.
10. History of radiation therapy or chemotherapy.
11. Congenital intracranial hypertension.
12. Femoral head slipped epiphysis (SCFE).
13. Spinal scoliosis > 15°.
14. Participation in any other drug clinical trial within the past 3 months (as a subject).
15. Other factors deemed unsuitable for participation in the study by the investigator.