The Growth Hormone Deficiency Reversal Trial: Effect on final height of discontinuation vs continuation of growth hormone treatment in pubertal children with isolated growth hormone deficiency – A non-inferiority randomised controlled trial

The primary objective of the study is to compare the near **Final Height Standard Deviation Score (FH SDS)** in two groups of pubertal children with isolated **Growth Hormone Deficiency (GHD)**: those continuing growth hormone treatment (GH+) and those discontinuing it (GH-). Additionally, the study aims to evaluate the Mid-parental Target Height (TH), estimated from parental heights, and the difference between TH and FH, both in centimeters and SDS from FH reference data. This objective is clinically relevant as it seeks to determine the impact of continued versus discontinued growth hormone therapy on achieving final height, which is a critical outcome for children with GHD.

Secondary objectives include comparing the lipid profiles, specifically fasting lipids such as serum triglyceride and serum total cholesterol, and assessing bone health between the GH+ and GH- groups. These secondary outcomes are important for understanding the broader metabolic and skeletal effects of growth hormone therapy in this population.

The clinical trial involves **children** diagnosed with **Growth Hormone Deficiency (GHD)**, specifically targeting those with reversed Isolated Growth Hormone Deficiency (I-GHD) in established puberty. The study population includes both male and female participants, with an age range of 8-15 years for girls and 9-17 years for boys. Participants are required to have a normal brain Magnetic Resonance Imaging (MRI) scan result, including a small anterior pituitary, and must have completed a minimum 6-week period of discontinuation of growth hormone medication prior to a growth hormone re-test. The trial population was selected based on these criteria, and children demonstrating GHD reversal, defined as a peak stimulated growth hormone equal to or greater than 6.7 μg/L using arginine or insulin tolerance test, are eligible to participate. The sponsor has not provided information regarding the total number of participants. The study includes a vulnerable population, and written informed consent is mandatory for participation.

The clinical trial is designed to evaluate the effects of discontinuation versus continuation of growth hormone treatment in pubertal children with isolated **Growth Hormone Deficiency** (GHD). This study is a non-inferiority, randomized, controlled trial with a double-blind design to ensure unbiased results. The trial is expected to span from January 2023 to January 2026, with participant involvement lasting up to one year. The primary endpoint is the Final Height in Standard Deviation Score (FH SDS), while secondary endpoints include growth-related metrics, bone health indices, and biochemical profiles.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, pubertal stage, and a normal brain MRI scan. Eligible children must demonstrate GHD reversal, defined by a peak stimulated GH level of at least 6.7 µg/L. Following the screening, participants will be randomized into either the continuation or discontinuation group. Regular follow-up visits will be scheduled to monitor growth parameters, bone age, and biochemical markers. The end-of-study visit will assess the final height and other endpoints.

The expected length of participant involvement is approximately one year, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial will utilize somatropin, administered via cutaneous use, with a maximum daily dose of 1 mg/kg. The study aims to provide insights into the optimal management of GHD in pubertal children, contributing to improved treatment strategies.

The clinical trial involves the administration of several **somatropin**-based treatments, each with specific pharmaceutical formulations and administration protocols. **NutropinAq** 10 mg/2 ml (30 IU) is a **solution for injection** provided by IPSEN PHARMA. It is administered via **cutaneous use** with a maximum daily dose of 1 mg/kg. The treatment period is limited to one day, and the solution is not formulated for pediatric use. Compliance is monitored through standard clinical trial procedures.

**Saizen** 8 mg/ml, provided by MERCK GESELLSCHAFT MBH, is a **solution for injection in a cartridge**. This formulation is also administered cutaneously with a maximum daily dose of 1 mg/kg, and the treatment duration is one day. The product is not specifically designed for pediatric patients, and participant adherence is tracked as per trial protocols.

**Omnitrope** 5 mg/1.5 ml, manufactured by SANDOZ GMBH, is another **solution for injection in a cartridge**. It follows the same administration route and dosing schedule as the other treatments, with a maximum daily dose of 1 mg/kg and a one-day treatment period. The formulation is not pediatric-specific, and compliance is ensured through trial monitoring.

**HUMATROPE** 6 mg, produced by ELI LILLY GES. M.B.H, is a **powder and solvent for solution for injection**. It is administered cutaneously with a maximum daily dose of 1 mg/kg, and the treatment period is one day. This formulation is not intended for pediatric use, and adherence is monitored according to clinical trial standards.

**Norditropin FlexPro** 15 mg/1.5 ml, from NOVO NORDISK PHARMA GMBH, is a **solution for injection in a prefilled pen**. It is administered via cutaneous use with a maximum daily dose of 1 mg/kg, and the treatment duration is one day. The product is not a pediatric formulation, and participant compliance is tracked through established trial procedures.

**Genotropin® MiniQuick** 0.2 mg, provided by PFIZER CORPORATION AUSTRIA GESELLSCHAFT M.B.H., is a **powder and solvent for solution for injection**. It is administered cutaneously with a maximum daily dose of 1 mg/kg, and the treatment period is one day. This formulation is not pediatric-specific, and adherence is monitored as per clinical trial protocols.

All treatments in this trial are administered via **cutaneous use**, with a consistent dosing schedule of 1 mg/kg per day for a maximum of one day. Participant compliance is monitored through standard clinical trial procedures, ensuring adherence to the treatment regimen. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this trial.

The clinical trial will assess the efficacy of **somatropin** in children with reversed Isolated Growth Hormone Deficiency (I-GHD) by evaluating the primary endpoint of Final Height in Standard Deviation Score (FH SDS). Secondary endpoints include growth-related measures such as the proportion of children reaching normal adult height and mid-parental Target Height, as well as the difference between a child's Target Height and Final Height in both Standard Deviation Score and centimeters. Bone-related endpoints will assess bone age delay and acceleration, and bone health index at Final Height. Biochemical parameters will include serum IGF-1 and lipid profiles, specifically fasting serum triglyceride and total serum cholesterol levels at Final Height.

Efficacy parameters will be measured using validated scales and laboratory tests. The schedule for collecting these parameters will align with the trial's timeline, which includes key timepoints such as the end of treatment. The trial is designed to compare near Final Height Standard Deviation Score (FH SDS) in the GH+ and GH- groups, Mid-parental Target Height (TH), and TH-FH from FH reference data. The trial is expected to conclude by January 2, 2026, with recruitment having started on January 2, 2023.