Evaluation of Somatropin and Letrozole in Enhancing Adult Height in Boys with Short Predicted Stature: A 4-Year Randomized Controlled Trial

The primary objective of this study is to evaluate whether **adult height** gain in boys with a short predicted height is greater following a 4-year combination therapy with **growth hormone** (Omnitrope) and the **aromatase inhibitor** (Letrozole), initiated at the onset of puberty, compared to those receiving only growth hormone therapy. This is clinically relevant as it addresses the potential for improved height outcomes in this population, which can have significant implications for physical and psychological well-being.

Secondary objectives include assessing differences in body composition, insulin sensitivity, and adult height outcomes between treatment groups after a 4-year period. The study also aims to monitor safety and identify predictors of height gain, such as birth metrics and parental height. Additionally, it examines whether aggression levels, quality of life, bone mineral density, and **gonadotropin** levels differ between groups or change over the course of treatment. These secondary outcomes provide a comprehensive understanding of the broader impacts of the treatment beyond height gain alone.

The clinical trial focuses on a **male** population with **short predicted height**. Participants are boys who are in the early stages of puberty, specifically with a testicular volume of at least 4 ml. The age range for bone age is between 11 and 13 years. The study does not include female subjects, and the population is not considered vulnerable. The trial aims to evaluate the effectiveness of a combination therapy involving growth hormone and an aromatase inhibitor. The sponsor has not provided information regarding the total number of participants. Key lifestyle factors such as diet and physical activity are not specified. The selection criteria include a predicted adult height below or equal to -2.5 standard deviations, which translates to less than 164.0 cm, based on the Vlaamse groeicurve 2004 using the Greulich and Pyle Bayley Pinneau prediction method. Participants must have signed informed consent to be included in the study.

The clinical trial is designed to evaluate the **efficacy** and safety of a four-year pubertal therapy using **growth hormone** (Omnitrope) alone or in combination with an **aromatase inhibitor** (Letrozole) in boys with a short predicted height. This is a randomized, double-blind, controlled trial, which aims to determine if the combination therapy results in a greater adult height gain compared to growth hormone therapy alone. The trial is expected to last for approximately 13 years, with recruitment having started in March 2012 and an estimated end date in August 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as male gender, adult height prediction below or equal to -2.5 SD, pubertal status, and bone age between 11 and 13 years. Following the screening, participants will be randomized to receive either the combination therapy or growth hormone alone. Regular follow-up visits will be scheduled to monitor safety and efficacy outcomes, including measurements of height and other relevant clinical parameters. The end-of-study visit will occur at the conclusion of the four-year treatment period, where final assessments will be conducted to evaluate the primary endpoint of adult height gain.

The expected length of participant involvement is four years, corresponding to the duration of the treatment period. Conditions that may lead to early termination from the study include withdrawal of consent, significant adverse events, or non-compliance with the study protocol. The trial is conducted in accordance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of **Omnitrope**, a **somatropin**-based medication, which is a recombinant human growth hormone. Omnitrope is provided as a **solution for injection in a cartridge** and is administered via **subcutaneous injection**. The dosage is calculated based on the participant's body weight, with a maximum daily dose of 50 µg/kg and a total maximum dose of 2.70 mg. The treatment period extends up to 48 months. Omnitrope is commercially available and manufactured by Sandoz GmbH. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

In addition to Omnitrope, the trial includes the administration of **Letrozole Fair-Med Healthcare**, which contains the active substance **letrozole**. This medication is provided in the form of **film-coated tablets** and is taken **orally**. The maximum daily dose of letrozole is 1.25 mg, with the same maximum total dose. The treatment duration for letrozole is also up to 48 months. Letrozole is commercially available and produced by Rudipharm Limited. Participant compliance with the oral administration of letrozole is similarly monitored to ensure accurate adherence to the prescribed regimen.

Efficacy in this clinical trial will be assessed by evaluating the primary endpoint, which is the **adult height gain**. This is defined as the difference between the final height attained and the predicted adult height in boys with a low predicted adult height. The trial aims to determine if a 4-year combination therapy with growth hormone (Omnitrope) and the aromatase inhibitor (Letrozole), initiated at the onset of puberty, results in a greater adult height gain compared to treatment with growth hormone alone.