Evaluation of Losartan Potassium and Hydrochlorothiazide in Reducing Bone Resorption in Osteogenesis Imperfecta Patients Aged 16 and Above

The primary objective of the study is to establish the effective dose of **losartan** in patients aged 16 years and above with **Osteogenesis Imperfecta**, based on maximal reduction in the bone resorption marker carboxy-terminal crosslink of type I collagen telopeptide (CTX). This is clinically relevant as it aims to optimize treatment efficacy by identifying the appropriate dosage that effectively reduces bone resorption, a critical factor in managing Osteogenesis Imperfecta.

Secondary objectives include:

• Determining changes in proxy efficacy outcomes for bone turnover, mass, architecture, and strength using blood tests, High Resolution peripheral Quantitative CT (HRpQCT), Dual Energy X-ray Absorptiometry (DXA), and muscle strength using the "Timed Up and Go" test.
• Assessing changes in quality of life using a disease-specific tool (OI-QOL) and a validated generic tool (EQ-5D-5L-VAS).

The clinical trial involves a total of **15 participants** diagnosed with **Osteogenesis Imperfecta**, a genetic disorder characterized by fragile bones. The study population includes both male and female subjects aged **16 years and above**. Participants were selected based on specific inclusion criteria, such as having a diagnosis of osteogenesis imperfecta of any type and meeting certain treatment history requirements. Prior treatment with bisphosphonates or denosumab is permissible, provided appropriate washout periods have been observed. The trial does not restrict participation based on general health status, but subjects must not be taking prohibited concomitant medications and must not have any contraindications as determined by the investigator. Participants are required to agree not to engage in other interventional research projects during the study. The trial includes a vulnerable population, and women of childbearing potential must use effective contraception throughout the study. The sponsor has not provided specific information regarding lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of **losartan potassium** in patients aged 16 years and above diagnosed with **osteogenesis imperfecta**. This is a Phase IV, randomized, double-blind, controlled study aimed at determining the effective dose of losartan based on the maximal reduction in the bone resorption marker carboxy-terminal crosslink of type I collagen telopeptide (CTX). The trial is expected to commence recruitment on December 1, 2024, and conclude by December 1, 2026, with an estimated duration of 24 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, prior treatments, and the absence of contraindications. Following successful screening, participants will be randomized to receive either the investigational product or a control. The study will include follow-up visits at regular intervals to monitor safety, tolerability, and efficacy, with primary endpoints measured at week 24 and secondary endpoints assessed at weeks 8 and 24. The end-of-study visit will occur at the conclusion of the treatment period to evaluate the overall outcomes and any long-term effects.

The expected length of participant involvement is approximately 6 months, with conditions for early termination including adverse events, non-compliance, or withdrawal of consent. Participants are required to refrain from participating in other interventional studies during their involvement and must adhere to the study protocol, including the use of effective contraception for women of childbearing potential. The trial will be 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 an **experimental medication** containing the active substances **losartan potassium** and **hydrochlorothiazide**. This combination is provided in an oral pharmaceutical form, identified by the code PHF00082MIG. The medication is administered orally, with a maximum daily dose of 75 mg and a total maximum dose of 12,600 mg over the course of the study. The treatment period is limited to a maximum of six months. The primary objective of the trial is to determine the effective dose of losartan in patients aged 16 years and above with **osteogenesis imperfecta**, focusing on the reduction of the bone resorption marker carboxy-terminal crosslink of type I collagen telopeptide (CTX).

In addition to the experimental medication, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, although specific details are not provided in the source data. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is conducted under the sponsorship of Alfasigma S.p.A., and the medication is not classified as a pediatric formulation. The trial has been authorized in Italy, with the status of the trial being "Authorised" as of March 13, 2025.

Efficacy in the clinical trial titled "Matrix-Directed Therapy In Older Adolescents And Adults With Osteogenesis Imperfecta – The 'MOI-A' Study" will be assessed using both primary and secondary endpoints. The primary endpoint is the percentage change in the bone resorption marker **carboxy-terminal crosslink of type I collagen telopeptide (CTX)** from baseline to week 24. This marker is crucial for evaluating the effectiveness of the treatment in reducing bone resorption in patients with Osteogenesis Imperfecta.

Secondary endpoints include the percentage change in CTX from baseline to week 8, as well as the percentage change in other biomarkers such as TGFβ and P1NP from baseline to weeks 8 and 24. Additionally, changes in bone mineral density will be assessed using dual-energy X-ray absorptiometry (DXA) for lumbar spine areal bone mineral density (LSaBMD) and high-resolution peripheral quantitative computed tomography (HRpQCT) for radial and tibial total volumetric bone mineral density (vBMD) from baseline to week 24. Functional assessments will include changes in the Timed Up and Go test, and quality of life will be evaluated using the OI-QOL and EQ-5D-5L-VAS scales from baseline to week 24.