Evaluation of Safety and Tolerability of Tamoxifen Citrate in Cystic Fibrosis Patients Ineligible for CFTR Modulator Therapy

The primary objective of this exploratory study is to evaluate the **safety** and **tolerability** of tamoxifen citrate in patients with **cystic fibrosis** who do not possess mutations currently eligible for therapy with CFTR modulator drugs. This is clinically relevant as it seeks to expand treatment options for a subset of cystic fibrosis patients who are not candidates for existing modulator therapies, potentially improving their management and outcomes.

Secondary objectives include assessing the effects of tamoxifen on various clinical parameters:

• **Lung function**
• **Quality of life**
• **Pulmonary exacerbations**
• **Hospitalizations for pulmonary exacerbations**
• **Antibiotic cycles**
• **Body Mass Index (BMI)**
• **Sputum microbiology**
• **Sweat test**

The clinical trial involves participants diagnosed with **cystic fibrosis** who do not possess mutations currently eligible for therapy with CFTR modulator drugs. The study population includes both male and female subjects aged 18 years or older, with a predicted forced expiratory volume in 1 second (ppFEV1) between 40% and 90% of the predicted value for their age, sex, and height. Participants are required to be clinically stable in terms of their respiratory disease and routine CF therapy, including inhaled antibiotics, bronchodilators, anti-inflammatories, inhaled corticosteroids, and physiotherapy, must remain unchanged for at least 28 days prior to the study's commencement. The trial population was selected from individuals attending the CF Center in Verona, who are capable of performing reliable pulmonary function tests and communicating effectively with the investigator. Female participants must have a negative serum pregnancy test, and all sexually active participants are required to adhere to non-hormonal contraceptive methods during and for two months following the study. The sponsor has not provided information regarding the total number of participants. The study includes a vulnerable population, emphasizing the need for informed consent and compliance with study requirements.

The clinical trial is designed to evaluate the **safety** and tolerability of **tamoxifen** in patients with **cystic fibrosis** who do not have mutations currently eligible for therapy with CFTR modulator drugs. This is a phase IV, randomized, double-blind, controlled study. The trial is expected to commence on July 16, 2025, and conclude by November 15, 2026, with a total duration of 24 weeks for each participant. The study will involve multiple visits, starting with an inclusion (screening) visit to assess eligibility based on specific criteria, including age, pulmonary function, and clinical stability. Participants will be required to attend follow-up visits at regular intervals to monitor their health status and any adverse events. The primary endpoint will focus on the incidence of serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs) from baseline to week 24. Secondary endpoints will assess changes in pulmonary function, frequency of pulmonary exacerbations, hospitalizations, and other health parameters.

Participants will be involved in the study for approximately 24 weeks, with conditions for early termination including the occurrence of significant adverse events or non-compliance with study protocols. The study drug, **tamoxifen**, will be administered orally in the form of film-coated tablets, with a maximum daily dose of 20 mg. The trial will ensure that all participants provide informed consent and adhere to non-hormonal contraceptive methods during and after the study period. The end-of-study visit will involve a comprehensive evaluation of the participant's health status and the collection of final data on the study endpoints. This trial aims to provide valuable insights into the potential use of **tamoxifen** for patients with **cystic fibrosis** who are not candidates for existing CFTR modulator therapies.

The clinical trial involves the administration of **TAMOXIFEN**, marketed under the name **TAMOXENE 20 mg**. This medication is provided in the form of a **film-coated tablet**. The active substance, **tamoxifen citrate**, is a chemical compound classified under the ATC code **L02BA01**. The tablets are intended for **oral use** and are administered at a dosage of **20 mg** per day. The maximum treatment period for participants is **24 months**. The trial aims to evaluate the safety and tolerability of tamoxifen in patients with **cystic fibrosis** who do not have mutations currently eligible for therapy with CFTR modulator drugs. The medication is not a pediatric formulation and is designated as an orphan drug under the designation number **EU/3/17/1877**.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of tamoxifen. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial does not involve any additional devices or interventions beyond the administration of the film-coated tablets.

The efficacy of the clinical trial evaluating **tamoxifen** in patients with cystic fibrosis will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on safety and tolerability, specifically measuring the incidence of serious adverse events (SAEs), treatment-emergent adverse events (TEAEs), and treatment discontinuation due to adverse events from baseline to week 24. Additionally, the frequency of specific adverse events relevant to the indication, such as thromboembolic events, elevation of liver enzymes, and pulmonary exacerbations, will be analyzed, along with cumulative adverse event analyses, including the number of adverse events per patient.

Secondary endpoints will provide further insights into the efficacy of the treatment. These include evaluating the relative change in predicted forced expiratory volume in 1 second (ppFEV1) from baseline to week 24, the number of pulmonary exacerbations, and the time to the first pulmonary exacerbation up to week 24. The study will also assess the number of hospitalizations for cystic fibrosis lasting more than 24 hours and the time to the first such hospitalization. Additional measures include the absolute change in the respiratory domain score of the Cystic Fibrosis Questionnaire-Revised (CFQ-R) from baseline to week 24, the use of intravenous and oral antibiotics for sino-pulmonary signs and symptoms, changes in body mass index (BMI), sputum microbiology, and the amount of chloride measured with the sweat test at the beginning and end of the study.