Evaluation of Duloxetine and Furosemide for Management of Endocrine Therapy-Related Musculoskeletal Pain in ER+ HER2- Stage I-II Breast Cancer Patients

The primary objective of this study is to evaluate if patients with early **breast cancer** treated in either intervention arm, using **duloxetine** or **furosemide**, will experience better control of endocrine therapy-related musculoskeletal (MSK) pain, specifically **arthralgias**, **myalgias**, and/or bone pain, at 3 months. This is clinically relevant as effective management of these symptoms can significantly improve patient adherence to endocrine therapy, which is crucial for the treatment of ER-positive HER2-negative breast cancer stages I-II.

Secondary objectives include:

• Evaluating the rate of discontinuation of the endocrine therapy in either intervention arm compared to the standard arm.
• Assessing if patients in the intervention arms have better control of endocrine therapy-related MSK pain at 6 months.
• Determining if there is an improvement in global quality of life (QOL) for patients in the intervention arms.
• Evaluating improvements in emotional functioning for patients in the intervention arms.
• Assessing improvements in endocrine therapy-related symptoms for patients in the intervention arms.
• Evaluating the frequency and severity of toxicities according to CTCAE v5.0 across the three arms.

The clinical trial involves a total of **147 participants** diagnosed with **ER positive HER2 negative breast cancer stages I-II**. The study population includes both **female (pre- and postmenopausal)** and **male patients** aged **18 years and older**. Participants were selected based on their ongoing adjuvant endocrine therapy (ET) for ER positive HER2 negative breast cancer stages I-III, with a requirement of having received at least 3 months and up to 3 years of ET, and a plan to continue the same ET during the study. The trial does not include a vulnerable population. Participants must have experienced endocrine therapy-related musculoskeletal (MSK) pain, such as arthralgia, myalgia, or bone pain, evaluated as at least grade 2 according to CTCAE V5.0 for a minimum of 4 weeks prior to enrollment. The general health status of participants is assessed with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and they must have adequate organ function. Lifestyle considerations such as diet and physical activity are not specified in the trial data. The selection criteria ensure that participants have completed baseline assessments of patient-reported questionnaires and have provided written informed consent in accordance with ICH/GCP and national/local regulations.

The clinical trial is designed to evaluate the efficacy of **duloxetine** and **furosemide** in managing endocrine therapy-related musculoskeletal pain in patients with early-stage ER positive HER2 negative breast cancer. This is a pragmatic, randomized, double-blind, controlled trial. The trial will span approximately four years, with an estimated recruitment start date in March 2025 and an anticipated end date in May 2029. Participants will be randomly assigned to one of the intervention arms, receiving either duloxetine or furosemide, both administered orally. The primary objective is to assess the change in skeletal pain as measured by the EORTC QLQ-BR42 at three months.

The sequence of study visits includes an initial screening visit, where eligibility criteria are confirmed, followed by baseline assessments. Participants will undergo regular follow-up visits at three and six months to monitor changes in pain levels and overall quality of life, as assessed by the EORTC QLQ-C30 and EORTC QLQ-BR42 questionnaires. The end-of-study visit will occur at the conclusion of the six-month treatment period. The expected length of participant involvement is six months, with conditions for early termination including significant adverse events or withdrawal of consent.

Inclusion criteria require participants to be adults aged 18 years or older, with ongoing adjuvant endocrine therapy for ER positive HER2 negative breast cancer stages I-III, and experiencing at least grade 2 musculoskeletal pain. Exclusion criteria are not explicitly detailed. The trial will also monitor secondary endpoints, including the discontinuation of endocrine therapy and changes in global health status and emotional functioning. Safety will be assessed according to the CTCAE Version 5.0 for adverse events. Participants must adhere to contraceptive measures if of childbearing potential and meet specific organ function criteria to ensure safety and compliance throughout the trial.

The clinical trial involves the administration of two **experimental medications**: **furosemide** and **duloxetine**. **Furosemide** is a diuretic with the active substances **amiloride hydrochloride** and **furosemide**. It is administered orally in a pharmaceutical form identified as PHF00245MIG. The maximum daily dose of furosemide is 40 mg, with a total maximum dose of 7360 mg over a treatment period of up to 6 months. The administration schedule is designed to ensure optimal therapeutic outcomes while monitoring participant compliance through regular assessments.

**Duloxetine** is the second experimental medication used in this trial. It is administered orally in a pharmaceutical form identified as PHF00091MIG. The active substance, **duloxetine**, is a chemical compound with a maximum daily dose of 60 mg and a total maximum dose of 10830 mg over a treatment period of up to 6 months. The dosing schedule is structured to maintain consistent therapeutic levels, and participant adherence is monitored throughout the study duration.

Both medications are administered as part of a randomized controlled trial aimed at improving the quality of life for patients experiencing musculoskeletal pain related to endocrine therapy for early breast cancer. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The study's primary objective is to evaluate the efficacy of these interventions in controlling endocrine therapy-related musculoskeletal pain, including arthralgias, myalgias, and bone pain, at the 3-month mark.

Efficacy in the clinical trial titled "EORTC 2237-BCG-QLG: Improvement of Quality of Life through supportive treatments for Endocrine Therapy – related symptoms in patients with early Breast cancer; A pragmatic randomized Controlled Trial (QOL-ET-BC)" will be assessed using both primary and secondary endpoints. The primary endpoint is the change from baseline in the skeletal scale as assessed by the EORTC QLQ-BR42 at month 3. This scale evaluates issues such as joint problems, stiffness, pain, and aches or pains in the bones.

Secondary endpoints include the discontinuation of endocrine therapy, changes from baseline in the skeletal scale at month 6, and changes in Global health status/QoL and Emotional functioning scales according to the EORTC-QLQ-C30 questionnaire at 3 and 6 months. Additionally, changes from baseline in the Endocrine therapy symptoms scale according to the EORTC-BR42 questionnaire at 3 and 6 months will be measured. Safety will be monitored according to the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 for toxicity and Serious Adverse Event reporting.