Phase II Randomized Trial Evaluating Loratadine and Sirolimus in Lymphangioleiomyomatosis Patients

The primary objective of this Phase-II randomized clinical trial is to evaluate the **safety profile** of loratadine in combination with rapamycin over a 48-week period in patients with **lymphangioleiomyomatosis** (LAM). This involves assessing the incidence of adverse events, categorized by intensity, severity, and their relation to the treatment, comparing the combination therapy to rapamycin monotherapy. The clinical relevance of this objective lies in determining the safety and potential benefits of combining loratadine with rapamycin, which could offer a new therapeutic approach for managing LAM.

Secondary objectives include: - Assessing the **quality of life** and progression-free survival time of patients. - Monitoring changes in the established LAM serum biomarker **VEGFD**. - Evaluating the utility of the major histamine-derived metabolite **methylimidazoleacetic acid (MIAA)** for monitoring disease progression and the biological treatment effect. These objectives aim to provide a comprehensive understanding of the treatment's impact on disease progression and patient well-being.

The clinical trial focuses on evaluating the safety profile of **loratadine** in combination with rapamycin in patients diagnosed with **lymphangioleiomyomatosis** (LAM). The study population consists exclusively of female participants, aged 18 years and older, who have a definitive diagnosis of LAM based on international consensus and clinical guidelines. Participants must have been diagnosed within the last 10 years and must be on stable doses of rapamycin for at least the last three months. The trial does not include a vulnerable population. Participants are required to have a forced expiratory volume in one second (FEV1) greater than 35% and a diffusing capacity of the lungs for carbon monoxide (DLCO) greater than 20%. Additionally, oxygen saturation at rest must be above 85% without supplemental oxygen. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that the study population is homogenous in terms of health status and treatment history, allowing for a focused assessment of the treatment's safety profile.

The clinical trial is a **Phase-II randomized** study designed to evaluate the safety profile of **loratadine** in combination with **rapamycin** in patients diagnosed with **lymphangioleiomyomatosis** (LAM). The trial employs a **double-blind, controlled** methodology to ensure unbiased results. The study is set to last for a total duration of 48 weeks, with participant involvement expected to span the entire period unless early termination criteria are met. Participants will be randomly assigned to receive either the combination therapy or **rapamycin** monotherapy, with the primary endpoint being the incidence of adverse effects such as nausea, diarrhea, abdominal pain, vomiting, headache, and hypertransaminasemia. Secondary endpoints include the maintenance of clinical stability, reduction in hospitalizations, lung transplant necessity, and mortality rates.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as a definitive diagnosis of LAM, FEV1 > 35%, DLCO > 20%, and oxygen saturation > 85% at rest. Participants must also have been on stable doses of **rapamycin** for at least three months prior to randomization. Follow-up visits will be conducted at regular intervals to monitor safety and efficacy, with assessments including clinical evaluations and laboratory tests. The end-of-study visit will conclude the trial, where final evaluations will be conducted to assess the long-term effects of the treatment.

Participants are expected to remain in the study for the full 48 weeks unless they experience significant adverse events, withdraw consent, or if the investigator deems it necessary for their safety. The trial's design ensures rigorous monitoring and adherence to ethical standards, with the aim of providing valuable insights into the treatment of LAM with **loratadine** and **rapamycin**.

The clinical trial involves the administration of **Loratadine**, marketed as Loratadina NORMON 10 mg Comprimidos EFG, which is a **tablet** formulation. The active substance, loratadine, is a chemical compound classified under the ATC code R06AX13. Each tablet contains 10 mg of loratadine, and the maximum daily dose is set at 10 mg. The route of administration is **oral use**, and the treatment period extends up to 48 weeks. The product is manufactured by Laboratorios Normon, S.A., and is not a pediatric formulation. The trial aims to evaluate the safety profile of loratadine in combination with rapamycin in patients with lymphangioleiomyomatosis (LAM).

In addition to loratadine, the study involves the use of **rapamycin** as a comparator treatment. Rapamycin is administered as a monotherapy to assess its safety profile compared to the combination therapy with loratadine. The trial's main objective is to evaluate the incidence of adverse events, considering their intensity, severity, and relation to the treatment. The dosing schedule and participant compliance are monitored throughout the study to ensure adherence to the treatment protocol.

The efficacy of the treatment in this Phase-II randomized clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint focuses on the incidence of adverse effects associated with the combination of **loratadine** and rapamycin, including symptoms such as nausea, diarrhea, abdominal pain, vomiting, headache, and hypertransaminasemia. Secondary endpoints include the maintenance of clinical stability, defined as a forced expiratory volume in one second (FEV1) drop of less than 10% or a diffusing capacity of the lungs for carbon monoxide (DLCO) drop of less than 15%, a decrease in the number of hospitalizations for any cause and specifically for respiratory causes, lung transplant, and death.