Non-Inferiority Trial of Mifepristone and Letrozole Versus Methotrexate in the Management of Ectopic Pregnancy

The primary objective of this study is to evaluate if the combination of **mifepristone** and **letrozole** is non-inferior to **methotrexate** in treating **ectopic pregnancy** within a non-inferiority margin of 10%. This is clinically relevant as it may offer an alternative treatment option with potentially different safety and efficacy profiles, which could impact patient management and outcomes in ectopic pregnancy.

Secondary objectives include:

• Evaluating differences in treatment-related side effects between the combination of mifepristone and letrozole compared to methotrexate.
• Assessing differences in the proportion of patients requiring additional medical and/or surgical interventions between the groups.
• Determining differences in time to treatment response between the groups.
• Evaluating differences in post-treatment pregnancy rate and ovarian reserve between the groups.
• Identifying biomarkers for ectopic versus intrauterine pregnancy.
• Investigating background factors associated with successful treatment.

The clinical trial focuses on evaluating the treatment of **ectopic pregnancy** using a combination of mifepristone and letrozole compared to methotrexate. The study population consists exclusively of female participants, aged 18 years and older, who have a confirmed or highly suspected ectopic pregnancy requiring treatment. Participants must be able to comprehend verbal and written information and provide written consent to partake in the trial. The sponsor has not provided the total number of participants involved in the study. The trial does not include male subjects or vulnerable populations. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of a combination therapy involving **mifepristone** and **letrozole** compared to **methotrexate** in the treatment of ectopic pregnancy. This is a randomized, controlled, non-inferiority trial with a primary objective to determine if the combination therapy is non-inferior to methotrexate within a 10% margin. The trial is categorized as a Phase IV study, focusing on the safety and efficacy of existing products with marketing authorization. The trial is expected to conclude by December 31, 2026, with recruitment having commenced on September 1, 2023.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as confirmed ectopic pregnancy, age of 18 years or older, and the ability to provide informed consent. The trial involves multiple follow-up visits to monitor treatment response and safety, with the primary endpoint being the decline of serum hCG to less than 2 IU/L within 60 days without additional interventions. Secondary endpoints include the incidence of adverse events, time to resolution of ectopic pregnancy, and various biochemical and clinical assessments.

The expected duration of participant involvement is up to 60 days, with conditions for early termination including withdrawal of consent or the need for additional medical or surgical intervention. The trial employs a double-blind methodology to ensure unbiased results, with participants and investigators unaware of the treatment allocation. The study will also assess secondary outcomes such as adverse events, time to pregnancy, and pregnancy rates within the first year post-treatment. The trial's design ensures rigorous monitoring and data collection to evaluate the safety and efficacy of the treatment regimens.

The clinical trial involves the administration of **Methotrexate**, marketed as Methotrexate Teva 100 mg/ml, which is provided as a concentrate for solution for infusion. This pharmaceutical form is classified as an **injection** and is administered via **intramuscular injection**. The maximum daily and total dose is 100 mg, with a treatment period limited to one day. Methotrexate is a chemical substance, and its role in the trial is as a comparator to evaluate its efficacy against the test combination of other medications.

**Letrozole**, marketed as Letrozole Sandoz 2.5 mg, is provided in the form of film-coated tablets. This medication is administered **orally** with a maximum daily and total dose of 10 mg. The treatment period for Letrozole extends up to ten days. Letrozole is a chemical substance and is part of the test combination in the trial, aiming to assess its non-inferiority in treating ectopic pregnancy when used in conjunction with Mifepristone.

**Mifepristone**, marketed as Mifegyne 200 mg, is available in tablet form and is also administered **orally**. The maximum daily and total dose for Mifepristone is 200 mg, with a treatment period of one day. Mifepristone, a chemical substance, is included in the test combination alongside Letrozole to determine its effectiveness in comparison to Methotrexate for the treatment of ectopic pregnancy.

The efficacy of the treatment in this clinical trial will be assessed primarily by evaluating the proportion of patients who achieve a successful treatment response. This is defined as a decline in serum **hCG** levels to less than 2 IU/L without the need for any additional medical or surgical intervention within 60 days of treatment. This primary endpoint will provide a direct measure of the treatment's effectiveness in resolving ectopic pregnancy.

Secondary endpoints will include several additional measures to further assess efficacy and safety. These include the proportion of patients experiencing adverse events (AE) and serious adverse events (SAE) related to the treatment, as judged by the investigators. The need for additional medical or surgical interventions in each group will also be evaluated. Time to resolution of ectopic pregnancy, defined as the number of days from the start of medical treatment to achieving hCG levels below 2 IU/L, will be recorded. Additionally, **AMH** levels will be measured at baseline, 1 month, and 3 months post-treatment. The study will also assess time to pregnancy and pregnancy rates within the first year after treatment. Micro RNA profiles and **CA-125** levels will be analyzed, comparing patients treated for ectopic pregnancy to those with ultrasound-confirmed intrauterine pregnancy at the same gestational period. Background factors will be compared between patients with successful and unsuccessful treatment outcomes.