Evaluation of Contrast-Enhanced Ultrasound with Sulfur Hexafluoride for Diagnosing Adnexal Torsion in Suspected Cases: A Randomized Controlled Trial

The primary objective of this study is to evaluate a two-stage diagnostic strategy incorporating **contrast-enhanced ultrasound** compared to the standard diagnostic strategy, which does not include contrast evaluation, in cases of strong suspicion of **adnexal torsion**. The aim is to reduce the incidence of unnecessary emergency surgeries performed within six hours without confirmed torsion. This is clinically relevant as it seeks to improve diagnostic accuracy and prevent unwarranted surgical interventions, thereby reducing patient morbidity and healthcare costs.

Secondary objectives include:

• Comparing the effectiveness of the strategy including contrast ultrasound versus the standard strategy in patients without initial surgical management on various outcomes such as hospitalization rates, consultation rates, pain levels, secondary surgery rates, and complications related to delayed management of confirmed torsion.
• Assessing the effectiveness of the strategy in patients with initial surgical management by evaluating hospitalization duration, perioperative and postoperative complications, and pain levels.
• Evaluating the safety of administering SonoVue® in patients with a high suspicion of adnexal torsion, specifically within the experimental group.
• Assessing the acceptability and feasibility of the diagnostic procedure by relevant stakeholders, including gynecologists-obstetricians, to support the potential large-scale deployment of the strategy if proven effective.

The clinical trial focuses on evaluating a diagnostic strategy for **adnexal torsion**. The study population consists exclusively of female participants aged 18 and over, with no ongoing pregnancy or breastfeeding. Participants must have undergone a preliminary clinical examination relevant to the trial and have a strong suspicion of adnexal torsion with surgery planned. The trial does not include a vulnerable population, and all participants are required to be affiliated with or beneficiaries of a social security scheme. The sponsor has not provided information regarding the total number of participants. The selection criteria emphasize the absence of ongoing pregnancy or breastfeeding, ensuring the study's focus remains on the targeted medical condition without additional variables. Participants have been informed about the trial's organization, ensuring transparency and understanding of the study's objectives.

The clinical trial is designed to evaluate a two-stage diagnostic strategy for **adnexal torsion**, incorporating contrast-enhanced ultrasound compared to the standard diagnostic approach. This study is a randomized, controlled trial with an estimated duration from October 2024 to November 2027. Participants will be randomly assigned to either the experimental group, receiving the contrast-enhanced ultrasound, or the control group, undergoing the standard diagnostic procedure. The trial aims to assess the percentage of emergency surgical procedures performed without proven torsion within six hours of patient arrival.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility criteria are confirmed. Key inclusion criteria include being 18 years or older, having a strong suspicion of adnexal torsion with planned surgery, and not being pregnant or breastfeeding. Follow-up visits will occur at specified intervals to monitor outcomes such as hospitalization rates, pain levels, and any complications. The end-of-study visit will conclude the participant's involvement, with data collection on primary and secondary endpoints.

The expected length of participant involvement is approximately one month, with conditions for early termination including withdrawal of consent or the occurrence of serious adverse events. The trial will utilize **sulfur hexafluoride** as the active substance in the form of SonoVue, administered via intravenous infusion. The maximum daily and total dose is 4.8 ml, with a treatment period limited to one day. The study will ensure rigorous monitoring for any adverse events, particularly within 30 minutes post-injection, to ensure participant safety and data integrity.

The clinical trial involves the use of **SonoVue**, a diagnostic agent formulated as a **powder and solvent for dispersion for injection**. The active substance in SonoVue is **sulfur hexafluoride**, a chemical compound used as a contrast agent in ultrasound imaging. The pharmaceutical form of SonoVue is a dispersion for injection, specifically designed for intravenous infusion. The maximum daily dose and total dose of SonoVue is 4.8 milliliters, administered as a single dose. The treatment period is limited to one day, ensuring that the administration is completed within a short timeframe. The product is not a pediatric formulation and is not classified as an orphan drug. The administration of SonoVue is conducted under controlled conditions to ensure participant safety and compliance with the study protocol.

In this trial, the experimental treatment with SonoVue is compared to a standard diagnostic strategy that does not include contrast-enhanced ultrasound. The objective is to evaluate the effectiveness of a two-stage diagnostic strategy incorporating contrast evaluation in cases of suspected adnexal torsion. The comparator treatment involves the standard diagnostic approach without the use of SonoVue, serving as a control to assess the added value of the contrast agent in improving diagnostic accuracy. The study design ensures that all participants receive appropriate care, with the experimental and comparator treatments administered according to the established protocols. Participant compliance is monitored throughout the trial to ensure adherence to the dosing schedule and to collect accurate data on the outcomes of the diagnostic strategies being evaluated.

Efficacy in the clinical trial titled "COVARIAN: Contribution of contrast enhanced ultrasound for diagnosis of adnexal torsion: a randomized controlled trial" will be assessed using both primary and secondary endpoints. The primary endpoint is the percentage of surgical procedures performed in emergency (within 6 hours of patient arrival) without proven torsion, defined as no visible spiral turn during intraoperative assessment, in each group. This endpoint aims to evaluate the effectiveness of a two-stage diagnostic strategy that includes contrast-enhanced ultrasound compared to the standard diagnostic strategy without contrast.

Secondary endpoints include several measures to further assess the efficacy of the diagnostic strategy. These include the rate of hospitalization and consultation at 1 month, pain at 7 days evaluated by a numerical scale, rate of secondary surgery with proven torsion at 1 month, and rate of complications such as pelvic abscess, pelviperitonitis, necrotic aspect of the ovary, and non-conservative treatment at 1 month. Additionally, the length of hospitalization, intraoperative complications, postoperative complications at 1 month, and the incidence of serious adverse events within 30 minutes of injection of **SonoVue** will be collected. Quantitative and qualitative data from the process evaluation will also be compared to identify and remove potential obstacles to the use of contrast ultrasound in cases of suspected adnexal torsion.