Comparison of Iodixanol and Ethyl Esters of Iodised Fatty Acids for Hysterosalpingography in Women with Unexplained Infertility: A Randomized Controlled Trial

The primary objective of this study is to evaluate the effectiveness of **hysterosalpingography (HSG)** using oil-based versus water-based contrast media in achieving conception leading to live birth. This is clinically relevant as it aims to determine the optimal contrast medium for improving fertility outcomes in women with **infertility**. The study focuses on the occurrence of a positive pregnancy test followed by a live birth within six months post-randomization.

Secondary objectives include assessing various pregnancy-related outcomes and complications, such as:

• Biochemical pregnancy
• Clinical pregnancy
• Ongoing pregnancy
• Miscarriage
• Ectopic pregnancy
• Multiple pregnancy
• Time to event (pregnancy)
• Complications following HSG (infection, intravasation)
• Pregnancy outcomes (e.g., birth weight)
• Pregnancy complications
• Stillbirth
• Thyroid function of the woman (before and one month after HSG)
• Neonatal outcomes
• Additional fertility treatments (intra-uterine insemination, IVF, IVF/ICSI)
• Costs within six months after randomization
• Thyroid function of neonate (determined by heelprick)
• Anxiety level prior to HSG

The clinical trial involves a total of **437 participants** who are exclusively **female**. The study population is characterized by women experiencing **infertility**, specifically those with ovulation disorders, defined as having fewer than eight menstrual cycles per year, or those at high risk for tubal pathology. Participants are above the age of 38, and the trial does not include male subjects. The selection criteria focus on women with a medical history that may include positive chlamydia infection, pelvic inflammatory disease, known endometriosis, or previous abdominal surgeries such as tubectomy for ectopic pregnancy and appendectomy. The trial population is considered vulnerable, and lifestyle factors such as diet and physical activity are not specified in the available data. The sponsor has not provided additional information regarding the general health status or specific lifestyle considerations of the participants.

The clinical trial is designed as a **randomized controlled trial** to evaluate the efficacy of oil-based versus water-based contrast media for hysterosalpingography (HSG) in women experiencing **infertility**. The primary objective is to assess conception leading to live birth within six months post-randomization. The trial will involve the administration of two products: VISIPAQUE 320 mg I/ml and Lipiodol Ultra Fluide, 480 mg I/ml, both in the form of a **solution for injection** and administered via intrauterine use. The trial is expected to conclude by August 1, 2025, with recruitment having commenced on August 20, 2019.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on criteria such as ovulation disorders, high risk for tubal pathology, and age above 38 years. Following randomization, participants will receive the assigned contrast media during the HSG procedure. Follow-up visits will be scheduled to monitor outcomes, including biochemical and clinical pregnancy, ongoing pregnancy, and any complications such as infection or intravasation. The end-of-study visit will assess the primary endpoint of live birth and secondary endpoints, including pregnancy outcomes and thyroid function.

The expected duration of participant involvement is up to six months post-randomization, with conditions for early termination including withdrawal of consent or adverse events. The trial will ensure adherence to ethical standards and regulatory requirements, with all procedures conducted under blinded conditions to maintain the integrity of the data. The trial's design and methodology aim to provide robust evidence on the comparative effectiveness of the two contrast media in enhancing fertility outcomes.

The clinical trial involves the use of two experimental medications, both administered as a **solution for injection** via the intrauterine route. The first experimental medication is **VISIPAQUE 320 mg I/ml**, containing the active substance **iodixanol**. This pharmaceutical form is a solution for injection, specifically designed for intrauterine use. The maximum daily and total dose for this medication is 50 ml, with a treatment period limited to a single day. The medication is manufactured by GE Healthcare B.V. and is authorized for use in the Netherlands under the marketing authorization number RVG 17665. The active substance, iodixanol, is of chemical origin and classified under the ATC code V08AB09.

The second experimental medication is **Lipiodol Ultra Fluide, 480 mg I/ml**, which contains **ethyl esters of iodised fatty acids from poppyseed oil** as the active substance. Similar to the first medication, it is also a solution for injection intended for intrauterine use. The maximum daily and total dose for Lipiodol Ultra Fluide is 15 ml, with the treatment period also restricted to one day. This medication is produced by Guerbet and holds the marketing authorization number RVG 02806 in the Netherlands. The active substance is derived from a specified substance group and is categorized under the ATC code V08AD01.

Both medications are utilized in the context of a randomized controlled trial aimed at evaluating their efficacy in hysterosalpingography (HSG) for infertile women. The trial's main objective is to achieve conception leading to live birth, with a positive pregnancy test within six months post-randomization. Participant compliance with the dosing schedule is monitored to ensure adherence to the trial protocol.

The efficacy of the clinical trial titled "Oil- versus water-based contrast media for hysterosalpingography (HSG) in infertile women with unevaluated indications: a randomized controlled trial (H2Oil-2 study)" will be assessed primarily through the endpoint of conception leading to live birth, with a positive pregnancy test preceding the pregnancy within 6 months after randomization. This primary endpoint is designed to evaluate the effectiveness of the contrast media used during HSG in facilitating conception and successful pregnancy outcomes.

Secondary endpoints will provide additional insights into the efficacy of the intervention. These include biochemical pregnancy, clinical pregnancy, ongoing pregnancy, miscarriage, ectopic pregnancy, multiple pregnancy, time to pregnancy, and complications following HSG such as infection and intravasation. Further secondary endpoints encompass pregnancy outcomes like birth weight, pregnancy complications, stillbirth, thyroid function of the woman before and one month after HSG, neonatal outcomes, additional fertility treatments (e.g., intra-uterine insemination, IVF, IVF/ICSI), costs within 6 months after randomization, and thyroid function of the neonate determined by heelprick.

The trial will utilize a randomized controlled design to ensure the reliability of the results. The schedule for measuring and collecting these efficacy parameters will be aligned with the trial's timeline, with specific timepoints for assessments not explicitly detailed in the provided data. The trial is authorized to take place in the Netherlands, with the estimated end date set for August 1, 2025. The trial phase is categorized as phase 6, indicating a focus on evaluating the intervention's effectiveness in a real-world setting.