Table 1

Overview and timeline of the study

PhaseScreeningFertility treatmentFollow-up if not pregnant at 6 monthsFollow-up if not pregnant at
6 months
VisitScreening visit
(V1)
Start study visit
(V2)
Study visit
(V3)
Multiple visits depending on treatment plan (n)Study visit
(V4)
Study visit
(V5)
Follow-up visit
(V6a)
Follow-up visit
(V6b)
Follow-up visit
(V6c)
Follow-up visit
(V6d)
Follow-up visit
(V7)
Timing of visits−8 weeks to day 1Day 1+4 weeks (+2 weeks)+26 weeks (+2 weeks)+26 weeks (+8 weeks)+52 weeks (+2 weeks)15 weeks pregnancy (+2 weeks) (o)25 weeks pregnancy (+2 weeks) (o)35 weeks pregnancy (+2 weeks) (o)Post partum or miscarriage (+17 weeks) (o)
Informed consent (a)xx
Inclusion/exclusion criteriax
Demographics (b)x
Baseline data (c)x
Relevant medical and surgical history (d)x
Current medicationx
TSH, FT4xx (p)x (p)x
Anti-TPO, anti-TSH recx
Randomisationx (q)x (q)
Questionnaires:
  • EQ-5D-5L

  • FertiQol

x (r)x (r)x (t)
Hyfosy with or without tubal flushing with Lipiodol Ultra Fluide (e)(f)x (s)
Questionnaire:
VAS pain scores
x (u)
Use of analgetics during Hyfosyx
Discussion of fertility treatmentx (g)x
Phone contactx (v)x (w)x (x)x (x)x (y)
Screening and observation presence of pregnancy (h)xxxxx
Pregnancy and type (i)x
Evaluation reproductive outcome (j)x
Evaluation neonatal outcome (k)x (z)
Adverse reactions, serious adverse events and concomitant medication (l)xxxxxxxxxx
Miscarriage reporting (m)xxxxxxxx
  • (a) Patient need to sign the initial informed consent form before study-specific assessments at screening visit (V1). Additional informed consent form needs to be signed at Follow-up visit (V7).

  • (b) Year of birth, age and ethnicity of the patient.

  • (c) BMI, smoker status, duration and type of infertility (primary–secondary) and previous results of the fertility workup of the patient. Total motile sperm count (TMC) of male partner if applicable (yes/no) and use of donor sperm (yes/no). TMC of male partner should be mentioned in patient record of female participant.

  • (d) Previous diagnosis of endometriosis, previous ectopic pregnancy, previous Chlamydia infection, previous pelvic inflammatory disease, previous appendicitis (ruptured/unruptured).

  • (e) In the intervention group, Hyfosy is followed by tubal flushing with Lipiodol Ultra Fluide if at least one patent tube is present. No tubal flushing with Lipiodol Ultra Fluide will be performed after Hyfosy in the control group. An intervention group patient with no patent tubes at the time of Hyfosy will not be treated with the IMP for safety reasons.

  • (f) In case of intervention group, the following Hyfosy-related aspects must be assessed: exact amount of Lipiodol Ultra Fluide injected, the presence of reflux, type of catheter used, tubal patency details, time interval between injection of ExEm Foam and Lipiodol Ultra Fluide and visualisation of Lipiodol Ultra Fluide under ultrasound guidance.

  • (g) Expectant management for 4–6 months and/or intrauterine insemination for 3–4 cycles, to have another three cycles in case of three cycles of donor insemination without pregnancy or three ovulatory ovulation induction cycles without pregnancy, can be proposed when at least one tube is patent. A fixed period of time to perform expectant management before starting IUI is not mandatory. If therapy does not lead to an ongoing pregnancy, IVF can be proposed. Diagnostic/therapeutic laparoscopy and/or in vitro fertilisation will be proposed in case of a bilateral tubal block.

  • (h) In case of pregnancy: pelvic ultrasound scan at 7–8 weeks of pregnancy at the fertility clinic or gynaecologist, and referral to the obstetric department for pregnancy follow-up (standard of care).

  • (i) Pregnant (yes/no), pregnancy type and date of first day of the last menstrual cycle within 6 months after Hyfosy. Pregnancy status at the end of the fertility treatment phase will define whether the patient is pregnant or not pregnant, and conclude the appropriate follow-up phase of the patient.

  • (j) Reproductive outcome and pregnancy complications.

  • (k) Delivery date, number of babies, gender and birth weight, gestational date at delivery, admission to neonatal care (if needed), full name baby(s) and birth date (to obtain thyroid function by heel prick test).

  • (l) Safety findings female participant and neonate (live birth till heel prick test).

  • (m) Contact to define date of miscarriage, performed as outpatient visit or by phone. In addition: phone contact to perform follow-up visit (V6a) at 52 weeks (+2 weeks) and if pregnant at study visit five also follow-up visit 7. Miscarriage definition: Spontaneous loss of an intrauterine pregnancy prior to 22 completed weeks of gestational age.

  • (n) Visits depending on treatment plan: consultation, pelvic ultrasound, serum hormonal analysis, intrauterine insemination, in vitro fertilisation (standard of care).

  • (o) The duration of pregnancy is calculated in weeks of amenorrhoea since first day of last menstrual period or related to expected date of delivery.

  • (p) If TSH and/or FT4 are abnormal, there will be a monthly (±2 weeks) check for TSH and FT4 until normalisation with a maximum of 6 months.

  • (q) Randomisation needs to be performed before Hyfosy but after successful screening by the local or central study coordinator. Patients may have no knowledge of the allocated group until all baseline assessments are performed.

  • (r) The questionnaires will be provided at screening electronically (or on paper as back-up), and need to be completed before Hyfosy on the start study visit (V2).

  • (s) A randomised patient who has no patent tube at the time of Hyfosy will appear ineligible at that time, but will still be followed up following the trial procedures.

  • (t) The questionnaires will be provided at study visit V5 electronically (or on paper as back-up), and need to be completed within 2 weeks after the visit.

  • (u) To be completed directly after Hyfosy and flush in the intervention group,.

  • (v) Contact to make appointment for study visit (V5). The patient’s menstrual cycle needs to be taken into account during scheduling to be able to determine on study visit (V5) if the patient became pregnant in the fertility treatment phase (ie, the first day of the last menstrual cycle in which the patient conceives was within 6 months after Hyfosy).

  • (w) Provide patient with electronic treatment report (paper as back-up) to be filled out and resend within 2 weeks before follow-up visit (V6a). Thereafter, contact to discuss treatment report: determine if the participant became pregnant outside the fertility treatment phase (after study visit V5), pregnancy type and treatment plan.

  • (x) Contact to follow-up on pregnancy and type of pregnancy. These phone calls do not need to be performed if the patient is already 15 and/or 25 weeks pregnant before study visit (V5), as the pregnancy will be followed up during the fertility treatment phase.

  • (y) Contact to make appointment for follow-up visit (V7).

  • (z) Not applicable in case of miscarriage.

  • Assessments and treatment IMP in bold are not standard of care and are reimbursed by the sponsor’s budget.

  • BMI, body mass index; EQ-5D-DL, Euro Quality - 5 dimensions -5 levels; FT4, Free Thyrxine 4; IMP, Investigational Medicinal Product; IUI, Intra-uterine Insemination; TPO, Thyroid Peroxidase; TSH, Thyroid Stimulating hormone; VAS, Visual Analogue Scale.