Effect of Oxytocin Antagonist on Reduction of Uterine Contractions
Condition: In Vitro Fertilisation (IVF) Treatment
Study type: Interventional
Phase: Phase 2

Summary: 
      The main purpose of this clinical research trial was to evaluate the effects of barusiban
      compared to placebo on uterine contractions on luteal phase uterine contractions in oocyte
      donors supplemented with progesterone.
    

Detailed description: 
      This was a randomised, double-blind, parallel groups, placebo-controlled, multi-centre trial.
      It was designed to evaluate the efficacy of barusiban, a selective oxytocin antagonist, on
      reducing the frequency of uterine contractions on the day of embryo transfer.

      Participants in this trial were oocyte donors who had undergone controlled ovarian
      hyperstimulation in the long gonadotrophin-releasing hormone (GnRH) agonist protocol or the
      multiple-dose GnRH antagonist protocol, had received human chorionic gonadotrophin (hCG) for
      triggering of final follicular maturation and had undergone oocyte retrieval (OR) with a
      yield of ≥ 6 cumulus-oocyte-complexes. The duration of the trial was two days: Day OR +2
      (screening, randomisation and dosing of investigational medicinal product) and Day OR +3
      (end-of-trial).

      On Day OR +2, participants were screened and subsequently randomised to barusiban or placebo.
      All participants received an intravenous (IV) bolus for 1 minute followed by an IV infusion
      for up to 59 minutes, administered via an indwelling catheter, of barusiban or placebo. Bolus
      volume and infusion rate were identical for barusiban and placebo. A mock embryo transfer
      (MET) procedure was performed 40 minutes after start of dosing and included intrauterine
      administration of a non-radioactive ultrasound contrast agent (SONOVUE) via the embryo
      transfer catheter. Transvaginal ultrasound of around 5 minutes duration was performed at
      seven time points on Day OR +2 and covered a span of approximately 2.5 hours including
      pre-dosing, during dosing, before and after mock embryo transfer, and post-dosing. The
      transvaginal ultrasound recordings were analysed for frequency of uterine contractions and
      other uterine contractility parameters by a central independent assessor, blinded to
      treatment allocation. Movement of the ultrasound contrast agent after the mock embryo
      transfer procedure was evaluated by the central independent assessor.

      As an attempt to document the impact of uterine contractions on potential embryo expulsion,
      an exploratory evaluation of the movement of an ultrasound contrast agent
      (SONOVUE)administered intrauterinely via an embryo transfer catheter during the mock embryo
      transfer was performed. The anatomical point of release of the ultrasound contrast agent
      (correct or incorrect deposition site, and estimated distance from fundus) as well as any
      immediate movement (yes/no) of the bolus was recorded by the central independent assessor.

      Definitions:

      The frequency of uterine contractions was defined as the number of uterine contractions per
      minute. A contraction was defined as one sequential upward and downward vertical displacement
      of the endometrial / myometrial interface over time. The frequency was the inverse of period
      converted to contractions per minute.

      The period was the average time it took to complete one contraction during the studied time
      interval. It was calculated from both the peaks and the troughs at the anterior and posterior
      endometrial /myometrial interfaces. The period was measured in seconds per contraction.

      The external contractile measure was the mean wave amplitude in mm at the lumenal surface.
      This metric was measured at the lumenal peaks and troughs only and was a measurement designed
      to study the relationship between endometrial wave activity, manifest as bulk motion of the
      uterus, versus internal contractile strength. The external contractile measure was reported
      in mm/contraction. The external contractile measure quantified the movement of the uterus as
      a whole as measured at the lumen, i.e. the motion of the uterus relative to the body.

      The internal contractile measure was the strength of the contractions based upon the sum of
      the contraction amplitudes measured at the anterior and posterior endometrial / myometrial
      interfaces. The amplitude at each interface was defined as the average difference between the
      endometrial / myometrial-lumenal distance measured at the peaks and troughs of the
      endometrial / myometrial interfaces. The internal contractile measure was reported in
      mm/contraction. The internal contractile measure quantified the movement of the endometrium
      relative to the lumen, i.e. the motion internal to the uterus.

      The total contractile measure was the sum of the external contractile measure and the
      internal contractile measure and quantified total muscle movement in the uterus. If the waves
      at the anterior and posterior endometrial / myometrial interfaces were in phase then there
      was no endometrial motion relative to the lumen and the motion was a pure wave motion with
      the internal contractile measure equal to zero. The total contractile measure was reported in
      mm/contraction.

      Inter-subendometrial space was measured clinically as the distance between the anterior
      stratum basalis and posterior stratum basalis layers in mid-sagittal plane at an anatomic
      location between 5 and 10 mm from the fundus. All clinical inter-subendometrial space
      measurements were made by selecting a clear image of the uterus, waiting for any contractions
      to pass and freezing the image.

      A linear distance measurement was then taken between the anatomic landmarks described above.
      Inter-subendometrial space was calculated from existing measurements using the mean of all
      measurements identifying the endometrial-myometrial interfaces on the superior and inferior
      surfaces in each endometrial strip when the arrows identifying endometrial contractions were
      placed for motion analysis. Inter-subendometrial space was reported in mm.

      The direction of wave propagation was classified as one of the following:

        -  Fundal (from cervix to fundus)

        -  Cervical (from fundus to cervix)

        -  Convergent (opposing) starting simultaneously from cervix and fundus

        -  Focal local contractions (which are not involving the whole uterine walls)

        -  No activity

        -  NE: not evaluable At each assessment time point, the most predominant type of direction
           of wave propagation was recorded.

      Dispersion of the ultrasound contrast agent bolus after release from the catheter was
      recorded as yes/no and number of dispersed fragments, if applicable.

      Location of the ultrasound contrast agent bolus was categorised as follows:

        -  Upper 1/3 (fundal) part of uterine cavity

        -  Central 1/3 of uterine cavity

        -  Lower 1/3 (cervical) part of the uterine cavity

        -  Intralumenal part of Fallopian tube

        -  Intra-cervical

        -  Vaginal

        -  NE: not evaluable Distance from the apex of the fundus at the myometrial-endometrial
           interface to the position of the microdroplet of ultrasound contrast agent was recorded
           in mm.

      Velocity of the bolus of ultrasound contrast agent was assessed from distance and time, and
      was recorded in mm/hour.
    

Intervention name(s): Barusiban; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): IV bolus of 20 mg for 1 minute followed by an IV infusion of 19 mg for up to 59 minutes. The maximum total duration of administration was 60 minutes.; IV bolus of saline (sodium chloride 0.9%) for 1 minute followed by an IV infusion of saline (sodium chloride 0.9%) for up to 59 minutes. Details on injection volume, infusion rates and doses are tabulated below.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment