InfertilityREFRESHNCT02061228
REFRESH: Receptivity Enhancement by Follicular-phase Renewal After Endometrial ScratcHing
A study testing Pipelle de Cornier® in people with Infertility, run by Universitair Ziekenhuis Brussel at 1 site in Belgium.
Trial summary
A randomised controlled open-label clinical trial to assess the effect of artificially induced endometrial injury and repair during ovarian stimulation on the clinical pregnancy rate of an antagonist downregulated in-vitro fertilisation cycle Read more about this study
- Who is it for?
- Ages 18 to 40 years, women only
- Conditions the study is for
- Infertility
- What is being tested?
- Pipelle de Cornier®
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 200 participants
- Where
- 1 siteBelgium
- Study dates
- Mar 2014to 30 Sep 2018
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- Fresh IVF/ICSI cycle
- Antagonist down-regulation
- Signed informed consent
Who cannot join
- Other known reasons for impaired implantation (i.e. hydrosalpinx, fibroid distorting the endometrial cavity, Asherman's syndrome, thrombophilia or endometrial tuberculosis)
- Oocyte donation acceptors
- Frozen egg transfers
- Embryos planned to undergo preimplantation genetic diagnosis (PGD)
- BMI >35 or <18
- Women already recruited for another trial on medically assisted procreation during the same cycle
- Women who have previously enrolled in the trial
- Those unable to comprehend the investigational nature of the proposed study
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Endometrial Receptivity Enhancement Through Induced Injury and Repair During Ovarian Stimulation in an Antagonist Down-regulated Cycle
A randomised controlled open-label clinical trial to assess the effect of artificially induced endometrial injury and repair during ovarian stimulation on the clinical pregnancy rate of an antagonist downregulated in-vitro fertilisation cycle
Read the detailed description
Ovarian stimulation, ultrasound and hormonal monitoring, ovulation induction, oocyte retrieval, embryology procedure, IVF and luteal support will be according to how they are normally performed in our centre.
All women included will undergo artificial ovarian stimulation with gonadotropin-releasing hormone (GnRH) antagonist downregulation with daily injections of either ganirelix or cetrorelix. Treating physicians will opt on which exogenous gonadotropins should be used according to the patient's profile and preference and can include either recombinant follicle stimulating hormone (FSH) or highly purified urinary human menopausal gonadotropin (HP-HMG). Ovarian stimulation will commence after it is confirmed that the patient is not pregnant and has basal levels of oestradiol, progesterone, FSH and luteinizing hormone (LH). The stimulation will be monitored simultaneously by pelvic ultrasound and hormonal analysis (oestradiol, progesterone), starting on day 6 of stimulation and then every 1 to 3 days, according to the individual endocrine profile and follicular development.
Final oocyte maturation will be triggered with either 5000/10000 IU of human menopausal human chorionic gonadotropin (hCG) or 150 IU of recombinant hCG when more than 2 follicles of ≥17 mm are present. Oocyte retrieval will be performed 36 hours after hCG administration under either local anaesthesia with analgesic premedication or general anaesthesia, according to patient preference.
IVF or IVF/intracytoplasmatic sperm injection (ICSI) will be performed, using the specimen of sperm made available by the male progenitor on the day of oocyte retrieval. According to embryo quality, embryo transfer to the uterine cavity will be performed on either the 3rd or 5th day of development under ultrasound guidance whenever possible. Following embryo transfer, luteal support will be provided with vaginally administered progesterone 200 mg tid.
For clarity, cycle cancelation is defined as any interruption of the ART process that occurs before fresh embryo transfer. Cycle cancelation will occur a) upon patient request, b) if inadequate follicular development occurs, c) if no embryo is available for transfer.
- Conditions
- Infertility
- Being tested
- Pipelle de Cornier®
- Medical subject headings
- Infertility
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Pipelle de Cornier®Device
Women in the intervention group will undergo an endometrial biopsy on the 6th day of ovarian stimulation using a Pipelle de Cornier® (CCD International, Paris, France). This class I individually and sterile-packaged medical device, complies with Directive 93/42/European Economic Community (EEC) and is routinely used in our centre for endometrial sampling. It is comprised of a flexible disposable polypropylene suction cannula with an outer diameter of 3.1 mm and a 2.4 mm diameter opening on the distal end, on one side of the cannula. An inner plunger creates a vacuum essential for the blind endometrial biopsy. After the introduction of the Pipelle into the uterine cavity, it will be rotated 360 degrees and moved up and down four times after withdrawing the piston.
| Study group | Role | What they receive |
|---|---|---|
| Control arm | No intervention | Women undergoing exogenous gonadotropin ovarian stimulation for ART in an antagonist downregulated cycle. |
| Induced endometrial injury arm | Experimental | Women undergoing exogenous gonadotropin ovarian stimulation for ART in an antagonist downregulated cycle. Additionally, they will undergo an endometrial biopsy on the 6th day of ovarian stimulation using a Pipelle de Cornier® (CCD International, Paris, France). Receives: Device: Pipelle de Cornier® |
What is being measured
The primary outcome is the main question the study is designed to answer.
Clinical pregnancy rate
Sample size calculation was based on the adequate sample which would simultaneously 1) allow two safety-check interim analyses (at one-third and two-thirds of recruitment) and 2) have an 80% power to detect an increase of 15% in clinical pregnancy rate (from 32% to 47%) in the intervention group [using a two-side Fisher-exact test with a significance level (alfa) of 0.05]. Using a 1:1 randomisation ratio, each group would require approximately 180 patients, adding up to a total of 360 patients required for the trial.
Measured: 12 weeks
Secondary outcomes (3)
Live-birth rate
Delivery of at least one live born
Measured: 42 weeks
Complication rate
Pain during biopsy, failed biospy and occurance of a premature delivery (<37 weeks) and low birth weight delivery (<2500 g)
Measured: 42 weeks
Effect on the endometrial histology and expression
Histology and RNA expression analysis of collected samples
Measured: 2 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Feb 2014 (estimated)
- Study startMar 2014
- Primary completion26 Feb 2018
- Study completion30 Sep 2018
Why it stopped: Safety concerns, apparent futility and protracted recruitment
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for InfertilityStudies of the same condition, open and under way.
- More trials run by Universitair Ziekenhuis BrusselThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 200 participants (actual)
Sponsor and investigators
- Lead sponsor
- Universitair Ziekenhuis Brussel
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Samuel Santos-Ribeiro, Universitair Ziekenhuis Brussel
- Investigators
- Samuel Santos-Ribeiro, MD, Principal investigator, Universitair Ziekenhuis BrusselShari Mackens, MD, Study chair, Universitair Ziekenhuis BrusselDominic Stoop, PhD, Principal investigator, Universitair Ziekenhuis BrusselHerman Tournaye, PhD, Study chair, Universitair Ziekenhuis Brussel
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02061228
- Sponsor's protocol ID
- 29012014REFRESH
- Other IDs
- 2014-000442-29, 2014
- Acronym
- REFRESH
- Status last verified
- Dec 2019
- First submitted
- 10 Feb 2014
- Last updated
- 18 Dec 2019
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Publications
Mackens S, Santos-Ribeiro S, Racca A, Daneels D, Koch A, Essahib W, Verpoest W, Bourgain C, Van Riet I, Tournaye H, Brosens JJ, Lee YH, Blockeel C, Van de Velde H. The proliferative phase endometrium in IVF/ICSI: an in-cycle molecular analysis predictive of the outcome following fresh embryo transfer. Hum Reprod. 2020 Jan 1;35(1):130-144. doi: 10.1093/humrep/dez218.
PubMed 31916571Santos-Ribeiro S, Mackens S, Tournaye H, Blockeel C, Stoop D. Endometrial receptivity enhancement through induced injury and repair during ovarian stimulation: the Receptivity Enhancement by Follicular-phase Renewal after Endometrial ScratcHing (REFRESH) trial protocol. Hum Reprod Open. 2017 Nov 24;2017(3):hox022. doi: 10.1093/hropen/hox022. eCollection 2017.
PubMed 30895236
Study at a glance
From the registry record, last updated by the sponsor on 18 Dec 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Endometrial Receptivity Enhancement Through Induced Injury and Repair During Ovarian Stimulation in an Antagonist Down-regulated Cycle
- ClinicalTrials.gov ID
- NCT02061228
- Acronym / sponsor ID
- REFRESH / 29012014REFRESH
- Conditions
- Infertility
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Safety concerns, apparent futility and protracted recruitment
- Enrolment
- 200 participants (actual)
- Lead sponsor
- Universitair Ziekenhuis BrusselUniversity, hospital or other
- Study start
- Mar 2014
- Primary completion
- 26 Feb 2018 (actual)
- Study completion
- 30 Sep 2018 (actual)
- First posted
- 12 Feb 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
A randomised controlled open-label clinical trial to assess the effect of artificially induced endometrial injury and repair during ovarian stimulation on the clinical pregnancy rate of an antagonist downregulated in-vitro fertilisation cycle
Detailed description
Ovarian stimulation, ultrasound and hormonal monitoring, ovulation induction, oocyte retrieval, embryology procedure, IVF and luteal support will be according to how they are normally performed in our centre.
All women included will undergo artificial ovarian stimulation with gonadotropin-releasing hormone (GnRH) antagonist downregulation with daily injections of either ganirelix or cetrorelix. Treating physicians will opt on which exogenous gonadotropins should be used according to the patient's profile and preference and can include either recombinant follicle stimulating hormone (FSH) or highly purified urinary human menopausal gonadotropin (HP-HMG). Ovarian stimulation will commence after it is confirmed that the patient is not pregnant and has basal levels of oestradiol, progesterone, FSH and luteinizing hormone (LH). The stimulation will be monitored simultaneously by pelvic ultrasound and hormonal analysis (oestradiol, progesterone), starting on day 6 of stimulation and then every 1 to 3 days, according to the individual endocrine profile and follicular development.
Final oocyte maturation will be triggered with either 5000/10000 IU of human menopausal human chorionic gonadotropin (hCG) or 150 IU of recombinant hCG when more than 2 follicles of ≥17 mm are present. Oocyte retrieval will be performed 36 hours after hCG administration under either local anaesthesia with analgesic premedication or general anaesthesia, according to patient preference.
IVF or IVF/intracytoplasmatic sperm injection (ICSI) will be performed, using the specimen of sperm made available by the male progenitor on the day of oocyte retrieval. According to embryo quality, embryo transfer to the uterine cavity will be performed on either the 3rd or 5th day of development under ultrasound guidance whenever possible. Following embryo transfer, luteal support will be provided with vaginally administered progesterone 200 mg tid.
For clarity, cycle cancelation is defined as any interruption of the ART process that occurs before fresh embryo transfer. Cycle cancelation will occur a) upon patient request, b) if inadequate follicular development occurs, c) if no embryo is available for transfer.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Control arm | No intervention | –Women undergoing exogenous gonadotropin ovarian stimulation for ART in an antagonist downregulated cycle. |
| Induced endometrial injury arm | Experimental | Device: Pipelle de Cornier®Women undergoing exogenous gonadotropin ovarian stimulation for ART in an antagonist downregulated cycle. Additionally, they will undergo an endometrial biopsy on the 6th day of ovarian stimulation using a Pipelle de Cornier® (CCD International, Paris, France). |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- Fresh IVF/ICSI cycle
- Antagonist down-regulation
- Signed informed consent
Key exclusion criteria (8 listed)
- Other known reasons for impaired implantation (i.e. hydrosalpinx, fibroid distorting the endometrial cavity, Asherman's syndrome, thrombophilia or endometrial tuberculosis)
- Oocyte donation acceptors
- Frozen egg transfers
- Embryos planned to undergo preimplantation genetic diagnosis (PGD)
- BMI >35 or <18
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Pipelle de Cornier®Women in the intervention group will undergo an endometrial biopsy on the 6th day of ovarian stimulation using a Pipelle de Cornier® (CCD International, Paris, France). This class I individually and sterile-packaged medical device, complies with Directive 93/42/European Economic Community (EEC) and is routinely used in our centre for endometrial sampling. It is comprised of a flexible disposable polypropylene suction cannula with an outer diameter of 3.1 mm and a 2.4 mm diameter opening on the distal end, on one side of the cannula. An inner plunger creates a vacuum essential for the blind endometrial biopsy. After the introduction of the Pipelle into the uterine cavity, it will be rotated 360 degrees and moved up and down four times after withdrawing the piston. | Device | Induced endometrial injury arm |
Primary outcome
Clinical pregnancy rate
Time frame: 12 weeks
Sample size calculation was based on the adequate sample which would simultaneously 1) allow two safety-check interim analyses (at one-third and two-thirds of recruitment) and 2) have an 80% power to detect an increase of 15% in clinical pregnancy rate (from 32% to 47%) in the intervention group [using a two-side Fisher-exact test with a significance level (alfa) of 0.05]. Using a 1:1 randomisation ratio, each group would require approximately 180 patients, adding up to a total of 360 patients required for the trial.
3 secondary outcomes
Live-birth rate
Time frame: 42 weeks
Complication rate
Time frame: 42 weeks
Effect on the endometrial histology and expression
Time frame: 2 weeks
Results and safety
The study was stopped early (reason given: Safety concerns, apparent futility and protracted recruitment). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Dec 2019.
- Derived from this study: PubMed 31916571Mackens S, Santos-Ribeiro S, Racca A, Daneels D, Koch A, Essahib W, Verpoest W, Bourgain C, Van Riet I, Tournaye H, Brosens JJ, Lee YH, Blockeel C, Van de Velde H. The proliferative phase endometrium in IVF/ICSI: an in-cycle molecular analysis predictive of the outcome following fresh embryo transfer. Hum Reprod. 2020 Jan 1;35(1):130-144. doi: 10.1093/humrep/dez218.
- Derived from this study: PubMed 30895236Santos-Ribeiro S, Mackens S, Tournaye H, Blockeel C, Stoop D. Endometrial receptivity enhancement through induced injury and repair during ovarian stimulation: the Receptivity Enhancement by Follicular-phase Renewal after Endometrial ScratcHing (REFRESH) trial protocol. Hum Reprod Open. 2017 Nov 24;2017(3):hox022. doi: 10.1093/hropen/hox022. eCollection 2017.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Samuel Santos-Ribeiro, MD principal investigator
Universitair Ziekenhuis Brussel
Shari Mackens, MD study chair
Universitair Ziekenhuis Brussel
Dominic Stoop, PhD principal investigator
Universitair Ziekenhuis Brussel
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Pipelle de Cornier® in people with Infertility, run by Universitair Ziekenhuis Brussel at 1 site in Belgium.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 18 Dec 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was stopped early (reason given: Safety concerns, apparent futility and protracted recruitment). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Clinical pregnancy rate (time frame: 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02061228, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Dec 2019.