IVFPhase 2RIOTCNCT04524026
RIOTC: Reducing the Impact of Ovarian Stimulation. Novel Approaches to Luteal Support in IVF-Study 2
A Phase 2 study testing Letrozole 5 mg in people with IVF, run by Nicholas Macklon at 2 sites in Denmark.
Trial summary
The goal of the randomised controlled study (RCT) is to identify novel strategies that can improve the luteal phase endocrinology after ovarian stimulation, with the aim of using less or no luteal support in IVF while making the endometrium thinner and more receptive to embryo implantation. Read more about this study
- Who is it for?
- Ages 18 to 35 years, women only
- Conditions the study is for
- IVF
- What is being tested?
- Letrozole 5 mg
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 25 participants
- Where
- 2 sitesDenmark
- Study dates
- 18 Sep 2018to 30 Nov 2020
- Phase
- Phase 2
- 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 35 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- Meet the clinical criteria for acceptance as oocyte donors (healthy women who volunteers to donate oocytes to other women).
- Regular ovulatory cycle of 26-32 days.
- Age: 18-35 years old.
- Written consent.
Who cannot join
- Contraindications for ovarian stimulation or aspiration of oocytes according to local guidelines
- Polycystic Ovary Syndrome (PCOS)
- Allergy towards study drug
- Women who have had a hormone or copper intra-uterine device (IUD) within 3 months
- Exclusion of patients after earlier inclusion in the study in case of
- Patient withdrawal of consent
Show all 11Show fewer
- Lack of compliance with medication
- Medical complication arising from IVF treatment that requires the cycle to be terminated
- Serious adverse events (SAE) or serious adverse reactions (SAR) including severe allergy to study drug.
- Specific ARs to study drug: severe degree of hot flushed, severe degree of nausea/vomiting, severe diarrhea, severe degree of muscle and joint pain.
- In case of exclusion of a patient after earlier inclusion in the study, a new patient will be included.
Trial locations and contacts
2 sites in 1 country.
Denmark2 sites
Herlev Hospitals Fertilitetsklinik
Herlev, 2730
Sjællands Fertilitetsklinik
Køge, 4600
About this study
Official title: RIOTC: Reducing the Impact of Ovarian Stimulation. Novel Approaches to Luteal Support in IVF - Study 2
The goal of the randomised controlled study (RCT) is to identify novel strategies that can improve the luteal phase endocrinology after ovarian stimulation, with the aim of using less or no luteal support in IVF while making the endometrium thinner and more receptive to embryo implantation.
Read the detailed description
The high estradiol levels generated in IVF by multiple dominant follicles at the follicular-luteal phase transition generate powerful negative feedback at the pituitary gland, effectively switching off gonadotropin production. Without stimulation by endogenous luteinizing hormone (LH), the corpora lutea undergo involution and menstruation follows, preventing the establishment of pregnancy.
To address these detrimental effects of ovarian stimulation, the investigators will do a RCT with the use of aromatase inhibitors, which suppress the conversion of androgens to estrogens to ameliorate the unwanted effects of high estrogens.
This study is designed to test the hypothesis that preventing supra-physiological estrogen levels during ovarian stimulation restricts pituitary suppression sufficiently to allow LH levels to rise and support the corpora lutea, leading to a normal post-ovulatory luteal phase, evidenced by a normal duration and luteal phase endocrine profile. To test this, consenting oocyte donors will be randomized to receive co-treatment with aromatase inhibitors or no co-treatment during ovarian stimulation. Following oocyte retrieval, no luteal support will be provided to donors in both Groups.
- Conditions
- IVF
- Being tested
- Letrozole 5 mg
- Keywords
- Letrozole, aromatase inhibitor, luteal phase, IVF
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Letrozole 5 mgDrug
Also called Aromatase inhibitor
recFSH and co-treatment with letrozole 5 mg/day from stimulation day 1 on cycle day 2 or 3 until the day before GnRH agonist administration to trigger final oocyte maturation. GnRH antagonist 0.25 mg/day from stimulation day 5 until day of GnRH agonist administration. No luteal phase support.
| Study group | Role | What they receive |
|---|---|---|
| Intervention | Experimental | recFSH and co-treatment with letrozole 5 mg/day from stimulation day 1 on cycle day 2 or 3 until the day before gonadotrophin releasing hormone(GnRH) agonist administration to trigger final oocyte maturation. GnRH antagonist 0.25 mg/day from stimulation day 5 until day of GnRH agonist administration. No luteal phase support. Receives: Drug: Letrozole 5 mg |
| Control group | No intervention | recFSH from stimulation day 1 on cycle day 2 or 3 until the day before GnRH agonist administration to trigger final oocyte maturation. GnRH antagonist 0.25 mg/day from stimulation day 5 until day of GnRH agonist administration. No luteal phase support. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Length of luteal phase (days from aspiration untill bleeding)
Difference in lengths of days until bleeding (from aspiration until first day of bleeding) of the luteal phase between intervention group and control group.
Measured: Up to three weeks
Secondary outcomes (3)
Phase of endometrial receptivity according to Endometrial Receptivity Array (ERA) test
Difference in established endometrial tissue and secretion markers of endometrial receptivity between intervention group and controls (genomic profile assessed by ERA test).
Measured: ERA-test is taken 5 days after aspiration of oocytes.
Estradiol (E2),progesterone (P), luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels.
Differences in the area under the curve for plasma E2, P, LH and FSH levels from day of OPU until day 14 post OPU between intervention group and control group.
Measured: Blood samples are taken on 1 day of oocyte aspiration, 2 days after, 5 days after and 14 days after.
Endometrium thickness.
Difference in endometrium thickness 5 days post oocyte pick-up (OPU) between intervention group and controls.
Measured: Endometrium thickness is measured on 1 day of oocyte aspiration, 2 days after and 5 days after.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Aug 2020
- Study start18 Sep 2018
- Primary completion30 Nov 2020
- Study completion30 Nov 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for IVFStudies of the same condition, open and under way.
- 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 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 25 participants (actual)
Sponsor and investigators
- Lead sponsor
- Nicholas Macklon
- Sponsor type
- University, hospital or other
- Collaborators
- Gedeon Richter Ltd., Igenomix
- Responsible party
- Sponsor-investigator, Nicholas Macklon, Zealand University Hospital
- Investigators
- Nicholas Stephen Macklon, Professor, Principal investigator, ProfessorMarianne Dreyer Holt, MD, Study director, PhD student
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04524026
- Sponsor's protocol ID
- REG-210-2017
- Other IDs
- 2017-004433-93, 2017
- Acronym
- RIOTC
- Status last verified
- Jan 2021
- First submitted
- 7 Sep 2018
- Last updated
- 14 Jan 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Dreyer Holt M, Skouby SO, Bulow NS, Englund ALM, Birch Petersen K, Macklon NS. The Impact of Suppressing Estradiol During Ovarian Stimulation on the Unsupported Luteal Phase: A Randomized Controlled Trial. J Clin Endocrinol Metab. 2022 Aug 18;107(9):e3633-e3643. doi: 10.1210/clinem/dgac409.
PubMed 35779242
Study at a glance
From the registry record, last updated by the sponsor on 14 Jan 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- RIOTC: Reducing the Impact of Ovarian Stimulation. Novel Approaches to Luteal Support in IVF - Study 2
- ClinicalTrials.gov ID
- NCT04524026
- Acronym / sponsor ID
- RIOTC / REG-210-2017
- Conditions
- IVF
- Keywords
- Letrozole, aromatase inhibitor, luteal phase, IVF
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 25 participants (actual)
- Lead sponsor
- Nicholas MacklonUniversity, hospital or other
- Collaborators
- Gedeon Richter Ltd., Igenomix
- Study start
- 18 Sep 2018 (actual)
- Primary completion
- 30 Nov 2020 (actual)
- Study completion
- 30 Nov 2020 (actual)
- First posted
- 24 Aug 2020 (actual)
- 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.
The goal of the randomised controlled study (RCT) is to identify novel strategies that can improve the luteal phase endocrinology after ovarian stimulation, with the aim of using less or no luteal support in IVF while making the endometrium thinner and more receptive to embryo implantation.
Detailed description
The high estradiol levels generated in IVF by multiple dominant follicles at the follicular-luteal phase transition generate powerful negative feedback at the pituitary gland, effectively switching off gonadotropin production. Without stimulation by endogenous luteinizing hormone (LH), the corpora lutea undergo involution and menstruation follows, preventing the establishment of pregnancy.
To address these detrimental effects of ovarian stimulation, the investigators will do a RCT with the use of aromatase inhibitors, which suppress the conversion of androgens to estrogens to ameliorate the unwanted effects of high estrogens.
This study is designed to test the hypothesis that preventing supra-physiological estrogen levels during ovarian stimulation restricts pituitary suppression sufficiently to allow LH levels to rise and support the corpora lutea, leading to a normal post-ovulatory luteal phase, evidenced by a normal duration and luteal phase endocrine profile. To test this, consenting oocyte donors will be randomized to receive co-treatment with aromatase inhibitors or no co-treatment during ovarian stimulation. Following oocyte retrieval, no luteal support will be provided to donors in both Groups.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Intervention | Experimental | Drug: Letrozole 5 mgrecFSH and co-treatment with letrozole 5 mg/day from stimulation day 1 on cycle day 2 or 3 until the day before gonadotrophin releasing hormone(GnRH) agonist administration to trigger final oocyte maturation. GnRH antagonist 0.25 mg/day from stimulation day 5 until day of GnRH agonist administration. No luteal phase support. |
| Control group | No intervention | –recFSH from stimulation day 1 on cycle day 2 or 3 until the day before GnRH agonist administration to trigger final oocyte maturation. GnRH antagonist 0.25 mg/day from stimulation day 5 until day of GnRH agonist administration. No luteal phase support. |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Meet the clinical criteria for acceptance as oocyte donors (healthy women who volunteers to donate oocytes to other women).
- Regular ovulatory cycle of 26-32 days.
- Age: 18-35 years old.
- Written consent.
Key exclusion criteria (11 listed)
- Contraindications for ovarian stimulation or aspiration of oocytes according to local guidelines
- Polycystic Ovary Syndrome (PCOS)
- Allergy towards study drug
- Women who have had a hormone or copper intra-uterine device (IUD) within 3 months
- Exclusion of patients after earlier inclusion in the study in case of
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 |
|---|---|---|
| Letrozole 5 mgAlso: Aromatase inhibitorrecFSH and co-treatment with letrozole 5 mg/day from stimulation day 1 on cycle day 2 or 3 until the day before GnRH agonist administration to trigger final oocyte maturation. GnRH antagonist 0.25 mg/day from stimulation day 5 until day of GnRH agonist administration. No luteal phase support. | Drug | Intervention |
Primary outcome
Length of luteal phase (days from aspiration untill bleeding)
Time frame: Up to three weeks
Difference in lengths of days until bleeding (from aspiration until first day of bleeding) of the luteal phase between intervention group and control group.
3 secondary outcomes
Phase of endometrial receptivity according to Endometrial Receptivity Array (ERA) test
Time frame: ERA-test is taken 5 days after aspiration of oocytes.
Estradiol (E2),progesterone (P), luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels.
Time frame: Blood samples are taken on 1 day of oocyte aspiration, 2 days after, 5 days after and 14 days after.
Endometrium thickness.
Time frame: Endometrium thickness is measured on 1 day of oocyte aspiration, 2 days after and 5 days after.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Jan 2021.
- Derived from this study: PubMed 35779242Dreyer Holt M, Skouby SO, Bulow NS, Englund ALM, Birch Petersen K, Macklon NS. The Impact of Suppressing Estradiol During Ovarian Stimulation on the Unsupported Luteal Phase: A Randomized Controlled Trial. J Clin Endocrinol Metab. 2022 Aug 18;107(9):e3633-e3643. doi: 10.1210/clinem/dgac409.
- Individual participant dataSharing planned: No
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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.
Nicholas Stephen Macklon, Professor principal investigator
Professor
Marianne Dreyer Holt, MD study director
PhD student
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Letrozole 5 mg in people with IVF, run by Nicholas Macklon at 2 sites in Denmark.
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 4 inclusion and 11 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: finished, as of the sponsor's last update on 14 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Denmark. 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.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Length of luteal phase (days from aspiration untill bleeding) (time frame: Up to three 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 NCT04524026, which also lists 1 linked publication.
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 14 Jan 2021.