Recurrent Unexplained Implantation FailurePhase 3CERTIFYNCT05930613
Certolizumab in Recurrent Implantation Failure (RIF)
A Phase 3 study testing Certolizumab (CIMZIA® ; TNF-α antagonist) in people with Recurrent Unexplained Implantation Failure, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
Trial summary
Recurrent implantation failure (RIF), defined as the absence of clinical pregnancy after the transfer of three good-quality embryos, concerns up to 40% of IVF couples and is associated with a low success rate. The causes remain unexplained in over 50% of cases. Read more about this study
- Who is it for?
- Ages 18 to 40 years, women only
- Conditions the study is for
- Recurrent Unexplained Implantation Failure
- What is being tested?
- Certolizumab (CIMZIA® ; TNF-α antagonist)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 161 participants
- Where
- 1 siteFrance
- Study dates
- 30 Nov 2023to Apr 2029
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
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
- Women aged 18-40 years
- Idiopathic, male or tubal factor infertility
- Unexplained recurrent implantation failure defined as consecutive failure to obtain clinical pregnancy after at least transfers of 3 good-quality embryos (Istanbul criteria)
- Affiliation to a French social security system (beneficiary or legal)
- Informed and signed consent
Who cannot join
- Known cause of RIF among the following:
- Genetic parental anomalies
- Non-gestational diabetes mellitus of type I and II,
- Infectious disease
- Antiphospholipid syndrome
- Sickle cell disease
Show all 35Show fewer
- Diffuse adenomyosis
- No contraindication to Freeze-thaw embryo transfer (FET) treatment
- Linked to certolizumab:
- Hypersensitivity to the active substances or to any of the excipients
- Primary or secondary immunodeficiency (history of or currently active)
- Active uncontrolled infection
- Active tuberculosis
- Cardiac insufficiency (moderate to severe, New York Heart Association (NYHA) III/IV classes)
- Any malignant neoplasm except adequately treated basal or squamous cell carcinoma of the skin
- Immunization with a live/ attenuated vaccine within 4 weeks prior to baseline or simultaneously with treatment
- Cytopenia as defined by platelet count < 100 × 109/L (100,000/mm3), hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L), absolute neutrophil count < 2.0 × 109/L (2000/mm3), lymphocyte count < 0.5 × 109/L (500/mm3)
- Liver cytolysis (AST / ALT > 5 N)
- Insufficient kidney function, as defined by a serum creatinine of more than 3 mg/dL or creatinine clearance of 20 ml/min or less
- Demyelinating neurological disease
- Linked to rifampicin and isoniazid (RIFINAH®)
- Hypersensitivity to the active substances or to any of the excipients
- Porphyria
- Decreased blood-clotting from low vitamin K
- Liver cytolysis (AST / ALT >5 N)
- Combination with bictegravir, cobicistat, daclatasvir, dasabuvir, delamanid, grazoprevir / elbasvir, protease inhibitors boosted by ritonavir, isavuconazole, ledipasvir, lurasidone, midostaurine, ombitasvir / paritaprévir, praziquantel, rilpivirine, sofosbuvir, velpatasvir, voriconazole, voxilaprevir
- Acute hepatitis, hepatic failure or chronic hepatic disease
- Acute nephropathy
- Contraindication to anti-pneumococcal vaccination (Pneumovax®)
- Hypersensitivity to the active substances or to any of the excipients
- Other criteria:
- Absence of health insurance (include AME)
- Subject under guardianship or curatorship
- Subject deprived of their liberty by a judicial or administrative decision
- Participation in another interventional study or being in the exclusion period at the end of a previous study.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
France1 site, 1 recruiting
- Recruiting
Saint-Antoine Hospital - APHP
Paris, 75012
MEKINIAN Arsène, Pr, 01 71 97 07 65, arsene.mekinian@aphp.fr
About this study
Official title: Efficacy of Certolizumab in Women With Unexplained Recurrent Implantation Failure: a Double-blind Randomized Controlled Trial
Recurrent implantation failure (RIF), defined as the absence of clinical pregnancy after the transfer of three good-quality embryos, concerns up to 40% of IVF couples and is associated with a low success rate. The causes remain unexplained in over 50% of cases.
Various dysimmune changes (related to immune T cells profiles, pro-inflammatory cytokines levels) have been described in unexplained RIF as compared to fertile controls, and it has been estimated that such dysimmunity may occur in 50% of unexplained RIFs. Previous data on a benefit of general immune modulation by steroids or immunoglobulins are heterogenous and failed to demonstrate clinically significant benefit. The proinflammatory cytokine Tumor Necrosis Factor (TNF) α participates in the regulation of the immune balance of the endometrium, its peripheral blood and endometrial concentrations are increased in RIF patients as compared to fertile controls. In 2009, a pilot placebo controlled study showed that TNF-α antagonist treatment allowed a 56% live birth rate (versus 13% in controls) in 13 women with unexplained RIF. Due to the lack of maternal and fetal tolerance data, TNF-α antagonists were not further evaluated. Today, safety data issued from 1200 pregnancies are reassuring allowing the use of TNF-α antagonists during pregnancy (www.lecrat.org). In addition the TNF-α antagonist certolizumab does not cross the placental barrier.
We hypothesize that certolizumab may improve clinical pregnancy rates in women with unexplained RIF with a good safety profile.
Read the detailed description
The European Society of Human Reproduction and Embryology (ESHRE) consortium has proposed to define recurrent implantation failure (RIF) as the failure to obtain a clinical pregnancy after the transfer of three good-quality embryos according to the Istanbul consensus 2011. Although its prevalence is difficult to estimate, RIF could concern up to 40% of couples undergoing assisted reproductive technology (ART) treatments. More than 50% of RIF cases remain unexplained after extensive exploration and clinical pregnancy rate in this population is particularly low, estimated at about 15%.
Endometrial environment plays a crucial role in embryo implantation and early placental development. In normal pregnancy, the survival of the semi-allogeneic fetus is dependent on the induction of maternal immune tolerance, with regulatory T cells and Th-2 anti-inflammatory profile. Several studies show a misbalance of immune cells and cytokines expression in women with implantation failure. Most studies analyze immune cells and cytokines profile in peripheral blood, with few data on cells and cytokines profiles in endometrial tissues during the periimplantation period. However, the immune endometrial balance could be disturbed in up to 80% of RIF cases.
Tumor Necrosis Factor (TNF) α, together with other pro-inflammatory cytokines, participates in the regulation of the immune balance of the endometrium. TNF-α and TNF-α / interleukin (IL)-10 ratio are increased in the endometrium of RIF patients, which suggests they could be involved in physiopathology of RIF.
To date there is no effective treatment to improve the low clinical pregnancy rate in unexplained RIF. The repeated failure of embryo transfers and the lack of efficient treatment are associated with psychological distress in infertile couples and raises economic problems because of the important cost of in vitro fertilisation (IVF).
Some treatments with immunomodulatory effect, such as steroids, were previously evaluated. However, studies were small and included heterogeneous populations, resulting in inconclusive results.
Our hypothesis is that TNF-α antagonists may be particularly useful by blocking TNF-α induced excessive immune-response.
In a pilot placebo controlled study, TNF-α antagonists were associated with 56% live births versus 13% in controls, in 13 women with unexplained implantation failure. However, this treatment was not further evaluated in this indication because of the lack of tolerance data and the fear of congenital abnormalities.
Concerning the safety of TNF-α antagonists, we now have sufficient data as they are widely used since more than 15 years in several autoimmune and inflammatory diseases. More than 1200 women treated with TNF-α antagonists for an inflammatory disease have provided evidence of their safety in early pregnancy and the French national center of drug-related effects (www.lecrat.org) allows the use of TNF-α antagonists during pregnancy, except during the third trimester. Among TNF-α antagonists, certolizumab have the particularity not to cross the placental barrier and thus can be used during pregnancy, This is why we focus on this particular drug for this trial.
- Being tested
- Certolizumab (CIMZIA® ; TNF-α antagonist), Placebo (NaCl 0.9 % solution)
- Keywords
- Recurrent Implantation Failure, Immunomodulation, Anti-TNF-α, Certolizumab, Pregnancy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Certolizumab (CIMZIA® ; TNF-α antagonist)Drug
400mg of certolizumab injected subcutaneously monthly from 5 weeks before embryo transfer until 7 weeks of gestation (injections at 5 and 1 week before embryo transfer, 3 and 7 weeks after embryo transfer) for a total of 4 injections in case of ongoing intrauterine pregnancy.
Placebo (NaCl 0.9 % solution)Drug
NaCl 0,9% injected subcutaneously monthly from 5 weeks before embryo transfer until 7 weeks of gestation (injections at 5 and 1 week before embryo transfer, 3 and 7 weeks after embryo transfer) for a total of 4 injections in case of ongoing intrauterine pregnancy.
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | Certolizumab (CIMZIA® ; TNF-α antagonist ) Receives: Drug: Certolizumab (CIMZIA® ; TNF-α antagonist) |
| 2 | Placebo comparator | Placebo (NaCl 0.9 % solution) Receives: Drug: Placebo (NaCl 0.9 % solution) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Clinical pregnancy defined as the presence of cardiac activity on ultrasound scan
Presence of cardiac activity on ultrasound scan at 5 weeks +/- 6 days of gestation
Measured: 5 weeks +/- 6 days of gestation
Secondary outcomes (3)
Live birth
Measured: 22 to 40 weeks of gestation
Miscarriage
Miscarriage defined as spontaneous abortion or pregnancy stop
Measured: Before 12 weeks of gestation
All adverse events distinguishing serious adverse events
Adverse events of interest are :
- multiple pregnancies
- ectopic pregnancy
- fetal abnormalities
- small for gestational age
- intrauterine growth restriction
- preeclampsia
Measured: Through study completion, a maximum of 64 months and 3 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Jul 2023
- Study start30 Nov 2023
- Primary completionApr 2029 (estimated)
- Study completionApr 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Recurrent Unexplained Implantation FailureStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe 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 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 161 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Arsene MEKINIAN, Pr, Principal investigator, Assistance Publique - Hôpitaux de Paris
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05930613
- Sponsor's protocol ID
- APHP200031
- Other IDs
- 2021-005309-28
- Acronym
- CERTIFY
- Status last verified
- Dec 2023
- First submitted
- 22 May 2023
- Last updated
- 11 Dec 2023
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients. Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations.
Study at a glance
From the registry record, last updated by the sponsor on 11 Dec 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Efficacy of Certolizumab in Women With Unexplained Recurrent Implantation Failure: a Double-blind Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT05930613
- Acronym / sponsor ID
- CERTIFY / APHP200031
- Keywords
- Recurrent Implantation Failure, Immunomodulation, Anti-TNF-α, Certolizumab, Pregnancy
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 161 participants (estimated)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- 30 Nov 2023 (actual)
- Primary completion
- Apr 2029 (estimated)
- Study completion
- Apr 2029 (estimated)
- First posted
- 5 Jul 2023 (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.
Recurrent implantation failure (RIF), defined as the absence of clinical pregnancy after the transfer of three good-quality embryos, concerns up to 40% of IVF couples and is associated with a low success rate. The causes remain unexplained in over 50% of cases.
Various dysimmune changes (related to immune T cells profiles, pro-inflammatory cytokines levels) have been described in unexplained RIF as compared to fertile controls, and it has been estimated that such dysimmunity may occur in 50% of unexplained RIFs. Previous data on a benefit of general immune modulation by steroids or immunoglobulins are heterogenous and failed to demonstrate clinically significant benefit. The proinflammatory cytokine Tumor Necrosis Factor (TNF) α participates in the regulation of the immune balance of the endometrium, its peripheral blood and endometrial concentrations are increased in RIF patients as compared to fertile controls. In 2009, a pilot placebo controlled study showed that TNF-α antagonist treatment allowed a 56% live birth rate (versus 13% in controls) in 13 women with unexplained RIF. Due to the lack of maternal and fetal tolerance data, TNF-α antagonists were not further evaluated. Today, safety data issued from 1200 pregnancies are reassuring allowing the use of TNF-α antagonists during pregnancy (www.lecrat.org). In addition the TNF-α antagonist certolizumab does not cross the placental barrier.
We hypothesize that certolizumab may improve clinical pregnancy rates in women with unexplained RIF with a good safety profile.
Detailed description
The European Society of Human Reproduction and Embryology (ESHRE) consortium has proposed to define recurrent implantation failure (RIF) as the failure to obtain a clinical pregnancy after the transfer of three good-quality embryos according to the Istanbul consensus 2011. Although its prevalence is difficult to estimate, RIF could concern up to 40% of couples undergoing assisted reproductive technology (ART) treatments. More than 50% of RIF cases remain unexplained after extensive exploration and clinical pregnancy rate in this population is particularly low, estimated at about 15%.
Endometrial environment plays a crucial role in embryo implantation and early placental development. In normal pregnancy, the survival of the semi-allogeneic fetus is dependent on the induction of maternal immune tolerance, with regulatory T cells and Th-2 anti-inflammatory profile. Several studies show a misbalance of immune cells and cytokines expression in women with implantation failure. Most studies analyze immune cells and cytokines profile in peripheral blood, with few data on cells and cytokines profiles in endometrial tissues during the periimplantation period. However, the immune endometrial balance could be disturbed in up to 80% of RIF cases.
Tumor Necrosis Factor (TNF) α, together with other pro-inflammatory cytokines, participates in the regulation of the immune balance of the endometrium. TNF-α and TNF-α / interleukin (IL)-10 ratio are increased in the endometrium of RIF patients, which suggests they could be involved in physiopathology of RIF.
To date there is no effective treatment to improve the low clinical pregnancy rate in unexplained RIF. The repeated failure of embryo transfers and the lack of efficient treatment are associated with psychological distress in infertile couples and raises economic problems because of the important cost of in vitro fertilisation (IVF).
Some treatments with immunomodulatory effect, such as steroids, were previously evaluated. However, studies were small and included heterogeneous populations, resulting in inconclusive results.
Our hypothesis is that TNF-α antagonists may be particularly useful by blocking TNF-α induced excessive immune-response.
In a pilot placebo controlled study, TNF-α antagonists were associated with 56% live births versus 13% in controls, in 13 women with unexplained implantation failure. However, this treatment was not further evaluated in this indication because of the lack of tolerance data and the fear of congenital abnormalities.
Concerning the safety of TNF-α antagonists, we now have sufficient data as they are widely used since more than 15 years in several autoimmune and inflammatory diseases. More than 1200 women treated with TNF-α antagonists for an inflammatory disease have provided evidence of their safety in early pregnancy and the French national center of drug-related effects (www.lecrat.org) allows the use of TNF-α antagonists during pregnancy, except during the third trimester. Among TNF-α antagonists, certolizumab have the particularity not to cross the placental barrier and thus can be used during pregnancy, This is why we focus on this particular drug for this trial.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Drug: Certolizumab (CIMZIA® ; TNF-α antagonist)Certolizumab (CIMZIA® ; TNF-α antagonist ) |
| 2 | Placebo comparator | Drug: Placebo (NaCl 0.9 % solution)Placebo (NaCl 0.9 % solution) |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- Women aged 18-40 years
- Idiopathic, male or tubal factor infertility
- Unexplained recurrent implantation failure defined as consecutive failure to obtain clinical pregnancy after at least transfers of 3 good-quality embryos (Istanbul criteria)
- Affiliation to a French social security system (beneficiary or legal)
- Informed and signed consent
Key exclusion criteria (35 listed)
- Genetic parental anomalies
- Non-gestational diabetes mellitus of type I and II,
- Infectious disease
- Antiphospholipid syndrome
- Sickle cell disease
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 |
|---|---|---|
| Certolizumab (CIMZIA® ; TNF-α antagonist)400mg of certolizumab injected subcutaneously monthly from 5 weeks before embryo transfer until 7 weeks of gestation (injections at 5 and 1 week before embryo transfer, 3 and 7 weeks after embryo transfer) for a total of 4 injections in case of ongoing intrauterine pregnancy. | Drug | 1 |
| Placebo (NaCl 0.9 % solution)NaCl 0,9% injected subcutaneously monthly from 5 weeks before embryo transfer until 7 weeks of gestation (injections at 5 and 1 week before embryo transfer, 3 and 7 weeks after embryo transfer) for a total of 4 injections in case of ongoing intrauterine pregnancy. | Drug | 2 |
Primary outcome
Clinical pregnancy defined as the presence of cardiac activity on ultrasound scan
Time frame: 5 weeks +/- 6 days of gestation
Presence of cardiac activity on ultrasound scan at 5 weeks +/- 6 days of gestation
3 secondary outcomes
Live birth
Time frame: 22 to 40 weeks of gestation
Miscarriage
Time frame: Before 12 weeks of gestation
All adverse events distinguishing serious adverse events
Time frame: Through study completion, a maximum of 64 months and 3 weeks
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Dec 2023.
- Individual participant dataSharing planned: Yes. The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients. Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations.
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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.
Arsene MEKINIAN, Pr principal investigator
Assistance Publique - Hôpitaux de Paris
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Certolizumab (CIMZIA® ; TNF-α antagonist) in people with Recurrent Unexplained Implantation Failure, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
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 5 inclusion and 35 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: looking for participants now, as of the sponsor's last update on 11 Dec 2023. 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 France. 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. Some participants in this study may receive a placebo. 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Nathalie CHABBERT-BUFFET, Pr (01 56 01 55 10, nathalie.chabbert-buffet@aphp.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Clinical pregnancy defined as the presence of cardiac activity on ultrasound scan (time frame: 5 weeks +/- 6 days of gestation). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 11 Dec 2023.