Recurrent MiscarriagePhase 3BBQNCT03165136
Hydroxychloroquine for Prevention of Recurrent Miscarriage.
A Phase 3 study testing Hydroxychloroquine in people with Recurrent Miscarriage and First Trimester Abortion, run by University Hospital, Brest at 18 sites in France.
Trial summary
Recurrent miscarriage (RM) defined by >=3 consecutive losses affects 1% of fertile couples. Most women have recurrent early loss with a failure of development before 10 weeks' gestation. Standard investigations fail to reveal any apparent cause in >50% of couples. Read more about this study
- Who is it for?
- Ages 18 to 38 years, women only
- Conditions the study is for
- Recurrent Miscarriage, First Trimester Abortion
- What is being tested?
- Hydroxychloroquine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 300 participants
- Where
- 18 sitesFrance
- Study dates
- 4 Dec 2017to 1 Feb 2026
- Phase
- Phase 3
- 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 38 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- women aged from 18 to 38 years,
- women trying to conceive,
- women with at least 3 previous consecutive miscarriage in the first pregnancy trimester, of unknown origin (normal parental karyotypes, no uterine cavity abnormality, no antiphospholipid syndrome with other clinical events than RM in the first trimester of pregnancy.)
- women who have given their informed consent
Who cannot join
- ongoing pregnancy,
- Normal pregnancy since the last miscarriage,
- Uterine cavity abnormality,
- Abnormal parental karyotype,
- Antiphospholipid syndrome defined as both persistent positive antiphospholipid antibodies (40 IU or more of anticardiolipin or anti beta2 GPI IgG or IgM, and/or lupus anticoagulant) and a specific clinical setting (thrombotic or obstetrical, apart from RM)
- women with a contraindication or an indication to a treatment by hydroxychloroquine
- Previous exposure > 4 years to chloroquine or hydroxychloroquine
- impossible follow up
Trial locations and contacts
18 sites in 1 country.
18 sites in 1 country
France18 sites
Centre Hospitalier Annecy Genevois
Annecy, 74374
CH d'Auch
Auch, 32008
CHU Besançon
Besançon, 25030
CHRU de Brest
Brest, 29609
CHU Estaing
Clermont-Ferrand
CHRU de Lille
Lille, 59037
Hôpital Nord - Unité mère-enfant
Marseille, 13015
CH de Mont de Marsan
Mont-de-Marsan, 40000
CHU de Nantes
Nantes, 44093
Hopital Saint Antoine
Paris, 75012
Hôpital Bichat
Paris, 75018
Hopital Port Royal Cochin
Paris, 75679
CHG François Mitterand
Pau, 64 000
Centre hospitalier de Cornouaille
Quimper, 29000
Hôpital sud de Rennes
Rennes, 35200
CHU de Saint Etienne - Hôpital Nord
Saint-Etienne, 42 270
Nouvel Hôpital Civil
Strasbourg, 67091
CH de Bigorre
Tarbes, 65013
About this study
Official title: Prévention Des Fausses Couches Spontanées Répétées Par Hydroxychloroquine. Essai thérapeutique Multicentrique, randomisé, en Double Insu, Contre Placebo
Recurrent miscarriage (RM) defined by >=3 consecutive losses affects 1% of fertile couples. Most women have recurrent early loss with a failure of development before 10 weeks' gestation. Standard investigations fail to reveal any apparent cause in >50% of couples.
No study has demonstrated any benefit of any medication in women with Unexplained RM, in the presence or absence of an inherited thrombophilia.
Read more
Moreover, the benefit of aspirin and/or heparin has not been proved in women with Antiphospholipid (APL) antibody without other clinical manifestations of Antiphospholipid Syndrome.
Hydroxychloroquine (HQ) is a molecule whose properties (anti-thrombotic, vascular-protective, immunomodulatory, improved glucose tolerance, lipid-lowering, anti-infectious) could be useful against mechanisms of Unexplained RM.
There is no data concerning the benefit of HQ in RM in the presence or absence of antiphospholipid antibodies or any inherited thrombophilia.
Administration in (Systemic Lupus erythematosus (SLE) women and for Malaria prevention provides extensive safety data during pregnancy.
Oral administration makes possible treatment since the preconception period. For all of that and its low cost, hydroxychloroquine should be evaluated in RM whatever the woman thrombophilic status.
Read the detailed description
Regarding the mechanisms of unexplained RM, on the basis of animal models and clinical studies, many hypotheses were raised:
- Reduced ovarian reserve,
- Progesterone defect: a double-blind trial did not show any benefit of progesterone therapy.
- Thrombotic mechanisms and/or endothelial dysfunction: An association with some inherited thrombophilias was suggested. A prothrombotic state outside of pregnancy was measured in women with previous RM and without known thrombophilia.
- Immunological disturbances (high titers of anti-thyroid or APL antibodies, maternal carriage of specific HLA alleles and immunological reactions against male-specific minor antigens, increased numbers of peripheral blood natural killer, overexpression of TOLL receptors, increase of TH1 and TH17 processes). Consequently, immunomodulatory treatments were proposed and assessed (no impact of intravenous immunoglobulins and no conclusive benefit of corticosteroids).
- Miscellaneous: BMI> 30 and chronic endometritis. Besides, the experience gained from previous clinical trials in RM leads us to emphasize, that subcutaneous administration of heparin limits its assessment among fertile women. Indeed, the treatment could not be administrated before conception and consequently the exposure was often too short (injections cannot be routinely initiated before 5 weeks).
Except psychological support, there is no treatment whose benefit has been proved in unexplained RM, in the presence or in the absence of an inherited thrombophilia. Moreover the absence of benefit of some treatments has been clearly demonstrated. Although the prognostic is not so poor (live-birth rates around 70%), proposed therapeutic interventions are sometimes excessive (regarding possible side effects and cost): as intravenous immunoglobulins, assisted procreation ...anti-TNF.
Consequently, for the management of these distressed patients, investigating other therapeutic options is highly needed.
Regarding recurrent miscarriage in women with high titers of antiphospholipid but without any other previous clinical event listed in the antiphospholipid syndrome, the benefit of antithrombotic treatment remains controversial (negative results of the HepASA trial) and hydroxychloroquine has never been assessed, although retrospective studies are encouraging.
- Conditions
- Recurrent Miscarriage, First Trimester Abortion
- Being tested
- Hydroxychloroquine, Placebo
- Keywords
- Unexplained Recurrent Miscarriage, First trimester abortion, Hydroxychloroquine, Antiphospholipid antibody
- Medical subject headings
- Abortion, Habitual
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Hydroxychloroquine : 200 mg twice a day
PlaceboDrug
placebo of hydroxychloroquine
| Study group | Role | What they receive |
|---|---|---|
| Hydroxychloroquine | Experimental | The treatment will be orally administrated, at a daily dose of 400 mg of hydroxychloroquine . The treatment will be started before conception and will be stopped at the end of the tenth week of gestation or before in case of pregnancy loss. Receives: Drug: Hydroxychloroquine |
| Placebo | Placebo comparator | A similar placebo will be orally administrated every day. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
A live and viable birth
In case of preterm and/or low birth weight, we define the viability by the decision to transfer the newborn to a neonatal intensive care unit
Measured: At delivery
Secondary outcomes (13)
a live and viable birth (for the subgroup analyses)
Measured: At delivery
occurrence of pregnancy complications (Recurrent Miscarriage-any other premature termination of pregnancy-placental vascular disease)
Measured: Since the beginning of pregnancy up to delivery
gestation time (in weeks of amenorrhea) at delivery,
Measured: At delivery up
birth weight (in grams) at delivery
Measured: At delivery
survival of the newborn
Measured: At 28 days of the newborn
psychomotor development of the child (normal/abnormal)
Measured: at 6 months of age
psychomotor development of the child (normal/abnormal)
Measured: at 12 months of age
height (in centimeters)
Measured: at 6 months of age
height (in centimeters)
Measured: at 12 months of age
weight (in grams)
Measured: at 6 months of age
weight (in grams)
Measured: at 12 months of age
Cranial perimeter (in centimeters)
Measured: at 6 months of age
Cranial perimeter (in centimeters)
Measured: at 12 months of age
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 May 2017
- Study start4 Dec 2017
- Primary completion1 Nov 2025 (estimated)
- Study completion1 Feb 2026 (estimated)
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 Recurrent MiscarriageStudies 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 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Double Blind Randomized clinical trial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 300 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Hospital, Brest
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Elisabeth PASQUIER, MD, Principal investigator, EA3878 - University Hospital of Brest
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03165136
- Sponsor's protocol ID
- 29BRC16.0045
- Acronym
- BBQ
- Status last verified
- Sep 2023
- First submitted
- 3 May 2017
- Last updated
- 2 Oct 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Pasquier E, de Saint-Martin L, Marhic G, Chauleur C, Bohec C, Bretelle F, Lejeune-Saada V, Hannigsberg J, Plu-Bureau G, Cogulet V, Merviel P, Mottier D. Hydroxychloroquine for prevention of recurrent miscarriage: study protocol for a multicentre randomised placebo-controlled trial BBQ study. BMJ Open. 2019 Mar 20;9(3):e025649. doi: 10.1136/bmjopen-2018-025649.
PubMed 30898821
Study at a glance
From the registry record, last updated by the sponsor on 2 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prévention Des Fausses Couches Spontanées Répétées Par Hydroxychloroquine. Essai thérapeutique Multicentrique, randomisé, en Double Insu, Contre Placebo
- ClinicalTrials.gov ID
- NCT03165136
- Acronym / sponsor ID
- BBQ / 29BRC16.0045
- Conditions
- Recurrent Miscarriage, First Trimester Abortion
- Keywords
- Unexplained Recurrent Miscarriage, First trimester abortion, Hydroxychloroquine, Antiphospholipid antibody
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 300 participants (estimated)
- Lead sponsor
- University Hospital, BrestUniversity, hospital or other
- Study start
- 4 Dec 2017 (actual)
- Primary completion
- 1 Nov 2025 (estimated)
- Study completion
- 1 Feb 2026 (estimated)
- First posted
- 24 May 2017 (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 miscarriage (RM) defined by >=3 consecutive losses affects 1% of fertile couples. Most women have recurrent early loss with a failure of development before 10 weeks' gestation. Standard investigations fail to reveal any apparent cause in >50% of couples.
No study has demonstrated any benefit of any medication in women with Unexplained RM, in the presence or absence of an inherited thrombophilia.
Moreover, the benefit of aspirin and/or heparin has not been proved in women with Antiphospholipid (APL) antibody without other clinical manifestations of Antiphospholipid Syndrome.
Hydroxychloroquine (HQ) is a molecule whose properties (anti-thrombotic, vascular-protective, immunomodulatory, improved glucose tolerance, lipid-lowering, anti-infectious) could be useful against mechanisms of Unexplained RM.
There is no data concerning the benefit of HQ in RM in the presence or absence of antiphospholipid antibodies or any inherited thrombophilia.
Administration in (Systemic Lupus erythematosus (SLE) women and for Malaria prevention provides extensive safety data during pregnancy.
Oral administration makes possible treatment since the preconception period. For all of that and its low cost, hydroxychloroquine should be evaluated in RM whatever the woman thrombophilic status.
Detailed description
Regarding the mechanisms of unexplained RM, on the basis of animal models and clinical studies, many hypotheses were raised:
- Reduced ovarian reserve,
- Progesterone defect: a double-blind trial did not show any benefit of progesterone therapy.
- Thrombotic mechanisms and/or endothelial dysfunction: An association with some inherited thrombophilias was suggested. A prothrombotic state outside of pregnancy was measured in women with previous RM and without known thrombophilia.
- Immunological disturbances (high titers of anti-thyroid or APL antibodies, maternal carriage of specific HLA alleles and immunological reactions against male-specific minor antigens, increased numbers of peripheral blood natural killer, overexpression of TOLL receptors, increase of TH1 and TH17 processes). Consequently, immunomodulatory treatments were proposed and assessed (no impact of intravenous immunoglobulins and no conclusive benefit of corticosteroids).
- Miscellaneous: BMI> 30 and chronic endometritis. Besides, the experience gained from previous clinical trials in RM leads us to emphasize, that subcutaneous administration of heparin limits its assessment among fertile women. Indeed, the treatment could not be administrated before conception and consequently the exposure was often too short (injections cannot be routinely initiated before 5 weeks).
Except psychological support, there is no treatment whose benefit has been proved in unexplained RM, in the presence or in the absence of an inherited thrombophilia. Moreover the absence of benefit of some treatments has been clearly demonstrated. Although the prognostic is not so poor (live-birth rates around 70%), proposed therapeutic interventions are sometimes excessive (regarding possible side effects and cost): as intravenous immunoglobulins, assisted procreation ...anti-TNF.
Consequently, for the management of these distressed patients, investigating other therapeutic options is highly needed.
Regarding recurrent miscarriage in women with high titers of antiphospholipid but without any other previous clinical event listed in the antiphospholipid syndrome, the benefit of antithrombotic treatment remains controversial (negative results of the HepASA trial) and hydroxychloroquine has never been assessed, although retrospective studies are encouraging.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Double Blind Randomized clinical trial
| Arm | Type | Receives |
|---|---|---|
| Hydroxychloroquine | Experimental | Drug: HydroxychloroquineThe treatment will be orally administrated, at a daily dose of 400 mg of hydroxychloroquine . The treatment will be started before conception and will be stopped at the end of the tenth week of gestation or before in case of pregnancy loss. |
| Placebo | Placebo comparator | Drug: PlaceboA similar placebo will be orally administrated every day. |
Who may qualify
- Ages
- 18 to 38 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- women aged from 18 to 38 years,
- women trying to conceive,
- women with at least 3 previous consecutive miscarriage in the first pregnancy trimester, of unknown origin (normal parental karyotypes, no uterine cavity abnormality, no antiphospholipid syndrome with other clinical events than RM in the first trimester of pregnancy.)
- women who have given their informed consent
Key exclusion criteria (8 listed)
- ongoing pregnancy,
- Normal pregnancy since the last miscarriage,
- Uterine cavity abnormality,
- Abnormal parental karyotype,
- Antiphospholipid syndrome defined as both persistent positive antiphospholipid antibodies (40 IU or more of anticardiolipin or anti beta2 GPI IgG or IgM, and/or lupus anticoagulant) and a specific clinical setting (thrombotic or obstetrical, apart from RM)
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 |
|---|---|---|
| HydroxychloroquineHydroxychloroquine : 200 mg twice a day | Drug | Hydroxychloroquine |
| Placeboplacebo of hydroxychloroquine | Drug | Placebo |
Primary outcome
A live and viable birth
Time frame: At delivery
In case of preterm and/or low birth weight, we define the viability by the decision to transfer the newborn to a neonatal intensive care unit
13 secondary outcomes
a live and viable birth (for the subgroup analyses)
Time frame: At delivery
occurrence of pregnancy complications (Recurrent Miscarriage-any other premature termination of pregnancy-placental vascular disease)
Time frame: Since the beginning of pregnancy up to delivery
gestation time (in weeks of amenorrhea) at delivery,
Time frame: At delivery up
birth weight (in grams) at delivery
Time frame: At delivery
survival of the newborn
Time frame: At 28 days of the newborn
psychomotor development of the child (normal/abnormal)
Time frame: at 6 months of age
psychomotor development of the child (normal/abnormal)
Time frame: at 12 months of age
height (in centimeters)
Time frame: at 6 months of age
height (in centimeters)
Time frame: at 12 months of age
weight (in grams)
Time frame: at 6 months of age
weight (in grams)
Time frame: at 12 months of age
Cranial perimeter (in centimeters)
Time frame: at 6 months of age
Cranial perimeter (in centimeters)
Time frame: at 12 months of age
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Oct 2023.
- Derived from this study: PubMed 30898821Pasquier E, de Saint-Martin L, Marhic G, Chauleur C, Bohec C, Bretelle F, Lejeune-Saada V, Hannigsberg J, Plu-Bureau G, Cogulet V, Merviel P, Mottier D. Hydroxychloroquine for prevention of recurrent miscarriage: study protocol for a multicentre randomised placebo-controlled trial BBQ study. BMJ Open. 2019 Mar 20;9(3):e025649. doi: 10.1136/bmjopen-2018-025649.
- Individual participant dataSharing planned: No
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Efficacy of Recombinant Human G-CSF in Women With Unexplained Recurrent Miscarriage
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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.
Elisabeth PASQUIER, MD principal investigator
EA3878 - University Hospital of Brest
18 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Hydroxychloroquine in people with Recurrent Miscarriage and First Trimester Abortion, run by University Hospital, Brest at 18 sites 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 4 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: status not confirmed, as of the sponsor's last update on 2 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 18 sites 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?
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?
A live and viable birth (time frame: At delivery). 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 NCT03165136, 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 2 Oct 2023.