Hydroxychloroquine treatment for Recurrent Pregnancy Loss: a randomized double-blind placebo-controlled trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hvidovre Hospital

Participant type

Patients

Age range

18-64 years

Gender

Female

Therapeutic area

Diseases [C] - Female Urogenital Diseases and Pregnancy Complications [C13]

Trial duration

12 Apr 2017 → ongoing

Decision date (initial)

2024-07-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-515579-36-00

EudraCT number

2016-004981-24

ClinicalTrials.gov

NCT03305263

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To monitor the difference in live birth rate (LBR) among women allocated to treatment with Hydroxychloroquine (HCQ) and those allocated to placebo treatment, without exclusion of any included patients (Intention to treat (ITT) analysis).

Secondary objectives 4

1. The difference in LBR for women allocated treatment with HCQ and those allocated placebo treatment, according to the protocol. PL due to chromosome abnormalities, ectopic pregnancy, neglect of treatment, induced abortion or those who withdraw from the treatment earlier than the protocol dictates do not fall under the category of treatment failure, and these are excluded in this secondary analysis (Per protocol (PP) analysis).
2. Birth weight, duration of pregnancy, Apgar-score five minutes after birth and the number of days admitted into a neonatal department. Patients with RPL have an increased risk of preterm birth, perinatal morbidities, and low birth weight25,26. Hence, it is relevant to investigate whether treatment with HCQ can reduce these complications, or if treatment with HCQ reduces the rate of PL at the expense of an increased rate of perinatal complications. The rate of perinatal complications is compared to the placebo group in this analysis.
3. Immune and inflammatory profiles and trajectories in women treated with HCQ vs placebo and women with live birth vs another PL. Pre-pregnancy inflammatory levels will be contrasted between women treated with HCQ and placebo to identify high responders. Furthermore, repeated measures analysis enables the understanding of pregnancy-complications and identification of high-risk groups at early stages, which may benefit from treatment.
4. Monitoring metabolic activity measured by ultra-low dose FDG-PET/CT scans in a sub-study. Metabolic activity correlates with grade of inflammation and will be measured in the uterus and immune-related tissue such as bone marrow, spleen, thymus, and lymph nodes

Conditions and MedDRA coding

Recurrent Pregnancy Loss

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. ≥ 4 confirmed consecutive pregnancy losses prior to gestational age 22+0 in women with unexplained recurrent pregnancy loss (RPL)
2. ≥ 3 confirmed consecutive pregnancy losses prior to gestational age 22+0 in women with unexplained RPL with minimum one second trimester loss

Exclusion criteria 12

1. Age < 18 years or > 40 years
2. Prominent uterine abnormalities detected by hysterosalpingography/hysteroscopy or hydrosonography
3. Known prominent chromosome abnormalities for the couple trying to conceive
4. A menstrual cycle < 23 days or > 35 days if the pregnancy is conceived naturally. If the woman received fertility treatment the menstrual cycle has no consequence.
5. Detection of positive lupus-anticoagulant or positive IgG/IgM for anticardiolipin-antibodies (≥10 GPL kU/l, measured at the same laboratories at the Capital Region of Denmark) or plasma homocysteine ≥25 microgram/l by repeated measurements 12 weeks apart before the pregnancy.
6. Positive HIV test or test indicating chronic hepatitis B or C.
7. Psoriasis, retinopathic or serious hearing deficiency (contraindication for treatment with HCQ)
8. Current chronic disease implicating a constant consumption of immunomodulatory medicine or medicine potentially harmful to the pregnancy/embryo
9. Hgb ≤ 6.5 mmol/L, leucocytes < 3.5 E9/L, thrombocytes < 145 E9/L by the time of inclusion
10. Previous HCQ treatment in relation to conceive
11. > 1 previous live birth.
12. Previous participation in current study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The trial will conclude after the inclusion and follow-up (pregnancy loss or 6 months after live birth) for 186 women. Included women who become pregnant less than two months after starting the medication or do not achieve pregnancy within one year of starting the medication will be replaced 1:1 by new patients included in the trial.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hvidovre Hospital

Sponsor organisation

Hvidovre Hospital

Address

Kettegaard Alle 30

City

Hvidovre

Postcode

2650

Country

Denmark

Scientific contact point

Organisation

Hvidovre Hospital

Contact name

Henriette Svarre Nielsen

Public contact point

Organisation

Hvidovre Hospital

Contact name

Henriette Svarre Nielsen

Third parties 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications