Effect of HCQ Combined With LT4 on LBR in Euthyroid Women With URPL and TPO-Ab (QT-LIFE)

The Efficacy of Hydroxychloroquine Combined With Levothyroxine in Euthyroid Women With Thyroid Antibody Positive and Unexplained Recurrent Pregnancy Loss：A Multicenter, Randomized Controlled Study

The goal of this clinical trial is to learn if combined treatment of levothyroxine and hydroxychloroquine would improve the live birth of euthyroid women with thyroid peroxidase antibodies and unexplained recurrent pregnancy loss.

Researchers will compare combined treatment of levothyroxine and hydroxychloroquine to a treatment of levothyroxine alone to see if combined treatment works to improve live birth of euthyroid participants with thyroid peroxidase antibodies and unexplained recurrent pregnancy loss.

Participants will:

• Receive combined treatment of levothyroxine and hydroxychloroquine or treatment of levothyroxine alone every day at least 8 weeks before pregnancy, and continue their treatment till the end of pregnancy.
• Visit the clinic 4 weeks and 8 weeks after their treatments, and every 12 weeks before they get pregnant for checkups and tests. During their pregnancy, they will visit the clinic before gestation of 12 weeks, and will be followed up with phone call in the second trimester and after parturition.

Study Overview

• Status: Recruiting
• Conditions: Recurrent Pregnancy Loss; Euthyroid With Thyroid Antibodies
• Intervention / Treatment: Drug: hydroxychloroquine and levothyroxine; Drug: Levothyroxine

Detailed Description

Thyroid peroxidase antibodies (TPO-Ab) in euthyroid women are associated with recurrent pregnancy loss. According to 2017 Guidelines of the American Thyroid Association, administration of levothyroxine (LT4) to TPO-Ab-positive euthyroid pregnant women with a prior history of loss may be considered given its potential benefits in comparison with its minimal risk. However, it is a weak recommendation with low-quality evidence. Recently published randomised clinical trials showed that administration of LT4 does not improve pregnancy outcomes of euthyroid thyroid peroxidase antibody positive women with recurrent pregnancy loss. Published data showed TPO-Ab is related to immune imbalance. Hydroxychloroquine is a widely used immune modulator even in fields of autoimmune disorders during pregnancy and lactation. Nevertheless, the effect of hydroxychloroquine combined with LT4 on live birth rate of euthyroid women with TPO-Ab and unexplained recurrent pregnancy loss is unclear. Therefore, we designed a multicenter RCT to verify the study hypothesis that combined treatment of levothyroxine and hydroxychloroquine would improve the live birth rate of euthyroid women with thyroid peroxidase antibodies and unexplained recurrent pregnancy loss.

• Study Type: Interventional
• Enrollment (Estimated): 796
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510000
      • Recruiting
      • Sun Yat-Sen Memorial Hospital
      • Contact: Zhuoyao Mai, doctor; Phone Number: 020-81332233; Email: maizhuoyaoemma@126.com
    • Guangzhou, Guangdong, China, 510120
      • Not yet recruiting
      • Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
      • Contact: Hui Chen, M.D.; Email: chenhui9@mail.sysu.edu.cn
      • Contact: Zhuoyao Mai, M.D.; Email: maizhy5@mail.sysu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

1. Women with history of two or more pregnancy loss with the same male partner (including biochemical pregnancies).
2. Karyotype analyses show no pathological abnormalities in each individual of the recruited couple.
3. Women aged between 20 and 40 years old (including 20 and 40).
4. Lupus anticoagulant (LA), anticardiolipin antibody (ACA), and anti-beta2-glycoprotein I antibodies (anti-β2-GP1 Ab) tests are all negative.
5. It is confirmed by ultrasound or hysteroscopy that there are no pathological lesions that affect the morphology of the uterine cavity (such as submucosal uterine fibroids, uterine malformations).
6. TPO-Ab positive (TPO-Ab > 60 IU/mL using the Siemens kit of electrochemiluminescence method, or TPO-Ab > 34 IU/mL using the Roche kit of chemiluminescence method).
7. Biochemically euthyroid. TSH, free triiodothyronine (FT3), and free thyroxine (T4) are all within the reference range of corresponding laboratory testing in each research center.

Exclusion criteria:

1. Rheumatic diseases, such as systemic lupus erythematosus, undifferentiated connective tissue disease, etc.
2. Metabolic or endocrine diseases, such as diabetes.
3. Abnormal renal function: plasma creatinine level ≥130 μmol/L or abnormal liver function: alanine aminotransferase ≥80U/L or aspartate aminotransferase ≥80U/L.
4. Hypertension and malignant tumors.
5. Under treatment with glucocorticoids or immunosuppressor, including cyclosporine, azathioprine, prednisone, and methylprednisolone.
6. Body Mass Index (BMI) >28kg/m2.
7. Past history of hyperthyroidism, hypothyroidism, and thyroid malignant tumors;
8. Allergy to 4-aminoquinoline compound, or those with retinal or visual field lesions caused by 4-aminoquinoline compound.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: hydroxychloroquine and levothyroxine group; Corresponding oral treatment will be initiated after randomization and preconceptually, and continue to the end of pregnancy or until 60 weeks post-randomisation if pregnancy does not occur. Patients in the experimental group will be given a combined oral treatment of hydroxychloroquine (HCQ) and levothyroxine. Hydroxychloroquine sulfate tablets (Fenle, 0.1g) will be given at a total daily dose of 0.2g to 0.4g based on individual weight: patients weighing ≤46kg take HCQ tablets 0.2g/d, patients weighing >46kg and <62kg take HCQ tablets 0.3g/d, patients weighing ≥62kg take HCQ tablets 0.4g/d. Levothyroxine sodium tablets (Euthyrox, 50 μg) will be given 12.5μg ~50 μg daily based on patients' TSH levels and weights: TSH ≥ 2.5 mIU/L, the dosage is 50 μg/d; TSH < 2.5 mIU/L, the dosage is 25 μg/d; when the patient's weight is less than 50kg, the dosage is reduced by 50%.	Drug: hydroxychloroquine and levothyroxine; Hydroxychloroquine sulfate tablets (Fenle, 0.1g) will be given at a total daily dose of 0.2g to 0.4g based on individual weight as described above. During the study, if TSH is higher than 4.0 mIU/L or exceeds the lower limit of the reference range of the center in the first trimester, or TSH level exceeds the normal range of the center during the second or the third trimester, subjects will be instructed to suspend the medication and visit the Department of Endocrinology.
Other: levothyroxine group; Corresponding oral treatment will be initiated after randomization and preconceptually, and continued to the end of any pregnancy or until 60 weeks post-randomisation if pregnancy does not occur. Patients assigned in the control group will be given levothyroxine daily. Levothyroxine sodium tablets (Euthyrox, 50 μg) will be given 12.5μg ~50 μg daily based on patients' TSH levels and weights: TSH ≥ 2.5 mIU/L, the dosage is 50 μg/d; TSH < 2.5 mIU/L, the dosage is 25 μg/d; when the patient's weight is less than 50kg, the dosage is reduced by 50%.	Drug: Levothyroxine; Levothyroxine sodium tablets (Euthyrox, 50 μg) will be given 12.5μg ~50 μg daily based on patients' TSH levels and weights as described above. During the study, if TSH is higher than 4.0 mIU/L or exceeds the lower limit of the reference range of the center in the first trimester, or TSH level exceeds the normal range of the center during the second or the third trimester, subjects will be instructed to suspend the medication and visit the Department of Endocrinology.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Birth of a living child beyond 28 weeks	The primary outcome is the proportion of women with a live birth at or beyond 28 completed weeks. This proportion will be calculated with the denominator totalling all women randomised, and the numerator (i.e., treatment successes) totalling women who conceive within 60 weeks of randomisation and go on to give live birth at or beyond 28 weeks gestation.	After birth, within 24 months after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical pregnancy at 5 to 8 weeks	It is the proportion of women with a cardiac activity confirmed by ultrasound during 5 to 8 weeks of gestation. This proportion will be calculated with the denominator totalling all women randomised, and the numerator totalling women who have clinical pregnancy within 60 weeks of randomisation.	At 5-8 weeks of pregnancy
Miscarriage <28 weeks	Miscarriage that occurs less than 28 weeks of gestation	At 28 weeks of pregnancy
Gestation at miscarriage, weeks	Gestation at miscarriage, weeks	After the time of miscarriage, within 24 months after eligibility
On-going pregnancy at 12 weeks	On-going pregnancy at 12 weeks	At 12 weeks of pregnancy
Gestation at delivery >34 weeks/>37 weeks	Number of women who have a delivery at least 34 weeks of gestation. Number of women who have a delivery at least 37 weeks of gestation.	After birth, within 24 months after eligibility
Gestation at delivery, weeks	Gestation at delivery, weeks	After birth, within 24 months after eligibility
Birth weight, grams	Birth weight, grams	At birth, within 24 months after eligibility
APGAR score at 1 minute/5 minutes	APGAR score at 1 minute/5 minutes of the neonates.	After birth, within 24 months after eligibility
birth defects	Birth defects of the neonates.	At or short after birth, within 24 months after eligibility
Maternal antenatal complications,intrapartum complications,maternal postnatal complications	Hypertensive disorders of pregnancy, gestational diabetes, placenta previa, placental abruption, polyhydramnios, oligohydramnios, fetal growth restriction, postpartum hemorrhage and so on.	up to birth/immediately after delivery
Time to pregnancy.	It refers to the time interval from patients trying to prepare for pregnancy (after 8 weeks of medication) to successful pregnancy (intrauterine pregnancy confirmed by ultrasound).	At 5-8 weeks of pregnancy
live birth rate after at least 28 weeks of gestation among pregnant patients	It is the proportion of women with a live birth at or beyond 28 of completed weeks. This proportion will be calculated with the denominator totalling all women who have clinical pregnancy within 60 weeks of randomisation, and the numerator totalling women who have a live birth at or beyond 28 of completed weeks.	After birth, within 24 months after randomization

Collaborators and Investigators

• Sponsor: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2024
• Primary Completion (Estimated): March 1, 2035
• Study Completion (Estimated): March 1, 2037

Study Registration Dates

• First Submitted: June 25, 2024
• First Submitted That Met QC Criteria: October 21, 2024
• First Posted (Actual): October 22, 2024

Study Record Updates

• Last Update Posted (Estimated): September 23, 2025
• Last Update Submitted That Met QC Criteria: September 17, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: recurrent pregnancy loss; live birth; thyroid peroxidase antibody; euthyroid
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Pathologic Processes; Female Urogenital Diseases and Pregnancy Complications; Disease Attributes; Pregnancy Complications; Death; Thyroid Diseases; Recurrence; Abortion, Spontaneous; Fetal Death; Abortion, Habitual; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Amino Acids, Peptides, and Proteins; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Amino Acids; Amino Acids, Aromatic; Amino Acids, Cyclic; Quinolines; Aminoquinolines; Chloroquine; Thyroid Hormones; Hydroxychloroquine; Thyroxine
• Other Study ID Numbers: SYSKY-2024-342-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No