Chinese Herbal Medicine and Micronized Progesterone for Live Births in Threatened Miscarriage

Chinese Herbal Medicine and Micronized Progesterone for Live Births in Threatened Miscarriage: An International Cooperative Multicenter Randomized Controlled Trial

Threatened miscarriage is manifested by vaginal bleeding, with or without abdominal pain, while the cervix is closed and the fetus is viable and inside the uterine cavity. Threatened miscarriage is a common complication of pregnancy occurring in 20% of all clinically recognized pregnancies and about half of these will eventually result in pregnancy loss. The goal of this double-bind, randomized and double dummy controlled trial is to determine which of the two oral medications, CHM or micronized progesterone, and will mostly likely result in live birth in women with threatened miscarriage. We will evaluate the efficacy and safety of CHM and micronized progesterone for treating threatened miscarriage in this trial. Our primary outcome of this trial is a live birth. We hypothesize that: 1. treatment with CHM plus micronized progesterone placebo or micronized progesterone plus CHM placebo or CHM plus Micronized progesterone is more likely to result in live birth than the control arm which will be CHM placebo plus micronized progesterone placebo; 2. CHM plus micronized progesterone placebo and micronized progesterone plus CHM placebo will have similar treatment effects.

Study Overview

• Status: Recruiting
• Conditions: Threatened Miscarriage
• Intervention / Treatment: Drug: Chinese Herbal Medicine plus Progesterone Capsules; Drug: Chinese Herbal Medicine Placebo plus Progesterone Capsules Placebo; Drug: Chinese Herbal Medicine plus Progesterone Capsules Placebo; Drug: Chinese Herbal Medicine Placebo plus Micronized Progesterone

Detailed Description

The causes of spontaneous miscarriage are diverse and comprise chromosomal, genetic, anatomical, immunological, hormonal, infectious and psychological factors, the other factors contribute to an increased risk include advancing paternal and maternal age and mothers with systemic diseases, such as diabetes or thyroid dysfunction. However, the incidence is difficult to determine precisely due to occur very early during a pregnancy and almost 30% of early pregnancy may go unrecognized; the pathogenesis of pregnancy loss in this condition is still remains obscure. Compared with healthy women, the women with threatened miscarriage not only were found to have increased rate of antepartum haemorrhage, prelabour rupture of the membranes, preterm delivery, and intrauterine growth restriction, but also suffer significant psychological impairment including considerable anxiety and stress, depression, sleep disturbances, anger, and marital disturbances.

To date, therapies have limited effectiveness in treating threatened miscarriage and are empirical. Bed rest does not prevent pregnancy loss. Acetaminophen may have some effects on relieving pain only. The most commonly used prescription medication was human chorionic gonadotropin (hCG), maintaining the luteotrophic effects to support continued secretion of estrogen and progesterone, However, the beneficial effects of hCG still cannot be verified. Progesterone is another most commonly used traditional medication to treat threatened miscarriage, maintaining the endometrial proliferation and preventing spontaneous pregnancy loss. A number of recent studies in women with threatened miscarriage that has shown a reduction in pregnancy loss with progesterone treatment. Progestogens are a group of hormones, including both the natural female sex hormone progesterone and the synthetic forms. Micronized progesterone is a kind of progesterone; it is structurally and pharmacologically very similar to natural progesterone and has good oral bioavailability. It is especially suitable for women with threatened miscarriage as it does not have androgenic or oestrogenic effects on the foetus. A recent review of maternal use of Micronized progesterone during pregnancy also found no evidence for an increased risk of congenital malformations. However it may only be suitable to treat women with threatened miscarriage who have low progesterone levels due to corpus luteum deficiency at the first trimester pregnancy. There is no evidence to identify the beneficial effects of progesterone to treat threatened miscarriage due to others factors. At the same time, progesterone treatment is also expensive. New or adjuvant treatments that are suitable to treat women with threatened miscarriage due to various factors, and readily accessible, affordable, and safe are needed.

• Study Type: Interventional
• Enrollment (Anticipated): 1656
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Xiaoke Wu, Ph.D; Phone Number: +0086-13796025599; Email: xiaokewu2002@vip.sina.com

Study Locations

• China
  • Guangdong
    • Shenzhen, Guangdong, China
      • Recruiting
      • Shenzhen Hospital of Beijing University
      • Contact: Huiru Tang
      • Principal Investigator: Huiru Tang
  • Heilongjiang
    • Daqing, Heilongjiang, China
      • Recruiting
      • Daqing Longnan hospital
      • Contact: Xuewu Zhou
      • Principal Investigator: Xuewu Zhou
  • Jiangsu
    • Xuzhou, Jiangsu, China
      • Recruiting
      • Xuzhou Central Hospital
      • Principal Investigator: Bei Zhang
    • Xuzhou, Jiangsu, China
      • Recruiting
      • Xuzhou Maternal and Child Health Hospital
      • Contact: Zhenxing Hu
      • Principal Investigator: Zhenxing Hu
  • Jiangxi
    • Nanchang, Jiangxi, China
      • Recruiting
      • The Second Affiliated Hospital of Jiangxi University of Chinese Medicine
      • Contact: Ruining Liang
      • Principal Investigator: Ruining Liang
  • Liaoning
    • Dalian, Liaoning, China
      • Recruiting
      • Dalian Maternity Hospital
      • Contact: Rui Cao
      • Principal Investigator: Rui Cao
  • Shanxi
    • Taiyuan, Shanxi, China
      • Recruiting
      • Shanxi Province Hospital of Chinese medicine
      • Contact: Jinfeng Zhang
      • Principal Investigator: Jinfeng Zhang
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • Recruiting
      • Hangzhou hospital of Chinese medicine
    • Wenzhou, Zhejiang, China
      • Recruiting
      • Wenzhou Hospital of Chinese Medicine
      • Contact: Yun Sun

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 37 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion criteria

1. Age of women between 20-37 years.
2. Pregnant. The fetus is viable inside the uterine cavity during early pregnancy[1] (5-10 week gestations /35-70 days) as confirmed by positive serum hCG tests and ultrasound, and need to meet either of the following two terms: ① vaginal bleeding with or without abdominal pain, while the cervix is closed by speculum exam; ②Recurrent miscarriage (≥2 prior pregnancy losses including biochemical pregnancy and intrauterine pregnancy loss or a pregnancy loss ≥ 6 weeks from LMP).

Exclusion criteria

1. Multiple pregnancies (include twin pregnancies).
2. Ectopic pregnancy. We will define an ectopic pregnancy as any suspected adnexal mass or large amounts of free fluid in the pelvis without an accompanying intrauterine pregnancy.
3. Pregnancies of Unknown Location (PUL). This will include pregnancies with an hCG level >2500mIU/mL without visualization of an intrauterine or extrauterine (i.e. ectopic) pregnancies.
4. (4)Non-viable pregnancy. We will define a non-viable pregnancy as: ①an intrauterine pregnancy with a fetal pole without visualized fetal heart motion (>49 days); ②a gestational sac>20 mm in any diameter without a yolk sac; ③absence of a normal gestational sac at 5 weeks of pregnancy, absence of a yolk sac at 5.5-6 weeks of pregnancy, or absence of cardiac activity at 7 weeks of pregnancy by ultrasound; ④falling serum hCG values on serial visits or between baseline and randomization visit, or serial serum hCG levels which show a plateau (2-day increase ≤ 10%).
5. Intrauterine abnormalities and Fibroids distorting uterine cavity (as assessed by ultrasound).
6. Bleeding attributed to a vulvar, vaginal, or cervical source unrelated to the pregnancy.
7. For this threatened miscarriage, use of the same or similar Chinese medicine and/or progesterone more than one week.
8. Use of agents that may contribute to bleeding such as aspirin, NSAIDs, etc.
9. Presence of a congenital or acquired bleeding diathesis, i.e. Hemophilia, Von Willebrands's Disease, use of anti-coagulants, etc.
10. Presence of contributing major medical disorders (regardless of severity). These include poorly controlled diabetes, uncontrolled hypertension, systemic lupus erythematosus (SLE), untreated or active cancer (any cancer in remission or non-melanoma skin cancer is not included in the exclusion criteria), liver disease, renal disease, rheumatoid arthritis, cardiac disease, pulmonary disease other than mild asthma, neurologic disease requiring medical treatment, uncontrolled hypothyroidism, uncontrolled seizure disorder. Untreated vitamin B12 deficiency, severe anemia (hct < 30%), hemophilia, gout, nasal polyps, among others.
11. Known current or recent alcohol abuse or illicit drug use.
12. Known abnormal parental karyotype.
13. Unwilling to give informed consent.
14. Unwillingness to be randomized and do not want to take daily medications according to the protocol for up to 12 week gestations (84 days).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: FACTORIAL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: CHM+MP; CHM one dose in the morning and in the evening respectively until 12 weeks of gestations (84 days); MP 100mg tablet by mouth, every 8 hours until 12 weeks of gestations (84 days).	Drug: Chinese Herbal Medicine plus Progesterone Capsules; "New Shoutai Pill" Granules plus Micronized Progesterone Capsules; Other Names: "New Shoutai Pill" plus Micronized Progesterone
PLACEBO_COMPARATOR: CHM Placebo+MP Placebo; CHM Placebo one dose in the morning and in the evening respectively until 12 weeks of gestations (84 days); MP Placebo 100mg tablet by mouth, every 8 hours until 12 weeks of gestations (84 days).	Drug: Chinese Herbal Medicine Placebo plus Progesterone Capsules Placebo; "New Shoutai Pill" Granules Placebo plus Micronized Progesterone Capsules Placebo; Other Names: "New Shoutai Pill" Placebo plus Micronized Progesterone Placebo
EXPERIMENTAL: CHM+MP Placebo; CHM one dose in the morning and in the evening respectively until 12 weeks of gestations (84 days); MP Placebo 100mg tablet by mouth, every 8 hours until 12 weeks of gestations (84 days).	Drug: Chinese Herbal Medicine plus Progesterone Capsules Placebo; "New Shoutai Pill" Granules plus Micronized Progesterone Capsules Placebo; Other Names: "New Shoutai Pill" plus Micronized Progesterone Placebo
EXPERIMENTAL: CHM Placebo+MP; CHM Placebo one dose in the morning and in the evening respectively until 12 weeks of gestations (84 days); MP 100mg tablet by mouth, every 8 hours until 12 weeks of gestations (84 days).	Drug: Chinese Herbal Medicine Placebo plus Micronized Progesterone; "New Shoutai Pill" Granules Placebo plus Micronized Progesterone Capsules; Other Names: "New Shoutai Pill" Placebo plus Micronized Progesterone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Live birth rate	Cumulative live birth rate	>20 weeks of gestation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ongoing pregnancy rate	Cumulative Ongoing pregnancy rate	Beyond gestation 12 weeks
Ongoing pregnancy rate	Cumulative Ongoing pregnancy rate	Beyond gestation 20 weeks
Ongoing pregnancy rate	Cumulative Ongoing pregnancy rate	Beyond gestation 32 weeks
Live birth rate	Cumulative live birth rate	>37 weeks of gestation
Premature live birth rate	Cumulative Premature live birth rate	>24, but< weeks of gestation
Anti-β2 glycoprotein-I antibodies	The number or percentage of Anti-β2 glycoprotein-I antibodies positive patients	Baseline and end of treatment
Lupus anticoagulant	The number or percentage of Lupus anticoagulant positive patients	Baseline and end of treatment
Anti-cardiolipin antibody	The number or percentage of Anti-cardiolipin antibody positive patients	Baseline and end of treatment
Pregnancy loss rate	The number or percentage of patients who have a pregnancy loss	Before 20 weeks of gestation
Pregnancy loss rate	The number or percentage of patients who have a pregnancy loss	After 20 weeks of gestation
Serum Progesterone	Value (Units: ng/ml)	Baseline, each visit and end of the treatment
Zung Self-Rating Anxiety Scale	Change in scores	Baseline and end of treatment
SF-12 Health Survey	Change in scores	Baseline and end of treatment
Adverse event and/or serious adverse event	Pregnancy-induced hypertension, diabetes and antepartum haemorrhage, preterm birth, postdate delivery, preeclampsia and so on	During treatment, the second and third trimester, postpartum, fetus and newborn

Collaborators and Investigators

• Sponsor: Heilongjiang University of Chinese Medicine
• Investigators: Study Chair: Xiaoke Wu, Ph.D, First Affiliated Hospital of Heilongjiang Chinese Medicine University

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 1, 2017
• Primary Completion (ANTICIPATED): December 31, 2022
• Study Completion (ANTICIPATED): December 31, 2022

Study Registration Dates

• First Submitted: December 7, 2015
• First Submitted That Met QC Criteria: December 14, 2015
• First Posted (ESTIMATE): December 17, 2015

Study Record Updates

• Last Update Posted (ACTUAL): September 23, 2021
• Last Update Submitted That Met QC Criteria: September 22, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Chinese Herbal Medicine; Live Birth; Micronized Progesterone; Threatened Miscarriage; The First Trimester
• Additional Relevant MeSH Terms: Pregnancy Complications; Abortion, Spontaneous; Abortion, Threatened; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progestins; Progesterone
• Other Study ID Numbers: CHOP-IT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Subject's privacy is protected undoubtedly at the time of the informed consent signing

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No