Clinical trial NCT02633878: Chinese Herbal Medicine and/or Oral Progesterone Intervention Trial for Threatened Miscarriage
Official title: Chinese Herbal Medicine and/or Oral Progesterone for Live Births in Threatened Miscarriage: An International Cooperative Multicenter Randomized Controlled Trial (CHOP-IT)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Threatened Miscarriage
Keywords: Threatened Miscarriage
Micronized Progesterone
Chinese Herbal Medicine
Live Birth
Lead sponsor: Heilongjiang University of Chinese Medicine
Sponsor class: OTHER
First posted: 2015-12-17
Enrollment: 1656
Sex: FEMALE
Minimum age (years): 20
Maximum age (years): 37
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: 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 two by two factorial, placebo controlled randomized trial is to determine that two oral medications and their combination, will mostly likely result in live birth in women with threatened miscarriage. We will evaluate the efficacy and safety of Chinese herbal medicine (New Shoutai Wan, NSTW) and oral micronized progesterone (OP) for treating threatened miscarriage in this trial. Our primary outcome of this trial is live birth. We hypothesize that: 1. treatment with NSTW plus OP or OP placebo is more likely to result in live birth than NSTW placebo plus OP or placebo; 2. treatment with OP plus NSTW or NSTW placebo is more likely to result in live birth than OP placebo plus NSTW or NSTW placebo; 3. treatment with combination of NSTW and OP is more likely to result in live birth than combination of NSTW placebo and OP placebo.

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. The incidence is difficult to determine precisely because it occurs 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 were found not only to have increased rate of antepartum haemorrhage, prelabour rupture of the membranes, preterm delivery, and intrauterine growth restriction, but also suffer from 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, but it's beneficial effects still cannot be verified. Progesterone is another most commonly used standard medication, maintaining the endometrial proliferation and preventing poor decidualization. A number of recent studies in women with threatened miscarriage shown a reduction in pregnancy loss with progesterone treatment. But 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 of pregnancy. There is no evidence to show 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, readily accessible, affordable, and safe are needed to treat women with threatened miscarriage.

Eligibility criteria: Inclusion criteria:

1. Age of women between 20-37 years.
2. Pregnant. The fetus is viable inside the uterine cavity during early pregnancy (5-10 week gestations) by ultrasound and/or serum hCG changes.
3. Bleeding symptoms: vaginal bleeding with or without abdominal pain, while the cervix is closed in during speculum examination.

Exclusion criteria:

1. Multiple pregnancies (more than one gestational sac or fetal pole in ultrasonography).
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. 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 or submucosal 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. History of a congenital or acquired bleeding diathesis, i.e. Hemophilia, Von Willebrands's Disease, use of anti-coagulants, etc.
9. 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.
10. Known current or recent alcohol abuse or illicit drug use.
11. Known abnormal parental karyotype.
12. Unwilling to give informed consent.
13. Unwillingness to be randomized.

Primary outcomes:
measure: Live birth
timeFrame: At or beyond 20 completed weeks' gestation
Secondary outcomes:
measure: Pregnancy outcome: Ongoing pregnancy
timeFrame: Beyond 12 weeks' gestation
measure: Pregnancy outcome: Miscarriage during the first trimester
timeFrame: During the first trimester (at or before 12 weeks' gestation)
measure: Pregnancy outcome: Miscarriage during second and third trimesters
timeFrame: During second and third trimesters (beyond 12 weeks' gestation until 20 weeks)
measure: Pregnancy outcome: Termination
timeFrame: At any time during treatment (up to 2 months) and follow-up period (up to 1 year)
measure: Pregnancy outcome: Stillbirth
timeFrame: At or beyond 20 weeks' gestation
measure: Pregnancy outcome: Induced abortion
timeFrame: At any time during treatment (up to 2 months) and follow-up period (up to 1 year)
measure: Pregnancy outcome: Gestational age
timeFrame: Up to 1 day after delivery
measure: Pregnancy outcome: Preterm birth (Spontaneous or Iatrogenic)
timeFrame: Birth before 37 completed weeks' gestation (up to and including 36 weeks and 6 days of gestation)
measure: Pregnancy outcome: Extreme preterm birth (Spontaneous or Iatrogenic)
timeFrame: Birth beyond 20 weeks and before 28 completed weeks' gestation (up to and including 27 weeks and 6 days of gestation)
measure: Pregnancy outcome: Full-term birth
timeFrame: At or beyond 37 weeks' gestation, and before 42 weeks' gestation
measure: Pregnancy outcome: Post-term birth
timeFrame: At or beyond 42 weeks' gestation
measure: Neonatal outcome: Birth weight
timeFrame: When neonatal is born
measure: Neonatal outcome: Small for gestational age
timeFrame: When neonatal is born
measure: Neonatal outcome: Large for gestational age
timeFrame: When neonatal is born
measure: Neonatal outcome: Congenital malformation
timeFrame: At any time during treatment (up to 2 months) and follow-up period (up to 1 year)
measure: Other outcome: Mean change in TCM Symptom Questionnaire Score for Threatened Miscarriage
timeFrame: From date of randomization until the date of end of treatment, assessed up to 2 months
measure: Other outcome: Mean change in 12-Item Short-Form Health Survey Score
timeFrame: From date of randomization until the date of end of treatment, assessed up to 2 months
measure: Other outcome: Mean change in Self-Rating Anxiety Scale score
timeFrame: From date of randomization until the date of end of treatment, assessed up to 2 months
Other outcomes:
Locations:
city: Hefei
country: China
facility: First Affiliated Hospital of Anhui University of Chinese Medicine
state: Anhui
city: Guangzhou
country: China
facility: Guangdong Provincial Hospital of Chinese Medicine
state: Guangdong
city: Shenzhen
country: China
facility: Shenzhen Hospital of Beijing University
state: Guangdong
city: Daqing
country: China
facility: Daqing Longnan Hospital
state: Heilongjiang
city: Harbin
country: China
facility: First Affiliated Hospital, Heilongjiang University of Chinese Medicine
state: Heilongjiang
city: Luoyang
country: China
facility: Luoyang Hospital of Traditional Chinese Medicinel
state: Henan
city: Changsha
country: China
facility: First Affiliated Hospital, Hunan University of Chinese Medicine
state: Hunan
city: Changzhou
country: China
facility: Changzhou Hospital of Chinese Medicine
state: Jiangsu
city: Suqian
country: China
facility: Siyang People's Hospital
state: Jiangsu
city: Suqian
country: China
facility: Suqian Obstetrics and Gynecology Hospital
state: Jiangsu
city: Xuzhou
country: China
facility: Xuzhou Central Hospitall
state: Jiangsu
city: Xuzhou
country: China
facility: Xuzhou Maternal and Child Health Hospital
state: Jiangsu
city: Nanchang
country: China
facility: Jiangxi Maternal and Child Health Hospital
state: Jiangxi
city: Nanchang
country: China
facility: The Second Affiliated Hospital of Jiangxi University of Chinese Medicine
state: Jiangxi
city: Dalian
country: China
facility: Dalian Maternal Hospital
state: Liaoning
city: Dalian
country: China
facility: Dalian Municipal Women And Children's Medical Center
state: Liaoning
city: Shenyang
country: China
facility: Affiliated Hospital, Liaoning University of Chinese Medicine
state: Liaoning
city: Yinchuan
country: China
facility: Ningxia Hui Autonomous Region Hospital of traditional Chinese Medicine
state: Ningxia Hui Autonomous Region
city: Tai'an
country: China
facility: Taian City Central Hospital
state: Shandong
city: Taiyuan
country: China
facility: Shanxi Province Hospital of Chinese Medicine
state: Shanxi
city: Hangzhou
country: China
facility: Hangzhou Hospital of Chinese Medical
state: Zhejiang
city: Wenzhou
country: China
facility: Wenzhou Hospital of Chinese Medicine
state: Zhejiang
Study officials:
affiliation: First Affiliated Hospital of Heilongjiang Chinese Medicine University
name: Xiaoke Wu, Ph.D
role: STUDY_CHAIR
References: