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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Threatened Miscarriage

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Age of women between 20-37 years. 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 Multiple pregnancies (include twin pregnancies). 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. 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%). Intrauterine abnormalities and Fibroids distorting uterine cavity (as assessed by ultrasound). Bleeding attributed to a vulvar, vaginal, or cervical source unrelated to the pregnancy. For this threatened miscarriage, use of the same or similar Chinese medicine and/or progesterone more than one week. Use of agents that may contribute to bleeding such as aspirin, NSAIDs, etc. Presence of a congenital or acquired bleeding diathesis, i.e. Hemophilia, Von Willebrands's Disease, use of anti-coagulants, etc. 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. Known current or recent alcohol abuse or illicit drug use. Known abnormal parental karyotype. Unwilling to give informed consent. Unwillingness to be randomized and do not want to take daily medications according to the protocol for up to 12 week gestations (84 days).

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 37 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CHM+MP<br>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<br>* New Shoutai Pill Granules plus Micronized Progesterone Capsules<br>* Other names: New Shoutai Pill plus Micronized Progesterone;|
| Placebo Comparator: CHM Placebo+MP Placebo<br>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<br>* New Shoutai Pill Granules Placebo plus Micronized Progesterone Capsules Placebo<br>* Other names: New Shoutai Pill Placebo plus Micronized Progesterone Placebo;|
| Experimental: CHM+MP Placebo<br>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<br>* New Shoutai Pill Granules plus Micronized Progesterone Capsules Placebo<br>* Other names: New Shoutai Pill plus Micronized Progesterone Placebo;|
| Experimental: CHM Placebo+MP<br>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<br>* New Shoutai Pill Granules Placebo plus Micronized Progesterone Capsules<br>* Other names: New Shoutai Pill Placebo plus Micronized Progesterone;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Threatened Miscarriage, The First Trimester, Micronized Progesterone, Chinese Herbal Medicine, Live Birth