Acupuncture and Clomiphene Citrate on Live Birth in Anovulatory Women With Polycystic Ovary Syndrome

Study Overview
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Brief Summary
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The objectives of the present trial are to test the following three hypotheses in anovulatory women with PCOS: Acupuncture protocol 1 plus CC (Arm A) is more likely to result in live birth than acupuncture protocol 2 combined with CC (Arm B), Acupuncture protocol 2 plus CC (Arm B) is more likely to result in live birth than acupuncture protocol 1 plus placebo (Arm C), Acupuncture protocol 1 plus placebo (Arm C) is more likely to result in live birth than acupuncture protocol 2 plus placebo (Arm D).

Detailed Description
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This is a multicenter, randomized, controlled, 2 by 2 factorial clinical trial for Chinese women with PCOS. Primary outcomes: - Live birth rate Secondary outcomes: Ovulation rate Ongoing pregnancy rate Multiple pregnancy rate Miscarriage rate Hormonal profile Metabolic profile Side effect profile

Official Title
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Effect of Acupuncture and Clomiphene Citrate on Live Birth in Anovulatory Women With Polycystic Ovary Syndrome: A Randomized Controlled Trial (PCOSAct)

Conditions
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Pregnancy, Polycystic Ovary Syndrome, Infertility

Intervention / Treatment
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* Other: Acupuncture treatment 1
* Other: Acupuncture treatment 2
* Other: CC
* Other: CC placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of women between 20 and 40 years. Confirmed diagnosis of PCOS according to the modified Rotterdam criteria and all subjects must have anovulation plus either polycystic ovaries and/or hyperandro-genism. Patency of at least one tube and a normal uterine cavity shown by hysterosalpingogram, HyCosi or diagnostic laparoscopy. Semen analysis: a. Sperm concentration ≥15×106/ml and b. total motility (a+b+c) ≥40% or forward motility (a+b) ≥32% in the semen analysis of the husband (based on World Health Organization, 2010). Total motile sperm count ≥9 million [based on WHO (2010) criteria, volume 1.5 ml; conc 15 million; motility 40%. 1.5 x 15 x 0.04=9 million]. Exclusion Criteria: Exclusion of other endocrine disorders Patients with hyperprolactinemia (defined as two prolactin levels at least one week apart 25 ng/mL or greater or as determined by local normative values). The goal of eliminating patients with documented hyperprolactinemia is to decrease the heterogeneity of the PCOS population. These patients may be candidates for ovulation induction with alternate regimens (dopamine agonists). A normal level within the last year or on treatment is adequate for entry. Patients with FSH levels > 15 mIU/mL. A normal level within the last year is adequate for entry. Patients with uncorrected thyroid disease (defined as TSH < 0.2 mIU/mL or > 5.5 mIU/mL). A normal level within the last year is adequate for entry. Patients diagnosed with Type I or Type II diabetes who are poorly controlled (defined as a glycohemoglobin level > 7.0%), or patients receiving antidiabetic medications such as insulin, thiazolidinediones, acarbose, or sulfonylureas likely to confound the effects of study medication; patients currently receiving metformin XR for a diagnosis of Type I or Type II diabetes or for PCOS are also specifically excluded. Patients with suspected Cushing's syndrome. Use of hormonal or other medication including Chinese Herbal prescriptions which may affect the outcome at least in the past 2 months. Pregnancy within the past 6 weeks. Within 6 weeks post-abortion or postpartum. Breastfeeding within the last 6 months. Acupuncture within the last 6 months. Not willing to give written consent to the study. Additional exclusion criteria Patients on oral contraceptives, depot progestins, or hormonal implants (including Implanon). A two month washout period will be required prior to screening for patients on these agents. Longer washouts may be necessary for certain depot contraceptive forms or implants, especially where the implants are still in place. A one-month washout will be required for patients on oral cyclic progestins. Patients with liver disease defined as AST or ALT > 2 times normal or total bilirubin >2.5 mg/dL. Patients with renal disease defined as BUN > 30 mg/dL or serum creatinine> 1.4 mg/dL. Patients with significant anemia (Hemoglobin < 10 g/dL). Patients with a history of deep venous thrombosis, pulmonary embolus, or cerebrovascular accident. Patients with known heart disease that is likely to be exacerbated by pregnancy. Patients with a history of, or suspected cervical carcinoma, endometrial carcinoma, or breast carcinoma. A normal Pap smear result will be required for women 21 and over. Patients with a current history of alcohol abuse. Alcohol abuse is defined as > 14 drinks/week or binge drinking. Patients enrolled simultaneously into other investigative studies that require medications, proscribe the study medications, limit intercourse, or otherwise prevent compliance with the protocol. Patients who anticipate taking longer than a one month break during the protocol should not be enrolled. Patients taking other medications known to affect reproductive function or metabolism. These medications include oral contraceptives, GnRH agonists and antagonists, antiandrogens, gonadotropins, anti-obesity drugs, Chinese herbal formula, anti-diabetic drugs such as metformin and thiazolidinediones, somatostatin, diazoxide, ACE inhibitors, and calcium channel blockers. The washout period on all these medications will be two months. Patients with a suspected adrenal or ovarian tumor secreting androgens. Couples with previous sterilization procedures (vasectomy, tubal ligation) which have been reversed. The prior procedure may affect study outcomes, and patients with both a reversed sterilization procedure and PCOS are rare enough that exclusion should not adversely affect recruitment. Subjects who have undergone a bariatric surgery procedure in the recent past (< 12 months) and are in a period of acute weight loss or have been advised against pregnancy by their bariatric surgeon. Patients with untreated poorly controlled hypertension defined as a systolic blood pressure 160 mm Hg or a diastolic 100 mm Hg obtained on two measures obtained at least 60 minutes apart. Patients with known congenital adrenal hyperplasia.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 40 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acupuncture treatment 1 plus CC<br> | Other: Acupuncture treatment 1<br>* Two sets of acupuncture points will be alternated every second treatment. The first set consists of CV3, CV 6, and ST 29 bilaterally，SP 6 and SP 9 bilaterally. Needles will also be placed in LI bilaterally and GV 20. CV 3, CV 6, ST 29, SP 6, and SP 9 will be connected to and electrical stimulator and stimulated with low-frequency EA of 2Hz, 0.3 ms.<br>Other: CC<br>* CC 50 mg every day for 5 days (day 3-7 of cycle), for a total of 4 cycles. Non-response will be defined after 4 weeks of CC placebo administration with 3 consecutive weekly negative P4 and hCG levels. Then during the fifth week a higher dose consisting of one more tablet per day (up to 3 tablets per day at third or fourth cycles, if they remain non-responders) will be given 5 days.<br>|
| Active Comparator: Acupuncture treatment 2 plus CC<br> | Other: Acupuncture treatment 2<br>* Needles will be inserted to a depth of <5 mm, one in each shoulder and on in each upper arm at non-acupuncture points. Electrodes will be attached to the needles and the stimulator will be turned on at an intensity of zero (no active current) in order to mimic EA in the acupuncture treatment 1. No manual stimulation of the needles will be performed.<br>Other: CC<br>* CC 50 mg every day for 5 days (day 3-7 of cycle), for a total of 4 cycles. Non-response will be defined after 4 weeks of CC placebo administration with 3 consecutive weekly negative P4 and hCG levels. Then during the fifth week a higher dose consisting of one more tablet per day (up to 3 tablets per day at third or fourth cycles, if they remain non-responders) will be given 5 days.<br>|
| Active Comparator: Acupuncture treatment 1 plus CC placebo<br> | Other: Acupuncture treatment 1<br>* Two sets of acupuncture points will be alternated every second treatment. The first set consists of CV3, CV 6, and ST 29 bilaterally，SP 6 and SP 9 bilaterally. Needles will also be placed in LI bilaterally and GV 20. CV 3, CV 6, ST 29, SP 6, and SP 9 will be connected to and electrical stimulator and stimulated with low-frequency EA of 2Hz, 0.3 ms.<br>Other: CC placebo<br>* CC placebo 50 mg every day for 5 days (day 3-7 of cycle), for a total of 4 cycles. Non-response will be defined after 4 weeks of CC Placebo administration with 3 consecutive weekly negative P4 and hCG levels. Then during the fifth week a higher dose consisting of one more tablet per day (up to 3 tablets per day at third or fourth cycles, if they remain non-responders) will be given 5 days.<br>|
| Active Comparator: Acupucture treatment 2 and CC placebo.<br> | Other: Acupuncture treatment 2<br>* Needles will be inserted to a depth of <5 mm, one in each shoulder and on in each upper arm at non-acupuncture points. Electrodes will be attached to the needles and the stimulator will be turned on at an intensity of zero (no active current) in order to mimic EA in the acupuncture treatment 1. No manual stimulation of the needles will be performed.<br>Other: CC placebo<br>* CC placebo 50 mg every day for 5 days (day 3-7 of cycle), for a total of 4 cycles. Non-response will be defined after 4 weeks of CC Placebo administration with 3 consecutive weekly negative P4 and hCG levels. Then during the fifth week a higher dose consisting of one more tablet per day (up to 3 tablets per day at third or fourth cycles, if they remain non-responders) will be given 5 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Live birth rate |  | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ovulation rate |  | Up to 3 years | 
| Ongoing pregnancy rate | Up to 3 years | Aprial 2012 to July 2014 (up to 3 years) | 
| Multiple pregnancy rate |  | Up to 2 years | 
| Miscarriage rate | loss of an intrauterine pregnancy before 20 completed weeks of gestation. | Up to 2 years | 
| Hormonal profile | Hormonal profile include: Testosterone(T), Sex hormone-binding globulin (SHBG), Follicle stimulating hormone (FSH),Luteinizing hormone(LH),and Dehydroepiandrosterone sulfate (DHEAS). | Up to 2 years | 
| Metabolic profile | Metabolic profile includes: Serum glucose concentration, Insulin concentration, cholesterol, Triglycerides (TG), High density lipoprotein cholesterol (HDL-C) and Low density lipoprotein cholesterol (LDL-C) | Up to 2 years | 
| Side effect profile | Side effects of CC include hot flashes, mood changes, bloating, formation of ovarian cysts, and pain, extremely rare are pituitary apoplexy and deep venous thrombosis. The major side effects of acupuncture are local skin irritation, discomfort, and vasovagal reactions during the procedure. All above mentioned side effects will be recorded weekly. | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infertility, Polycystic Ovary Syndrome, Clomiphene citrate, Acupuncture