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

Sponsor

Heilongjiang University of Chinese Medicine (Other)

Overall Status

Completed

CT.gov ID

NCT01573858

Collaborator

Yale University (Other), Penn State University (Other), Göteborg University (Other), The University of Hong Kong (Other), Beijing University of Chinese Medicine (Other), Sichuan University (Other), Second Affiliated Hospital of Heilongjiang University of Chinese Medicine (Other), Harbin Medical University (Other), Daqing Oil Field Hospital (Other), Daqing Longnan Hospital (Other), Liaoning University of Traditional Chinese Medicine (Other), The First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine (Other), Tianjin Tanggu Maternity and Child Care Center (Other), Wenzhou Chinese Medicine Hospital (Other), Jiangsu Province Hospital of Traditional Chinese Medicine (Other), Hangzhou Chinese Medicine Hospital (Other), Shanxi Chinese Medicine Hospital (Other), Henan Chinese Medicine Hospital (Other), Maternal and Child Health Hospital of Xuzhou (Other), Huaian Maternal and Child Health Care Hospital (Other), The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine (Other), Suzhou Chinese Medicine Hospital (Other), Wuhan TongJi Hospital (Other), Hubei Chinese Medicine Hospital (Other), Jiangxi University of Chinese Medicine Affiliated Hospital (Other), The First Affiliated Hospital of Hunan University of Traditional Chinese Medicine (Other), The First Affiliated Hospital, Guangzhou University of Traditional Chinese Medicine (Other), Guangdong Provincial People's Hospital (Other), Guangzhou Liwan Chinese Hospital (Other), Dalian maternity hospital (Other)

1,000

Enrollment

Locations

Arms

Actual Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Pregnancy Polycystic Ovary Syndrome Infertility	Other: Acupuncture treatment 1 Other: Acupuncture treatment 2 Other: CC Other: CC placebo	N/A

Detailed Description

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

Study Design

Study Type:

Interventional

Actual Enrollment :

1000 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jul 6, 2012

Actual Primary Completion Date :

Nov 8, 2014

Actual Study Completion Date :

Oct 7, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Acupuncture treatment 1 plus CC	Other: Acupuncture treatment 1 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. Other: CC 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.
Active Comparator: Acupuncture treatment 2 plus CC	Other: Acupuncture treatment 2 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. Other: CC 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.
Active Comparator: Acupuncture treatment 1 plus CC placebo	Other: Acupuncture treatment 1 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. Other: CC placebo 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.
Active Comparator: Acupucture treatment 2 and CC placebo.	Other: Acupuncture treatment 2 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. Other: CC placebo 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.

Outcome Measures

Primary Outcome Measures

Live birth rate [Up to 3 years]

Secondary Outcome Measures

Ovulation rate [Up to 3 years]
Ongoing pregnancy rate [Aprial 2012 to July 2014 (up to 3 years)]
Up to 3 years
Multiple pregnancy rate [Up to 2 years]
Miscarriage rate [Up to 2 years]
loss of an intrauterine pregnancy before 20 completed weeks of gestation.
Hormonal profile [Up to 2 years]
Hormonal profile include: Testosterone(T), Sex hormone-binding globulin (SHBG), Follicle stimulating hormone (FSH),Luteinizing hormone(LH),and Dehydroepiandrosterone sulfate (DHEAS).
Metabolic profile [Up to 2 years]
Metabolic profile includes: Serum glucose concentration, Insulin concentration, cholesterol, Triglycerides (TG), High density lipoprotein cholesterol (HDL-C) and Low density lipoprotein cholesterol (LDL-C)
Side effect profile [Up to 2 years]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 40 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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:

1. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	First Affiliated Hospital，Anhui University of Chinese Medicine	Hefei	Anhui	China	230031
2	First Affiliated Hospital，Guangzhou University of Chinese Medicine	Guangzhou	Guangdong	China	510000
3	Guangzhou Liwan Chinese Hospital	Guangzhou	Guangdong	China	510000
4	Guangdong Chinese Hospital	Guangzhou	Guangdong	China	510120
5	Daqing LongNa Hospital	Daqing	Heilongjiang	China	163000
6	The Daqing Oilfield General Hospital	Daqing	Heilongjiang	China	163000
7	Forth Affiliated Hospital of Harbin Medical University	Harbin	Heilongjiang	China	150001
8	Second Affiliated Hospital，Heilongjiang University of Chinese Medicine	Harbin	Heilongjiang	China	150001
9	First Affiliated Hospital，Heilongjiang University of Chinese Medicine	Harbin	Heilongjiang	China	150040
10	Henan Chinese Medicine Hospital	Zhengzhou	Henan	China	450002
11	Wuhan Tongji Hospital	Wuhan	Hubei	China	430000
12	Hubei Chinese Medicine Hospital	Wuhan	Hubei	China	430060
13	First Affiliated Hospital，Hunan University of Chinese Medicine	Changsha	Hunan	China	410007
14	Maternal and Child Health Hospital of Huaian	Huaian	Jiangsu	China	223002
15	Suzhou Chinese Medicine Hospital	Suzhou	Jiangsu	China	215003
16	Maternal and Child Health Hospital of Xuzhou	Xuzhou	Jiangsu	China	221000
17	Jiangxi University of Chinese Medicine Affiliated Hospital	Nanchang	Jiangxi	China	330000
18	Dalian maternity hospital	Dalian	Liaoning	China	116000
19	Liaoning University of Chinese Medicine Affiliated Hospital	Shenyang	Liaoning	China	110000
20	Shanxi Chinese Medicine Hospital	Shangxi	Shanxi	China	030012
21	First Affiliated Hospital，Tianjin University of Chinese Medicine	Tianjin	Tianjin	China	300193
22	Tianjin Tanggu Maternity and Child Care Center	Tianjin	Tianjin	China	300451
23	Integrated Chinese and Western Medicine Hospital of Zhejiang Province	Hangzhou	Zhejiang	China	310000
24	Wenzhou Chinese Medicine Hospital	Wenzhou	Zhejiang	China	325000
25	Hangzhou Chinese Medicine Hospital	Hangzhou		China	310000

Sponsors and Collaborators

Heilongjiang University of Chinese Medicine
Yale University
Penn State University
Göteborg University
The University of Hong Kong
Beijing University of Chinese Medicine
Sichuan University
Second Affiliated Hospital of Heilongjiang University of Chinese Medicine
Harbin Medical University
Daqing Oil Field Hospital
Daqing Longnan Hospital
Liaoning University of Traditional Chinese Medicine
The First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine
Tianjin Tanggu Maternity and Child Care Center
Wenzhou Chinese Medicine Hospital
Jiangsu Province Hospital of Traditional Chinese Medicine
Hangzhou Chinese Medicine Hospital
Shanxi Chinese Medicine Hospital
Henan Chinese Medicine Hospital
Maternal and Child Health Hospital of Xuzhou
Huaian Maternal and Child Health Care Hospital
The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine
Suzhou Chinese Medicine Hospital
Wuhan TongJi Hospital
Hubei Chinese Medicine Hospital
Jiangxi University of Chinese Medicine Affiliated Hospital
The First Affiliated Hospital of Hunan University of Traditional Chinese Medicine
The First Affiliated Hospital, Guangzhou University of Traditional Chinese Medicine
Guangdong Provincial People's Hospital
Guangzhou Liwan Chinese Hospital
Dalian maternity hospital

Investigators

Principal Investigator: Xiaoke Wu, M.D., Ph.D., First Affiliated Hospital of Heilongjiang Chinese Medicine University
Principal Investigator: Lihui Hou, M.D., First Affiliated Hospital of Heilongjiang Chinese Medicine University
Study Chair: Richard Legro, MD, Steering Committee, Pennsylvania State University College of Medicine
Study Chair: Heping Zhang, PHD, Data and Quality Control, Yale University