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

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

The objectives of the present trial are to test the following three hypotheses in anovulatory women with PCOS:

1. Acupuncture protocol 1 plus CC (Arm A) is more likely to result in live birth than acupuncture protocol 2 combined with CC (Arm B),
2. Acupuncture protocol 2 plus CC (Arm B) is more likely to result in live birth than acupuncture protocol 1 plus placebo (Arm C),
3. Acupuncture protocol 1 plus placebo (Arm C) is more likely to result in live birth than acupuncture protocol 2 plus placebo (Arm D).

Study Overview

• Status: Completed
• Conditions: Polycystic Ovary Syndrome; Infertility; Pregnancy
• Intervention / Treatment: Other: Acupuncture treatment 1; Other: CC; Other: Acupuncture treatment 2; Other: CC placebo

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 Type: Interventional
• Enrollment (Actual): 1000
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Hangzhou, China, 310000
    • Hangzhou Chinese Medicine Hospital
  • Anhui
    • Hefei, Anhui, China, 230031
      • First Affiliated Hospital，Anhui University of Chinese Medicine
  • Guangdong
    • Guangzhou, Guangdong, China, 510000
      • First Affiliated Hospital，Guangzhou University of Chinese Medicine
    • Guangzhou, Guangdong, China, 510000
      • Guangzhou Liwan Chinese Hospital
    • Guangzhou, Guangdong, China, 510120
      • Guangdong Chinese Hospital
  • Heilongjiang
    • Daqing, Heilongjiang, China, 163000
      • The Daqing Oilfield General Hospital
    • Daqing, Heilongjiang, China, 163000
      • Daqing LongNa Hospital
    • Harbin, Heilongjiang, China, 150001
      • Forth Affiliated Hospital of Harbin Medical University
    • Harbin, Heilongjiang, China, 150001
      • Second Affiliated Hospital，Heilongjiang University of Chinese Medicine
    • Harbin, Heilongjiang, China, 150040
      • First Affiliated Hospital，Heilongjiang University of Chinese Medicine
  • Henan
    • Zhengzhou, Henan, China, 450002
      • Henan Chinese Medicine Hospital
  • Hubei
    • Wuhan, Hubei, China, 430000
      • Wuhan Tongji Hospital
    • Wuhan, Hubei, China, 430060
      • Hubei Chinese Medicine Hospital
  • Hunan
    • Changsha, Hunan, China, 410007
      • First Affiliated Hospital，Hunan University of Chinese Medicine
  • Jiangsu
    • Huaian, Jiangsu, China, 223002
      • Maternal and Child Health Hospital of Huaian
    • Suzhou, Jiangsu, China, 215003
      • Suzhou Chinese Medicine Hospital
    • Xuzhou, Jiangsu, China, 221000
      • Maternal and Child Health Hospital of Xuzhou
  • Jiangxi
    • Nanchang, Jiangxi, China, 330000
      • Jiangxi University of Chinese Medicine Affiliated Hospital
  • Liaoning
    • Dalian, Liaoning, China, 116000
      • Dalian Maternity Hospital
    • Shenyang, Liaoning, China, 110000
      • Liaoning University of Chinese Medicine Affiliated Hospital
  • Shanxi
    • Shangxi, Shanxi, China, 030012
      • Shanxi Chinese Medicine Hospital
  • Tianjin
    • Tianjin, Tianjin, China, 300193
      • First Affiliated Hospital，Tianjin University of Chinese Medicine
    • Tianjin, Tianjin, China, 300451
      • Tianjin Tanggu Maternity and Child Care Center
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310000
      • Integrated Chinese and Western Medicine Hospital of Zhejiang Province
    • Wenzhou, Zhejiang, China, 325000
      • Wenzhou Chinese Medicine Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

1. 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. 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).
     2. 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].

2. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / 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: 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.; 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.
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Luo X, Yang XM, Cai WY, Chang H, Ma HL, Peng Y, Wu XK. Decreased Sex Hormone-Binding Globulin Indicated Worse Biometric, Lipid, Liver, and Renal Function Parameters in Women with Polycystic Ovary Syndrome. Int J Endocrinol. 2020 Jun 25;2020:7580218. doi: 10.1155/2020/7580218. eCollection 2020.
• Zhang D, Gao J, Liu X, Qin H, Wu X. Effect of Three Androgen Indexes (FAI, FT, and TT) on Clinical, Biochemical, and Fertility Outcomes in Women with Polycystic Ovary Syndrome. Reprod Sci. 2021 Mar;28(3):775-784. doi: 10.1007/s43032-020-00316-1. Epub 2020 Sep 28.
• Zhang D, Yang X, Li J, Yu J, Wu X. Effect of hyperinsulinaemia and insulin resistance on endocrine, metabolic and fertility outcomes in women with polycystic ovary syndrome undergoing ovulation induction. Clin Endocrinol (Oxf). 2019 Sep;91(3):440-448. doi: 10.1111/cen.14050. Epub 2019 Jun 28.
• Ma HL, Xie LZ, Gao JS, Cong J, Deng YY, Ng EHY, Liu JP, Wu XK. Acupuncture and clomiphene for Chinese women with polycystic ovary syndrome (PCOSAct): statistical analysis approach with the revision and explanation. Trials. 2018 Nov 1;19(1):601. doi: 10.1186/s13063-018-2942-7.
• Li J, Wu Q, Wu XK, Zhou ZM, Fu P, Chen XH, Yan Y, Wang X, Yang ZW, Li WL, Stener-Victorin E, Legro RS, Ng EH, Zhang H, Mol BWJ, Wang CC; for PCOSAct Study Group. Effect of exposure to second-hand smoke from husbands on biochemical hyperandrogenism, metabolic syndrome and conception rates in women with polycystic ovary syndrome undergoing ovulation induction. Hum Reprod. 2018 Apr 1;33(4):617-625. doi: 10.1093/humrep/dey027.
• Wu XK, Stener-Victorin E, Kuang HY, Ma HL, Gao JS, Xie LZ, Hou LH, Hu ZX, Shao XG, Ge J, Zhang JF, Xue HY, Xu XF, Liang RN, Ma HX, Yang HW, Li WL, Huang DM, Sun Y, Hao CF, Du SM, Yang ZW, Wang X, Yan Y, Chen XH, Fu P, Ding CF, Gao YQ, Zhou ZM, Wang CC, Wu TX, Liu JP, Ng EHY, Legro RS, Zhang H; PCOSAct Study Group. Effect of Acupuncture and Clomiphene in Chinese Women With Polycystic Ovary Syndrome: A Randomized Clinical Trial. JAMA. 2017 Jun 27;317(24):2502-2514. doi: 10.1001/jama.2017.7217.

Study record dates

Study Major Dates

• Study Start (Actual): July 6, 2012
• Primary Completion (Actual): November 8, 2014
• Study Completion (Actual): October 7, 2015

Study Registration Dates

• First Submitted: April 4, 2012
• First Submitted That Met QC Criteria: April 9, 2012
• First Posted (Estimate): April 10, 2012

Study Record Updates

• Last Update Posted (Actual): August 25, 2021
• Last Update Submitted That Met QC Criteria: August 24, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Infertility; Acupuncture; Polycystic Ovary Syndrome; Clomiphene citrate
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Endocrine System Diseases; Disease; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Polycystic Ovary Syndrome; Syndrome; Infertility
• Other Study ID Numbers: PCOSAct