Clinical trial NCT01573858: Acupuncture and Clomiphene Citrate on Live Birth in Anovulatory Women With Polycystic Ovary Syndrome
Official title: Effect of Acupuncture and Clomiphene Citrate on Live Birth in Anovulatory Women With Polycystic Ovary Syndrome: A Randomized Controlled Trial (PCOSAct)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Pregnancy
Polycystic Ovary Syndrome
Infertility
Keywords: Infertility
Polycystic Ovary Syndrome
Clomiphene citrate
Acupuncture
Lead sponsor: Heilongjiang University of Chinese Medicine
Sponsor class: OTHER
Collaborators: name: Yale University
name: Penn State University
name: Göteborg University
name: The University of Hong Kong
name: Beijing University of Chinese Medicine
name: Sichuan University
name: Second Affiliated Hospital of Heilongjiang University of Chinese Medicine
name: Harbin Medical University
name: Daqing Oil Field Hospital
name: Daqing Longnan Hospital
name: Liaoning University of Traditional Chinese Medicine
name: The First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine
name: Tianjin Tanggu Maternity and Child Care Center
name: Wenzhou Chinese Medicine Hospital
name: Jiangsu Province Hospital of Traditional Chinese Medicine
name: Hangzhou Chinese Medicine Hospital
name: Shanxi Chinese Medicine Hospital
name: Henan Chinese Medicine Hospital
name: Maternal and Child Health Hospital of Xuzhou
name: Huaian Maternal and Child Health Care Hospital
name: The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine
name: Suzhou Chinese Medicine Hospital
name: Wuhan TongJi Hospital
name: Hubei Chinese Medicine Hospital
name: Jiangxi University of Chinese Medicine Affiliated Hospital
name: The First Affiliated Hospital of Hunan University of Traditional Chinese Medicine
name: The First Affiliated Hospital, Guangzhou University of Traditional Chinese Medicine
name: Guangdong Provincial People's Hospital
name: Guangzhou Liwan Chinese Hospital
name: Dalian maternity hospital
First posted: 2012-04-10
Enrollment: 1000
Sex: FEMALE
Minimum age (years): 20
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).

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

Eligibility criteria: 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.

Primary outcomes:
measure: Live birth rate
timeFrame: Up to 3 years
Secondary outcomes:
measure: Ovulation rate
timeFrame: Up to 3 years
measure: Ongoing pregnancy rate
timeFrame: Aprial 2012 to July 2014 (up to 3 years)
measure: Multiple pregnancy rate
timeFrame: Up to 2 years
measure: Miscarriage rate
timeFrame: Up to 2 years
measure: Hormonal profile
timeFrame: Up to 2 years
measure: Metabolic profile
timeFrame: Up to 2 years
measure: Side effect profile
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Hefei
country: China
facility: First Affiliated Hospital，Anhui University of Chinese Medicine
state: Anhui
city: Guangzhou
country: China
facility: First Affiliated Hospital，Guangzhou University of Chinese Medicine
state: Guangdong
city: Guangzhou
country: China
facility: Guangzhou Liwan Chinese Hospital
state: Guangdong
city: Guangzhou
country: China
facility: Guangdong Chinese Hospital
state: Guangdong
city: Daqing
country: China
facility: Daqing LongNa Hospital
state: Heilongjiang
city: Daqing
country: China
facility: The Daqing Oilfield General Hospital
state: Heilongjiang
city: Harbin
country: China
facility: Forth Affiliated Hospital of Harbin Medical University
state: Heilongjiang
city: Harbin
country: China
facility: Second Affiliated Hospital，Heilongjiang University of Chinese Medicine
state: Heilongjiang
city: Harbin
country: China
facility: First Affiliated Hospital，Heilongjiang University of Chinese Medicine
state: Heilongjiang
city: Zhengzhou
country: China
facility: Henan Chinese Medicine Hospital
state: Henan
city: Wuhan
country: China
facility: Wuhan Tongji Hospital
state: Hubei
city: Wuhan
country: China
facility: Hubei Chinese Medicine Hospital
state: Hubei
city: Changsha
country: China
facility: First Affiliated Hospital，Hunan University of Chinese Medicine
state: Hunan
city: Huaian
country: China
facility: Maternal and Child Health Hospital of Huaian
state: Jiangsu
city: Suzhou
country: China
facility: Suzhou Chinese Medicine Hospital
state: Jiangsu
city: Xuzhou
country: China
facility: Maternal and Child Health Hospital of Xuzhou
state: Jiangsu
city: Nanchang
country: China
facility: Jiangxi University of Chinese Medicine Affiliated Hospital
state: Jiangxi
city: Dalian
country: China
facility: Dalian maternity hospital
state: Liaoning
city: Shenyang
country: China
facility: Liaoning University of Chinese Medicine Affiliated Hospital
state: Liaoning
city: Shangxi
country: China
facility: Shanxi Chinese Medicine Hospital
state: Shanxi
city: Tianjin
country: China
facility: First Affiliated Hospital，Tianjin University of Chinese Medicine
state: Tianjin
city: Tianjin
country: China
facility: Tianjin Tanggu Maternity and Child Care Center
state: Tianjin
city: Hangzhou
country: China
facility: Integrated Chinese and Western Medicine Hospital of Zhejiang Province
state: Zhejiang
city: Wenzhou
country: China
facility: Wenzhou Chinese Medicine Hospital
state: Zhejiang
city: Hangzhou
country: China
facility: Hangzhou Chinese Medicine Hospital
Study officials:
affiliation: First Affiliated Hospital of Heilongjiang Chinese Medicine University
name: Xiaoke Wu, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: First Affiliated Hospital of Heilongjiang Chinese Medicine University
name: Lihui Hou, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Steering Committee, Pennsylvania State University College of Medicine
name: Richard Legro, MD
role: STUDY_CHAIR
affiliation: Data and Quality Control, Yale University
name: Heping Zhang, PHD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.