A Multicenter Randomized Trial of Personalized Acupuncture, Fixed Acupuncture, Letrozole and Placebo on Live Birth for Infertility in Women With Polycystic Ovary Syndrome
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Enrollment
- 1,103
- Locations
- 1
- Primary Endpoint
- Live birth rate
Study Overview
Brief Summary
This study is a randomized assessor-blind controlled trial. A total of 1,103 women with PCOS will be recruited from 20 hospitals and randomly allocated into four groups: personalized acupuncture, fixed acupuncture, letrozole or placebo letrozole. Patients will receive treatment for 16 weeks and the primary outcome is live birth.
Detailed Description
Traditional Chinese Medicine (TCM) usually involves syndrome and disease differentiation, and for acupuncture selection of appropriate points and skillful needling techniques. Many clinical trials on acupuncture used fixed acupuncture protocols without accounting for individual differences. We here design a multicenter randomized controlled trial to evaluate whether personalized or fixed acupuncture increases the likelihood of live births for infertility in women with polycystic ovary syndrome (PCOS) compared with letrozole or placebo letrozole. We hypothesis that letrozole is more effective than personalized acupuncture and that personalized acupuncture is more effective than standardized acupuncture, which is more effective than placebo letrozole.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Triple (Participant, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 20 Years to 40 Years (Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age of women between 20 and 40 years.
- •Chronic oligomenorrhea or amenorrhea: oligomenorrhea is defined as an intermenstrual interval > 35 days or < 8 menstrual bleedings in the past year. Amenorrhea is defined as an intermenstrual interval >90 days.
- •Hyperandrogenism (either hirsutism or hyperandrogenemia) or polycystic ovaries on ultrasound. Hirsutism is determined by a modified Ferriman-Gallwey Score ≥ 5 at screening examination, and biochemical hyperandrogenism is defined as total testosterone (T) > 2.6 nmol/L and free testosterone ≥ 6.0 pg/mL. Polycystic ovaries are present when there are ≥ 12 antral follicles (2 - 9 mm) or ovarian volume > 10 mL on transvaginal scanning.
- •At least one patent tube shown by hysterosalpingogram or diagnostic laparoscopy within 3 years if the patient does not have a history of abortion or pelvic operation. If the patient has a history of pregnancy and no history of pelvic operation within the past 5 years, she is not required to undergo a tubal patency test.
- •Sperm concentration ⩾ 15 × 106/mL and total motility ⩾ 40% or total motile sperm count ⩾ 9 million in the semen analysis of the husband. Agree to have regular intercourse i.e. 2-3 times per week during the study period.
Exclusion Criteria
- •Exclusion of other endocrine disorders: a. patients with hyperprolactinemia (defined as two prolactin levels at least one week apart ≥ 25 ng/mL); b. Patients with FSH levels > 15 mIU/mL. A normal level within the last year is adequate for entry; c. 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. d. Patients diagnosed with Type I or Type II diabetes who are poorly controlled (defined as HbA1c level > 7.0%), or patients receiving antidiabetic medications such as metformin, insulin, thiazolidinediones, acarbose, or sulfonylureas. e. Patients with suspected Cushing's syndrome.
- •Use of other TCM treatments including Chinese herbal prescriptions and acupuncture in the past 3 months.
- •Use of other western medications known to affect reproductive function or metabolism in the past 2 months.
- •Pregnancy within the past 6 weeks.
- •Within 6 weeks postabortion or postpartum.
- •Breastfeeding within the last 6 months.
- •Not willing to give written consent to the study.
- •Additional exclusion criteria are as follows.
- •Patients taking other medications known to affect reproductive function or metabolism. These medications include oral contraceptives, depot progestins, hormonal implants (including Implanon), GnRH agonists and antagonists, antiandrogens, gonadotropins, antiobesity drugs, antidiabetic drugs such as metformin and thiazolidinediones, somatostatin, diazoxide, angiotensin-converting-enzyme (ACE) inhibitors, and calcium channel blockers. The washout period on these medicationswill be two months, 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 depot 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 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 into other investigative studies that require medications, prescribe 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 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 mmHg or a diastolic 100 mm Hg obtained on two measures obtained at least 60 minutes apart.
- •Patients with known congenital adrenal hyperplasia.
Arms & Interventions
Placebo letrozole
Women will receive placebo letrozole with no acupuncture from day 3 to day 7 of the spontaneous menstrual cycle or after a withdrawal bleeding following progestin. Placebo letrozole will be given in the same way as letrozole.
Intervention: Placebo letrozole (Drug)
Fixed acupuncture
Two sets of acupuncture points will be alternated every second treatment. The first set consists of CV 3, CV 6, ST 29 bilaterally, SP 6 bilaterally, SP 9 bilaterally, GV 20 and LI 4 bilaterally. The second set consists of 13 needles: ST 25 bilaterally, ST 29 bilaterally, CV 3, CV 6, SP 6 bilaterally, LR 3 bilaterally, PC 6 bilaterally and GV 20. The following points will be connected to an electrical stimulator: ST 25 bilaterally, ST 29 bilaterally, SP 6 bilaterally, LR 3 bilaterally.
Intervention: Acupuncture (Other)
Personalized acupuncture
Two sets of acupoints will be selected for the two types. The basic acupoint-prescription includes CV 4, CV 6, CV 12 and SP 6 bilaterally, ST 25 bilaterally, EX-CA 1 bilaterally, ST 40 bilaterally and SP 9 bilaterally. Additional point ST 36 bilaterally and moxibustion as adjuvant therapy will be added for the type of yang deficiency of spleen and kidney, while additional points K 13, LR 3 for the type of yin deficiency of liver and kidney. Besides, flexible modifications of 2-3 acupoints will be performed according to patients special symptoms.
Intervention: Acupuncture (Other)
Letrozole
Women in the letrozole group will be given letrozole (Femara, Novartis Pharmaceuticals, Basel, Switzerland) from day 3 to day 7 of the spontaneous menstrual cycle or after a withdrawal bleeding following progestin. The maximum daily dose of letrozole will be 7.5 mg (3 pills) daily for five days.
Intervention: Letrozole (Drug)
Outcomes
Primary Outcomes
Live birth rate
Time Frame: Up to 14 months
Live birth rate defined as a delivery after ≥20 weeks gestation.
Secondary Outcomes
- Luteinizing hormone(LH)(Up to 4 months)
- Cholesterol(Up to 4 months)
- Serum glucose concentration(Up to 4 months)
- Insulin concentration(Up to 4 months)
- Conception rate(Up to 4 months)
- Testosterone(T)(Up to 4 months)
- Sex hormone-binding globulin (SHBG)(Up to 4 months)
- Low density lipoprotein cholesterol (LDL-C)(Up to 4 months)
- The scores of Zung Self-reported Depression Scale (SDS)(Up to 4 months)
- Ovulation rate(Up to 4 months)
- Pregnancy rate(Up to 6.5 months)
- Triglycerides (TG)(Up to 4 months)
- The scores of short form 36 (SF 36)(Up to 4 months)
- The scores of polycystic ovary syndrome questionnaire (PCOSQ)(Up to 4 months)
- The scores of Zung Self-Rating Anxiety Scale (SAS)(Up to 4 months)
- Side effect profile(Up to 14 months)
- Pregnancy loss rate(Up to 9 months)
- Follicle stimulating hormone (FSH)(Up to 4 months)
- High density lipoprotein cholesterol (HDL-C)(Up to 4 months)
- The scores of Chinese quality of life (ChQOL) questionnaire(Up to 4 months)
Investigators
Hongxia Ma
professor
The First Affiliated Hospital of Guangzhou Medical University