Clinical trial NCT02491333: The RCT of Acupuncture on PCOS Combined With IR
Official title: The Effect of Acupuncture on Insulin Sensitivity of Women With Polycystic Ovary Syndrome and Insulin Resistance: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Polycystic Ovary Syndrome
Insulin Resistance
Keywords: polycystic ovary syndrome
acupuncture
insulin resistance
HOMA-IR
metformin
Lead sponsor: The First Affiliated Hospital of Guangzhou Medical University
Sponsor class: OTHER
Collaborators: name: The University of Hong Kong
name: Karolinska Institutet
First posted: 2015-07-08
Enrollment: 342
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objectives of this randomized controlled trial are to compare insulin sensitivity following true acupuncture + placebo metformin (Group 1) vs sham acupuncture + placebo metformin (Group 2) vs sham acupuncture + metformin (Group 3) in women with PCOS and IR.

Detailed description: 1.1 Study design This is a randomized double blind controlled. 1.2 Subject selection and exclusion Women with PCOS and IR will be recruited from the Department of Traditional Chinese Medicine in the first affiliated hospital of Guangzhou Medical University, Xuzhou maternity \& child health hospital, Liwan hospital of traditional Chinese medicine, and Hexian memorial affiliated hospital of Southern Medical University if they meet the inclusion criteria and do not have any exclusion criteria. Eligible subjects will be approached and sign the consent form after detailed explanation of the study design and comprehensive counseling.

1.3 Screening visit Women will be screened in the morning after an overnight 12 hour fast. Detailed information about the study design will be given.

1.3.1 Sign informed consent Informed consent will be signed after detailed counseling. 1.3.2 Perform physical examination Perform complete physical examination including height, weight, hip, and waist measurement. Height and weight will be recorded to the nearest 0.1 cm and 0.1 kg respectively. Waist and hip circumference will be recorded to the nearest 1 cm. And assessment of hirsutism by FG, acne standard acne lesion counts, and pelvic exam.

1.3.3 Perform transvaginal ultrasound of ovaries Ovaries, including the ovarian size in three dimensions, the size of the largest ovarian follicle/cyst and size of every follicle with a mean diameter greater than 10 mm, and total antral follicle count (small follicles with mean diameter \< 10 mm) of each ovary will be obtained through transvaginal ultrasound.

1.3.4 Check urine pregnancy test 1.3.5 Fasting blood samples to exclude other endocrine disorders Fasting (at least 4 h) blood samples will be taken to exclude any endocrine disorders:F-glucose, F-insulin, Hba1C (\>7%), C-peptide, TSH (\< 0.2 mIU/mL or \>5.5 mIU/mL), T3 (\<1.4 nmol/L or \>2.2nmol/L), and free T4 (\<10pmol/L or \>23pmol/L).

1.3.6 Progestin withdrawal Prescribe progestin to induce withdrawal bleed, after eligibility is determined.

1.4 Baseline visit After screening visit, if a woman fulfills inclusion criteria and has signed the informed consent she will be assigned to the baseline visit. Baseline visit takes place day 2 - 5 of a spontaneous period or after a withdrawal bleeding after an overnight fast.

1.4.1 Laboratory Examination Collect 20ml of blood, and 10ml of blood will be for the following tests. The remaining 10ml of blood will be stored for determination of DNA and sphingolipid later.

1. Circulating sex steroids: Fasting serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen (E2), prolactin (PRL) and T, sex hormone binding globulin (SHBG), and dehydroepiandrosterone sulfate (DHEAS).
2. Lipid profile: Triglycerides (TG), total cholesterol (TC), high density lipoprotein (HDL-C), low density lipoprotein (LDL-C), apolipoprotein A1 (Apoa1), apolipoprotein B (ApoB), BRT, Renal, and Liver Profile.
3. Glucose homeostasis: The oral glucose tolerance test (OGTT) with 75 g glucose. Blood samples will be obtained to measure plasma glucose, serum insulin and C-peptide at 0, 60, and 120 min during the OGTT.

1.4.2 Complete questionnaires Quality of life will be assessed by the short form 36(SF-36), the Chinese Quality of Life (ChiQOL), sleeping questionnaires, international physical activity questionnaire (IPAQ) and the Polycystic Ovary Syndrome Questionnaire (PCOS-QOL). Investigators will also assess symptoms of anxiety and depression by the Zung SAS and Zung SDS questionnaires. And complete the quantization table of traditional Chinese medicine (TCM) syndromes about PCOS.

1.4.3 Assess TCM syndromes of patients Syndrome differentiation (Bian Zheng) in TCM is the comprehensive analysis of clinical information gained by the four main diagnostic TCM procedures: observation, listening, questioning, and pulse analysis, and it is used to guide the choice of treatment either by acupuncture and/or TCM herbal formulae. In PCOS, patients are empirically differentiated to be four categories: 1) phlegm-dampness syndrome, 2) blood stasis syndrome, 3) phlegm, and 4) blood stasis.

2. Intervention arms 2.1 Information to all study subjects All participants will be advised about the importance of regular physical exercise and a balanced diet by a trained dietician. Importantly, they will be instructed not to change their exercise or diet habits during the entire study period.

True acupuncture or, sham acupuncture and metformin/placebo will be started 2 days after the baseline visit including OGTT. All subjects will be asked to use a barrier method for contraception. True and sham acupuncture treatment will be given three times per week. Each treatment session lasts for 30 minutes and can be separated by an interval of 1-3 days, with a maximum of 90 treatment sessions during 4 month. After the third treatment, all patients fill in the expectation and credibility questionnaire. Metformin or placebo will be given at 0.5g/times, 3 times one day and for 4 month.

2.1.1 True acupuncture protocol The rationale of acupuncture protocols is based on Western Medical theories and the study protocol follows the CONSORT and STRICTA recommendations.Investigators will use fixed acupuncture protocols. The acupuncture protocol of this RCT follows the protocol in the following studies: ClinicalTrial.gov NCT01457209 and NCT02026323.

Disposable, single-use, sterilized needles made of stainless steel, 0.25 x 30 mm and 0.30 x 40/50 mm (Hwoto, Suzhou Medical Appliance Fact. 215005 Suzhou, China) will be inserted to a depth of 15-35 mm in segmental acupuncture points located in abdominal and leg muscles with innervations corresponding to the ovaries. Two sets of acupuncture points will be alternated every second treatment. The first set consists of conception vessel (CV) 4, CV 12, and stomach (ST) 29 bilaterally and in the muscles above the knee, ST 34, and ST 32 bilaterally and below the knee, spleen (SP) 6 and ST 36. Needles will also be placed in extra segmental acupuncture points that do not innervate the ovaries large intestine (LI) 4 bilaterally. In total 14 needles will be placed and all will be stimulated manually by rotating the needle to evoke needle sensation (de qi) once when inserted. The following points will be connected to an electrical stimulator (Export Abteilung, Schwa-Medico GmbH,Wetzlarer Str. 41-43;35630 Ehringshausen): CV 4 to CV 12, ST 29 bilateral, ST34 to ST 32 bilateral. Stimulation are given as low-frequency EA of 2Hz, 0.3 ms pulse length and with an intensity adjusted to produce local muscle contractions without pain or discomfort. Needles not connected to the electrical stimulator will be manually stimulated to evoke needle sensation every 10 min, in total 4 times. The second set consists of 14 needles placed in segmental abdominal points and stimulated electrically: ST 27 bilaterally, CV6 connected to CV10; and leg points: SP10 connected to a non-acupuncture point located 6 cun proximal of patellas medial border (electrical stimulation), and SP 6 and liver (LR) 3 bilaterally (manual stimulation). Extra segmental points are pericardium (PC) 6 bilaterally (manual stimulation).

2.1.2 Needle insertion technique Needle insertion should be gentle. Tighten the skin by pressing around the area of needle insertion and gently insert the needle.

2.1.3 Needles and stimulation Needle size: 0.25 x 30 mm or 0.30 x 40 or 0.30 x 50 mm. Select needle length with respect to the patients'BMI: 0.25 x 30 mm needles in women with normal BMI; 0.30 x 40 mm needles in overweight women and 0.30 x 50 or 75 mm needles in obese women. Depth of insertion may vary from patients to patients. Needles are placed with a depth deep enough to reach muscle/fibrous tissue. When needle are inserted, stimulate the needle gently until de qi (needle sensation reflecting activation of sensory afferents). As soon as de qi has been reached, make sure that the needle does not hurt or cause any pain and discomfort. Manual stimulation of needles that is not attached to an electrical stimulator (see below) are stimulated when inserted, after 10 minutes, 20 minutes and immediately before they are removed after 30 minutes.

Attach the electrodes according to the protocol. Turn on the stimulator (program 10) and increase the intensity. The intensity will be as high as possible without pain or discomfort. The stimulation amplitude/intensity will be adjusted after 10 and 20 minutes at the same time as when needle stimulated manually are manipulated. After 30 minutes the stimulator is turned off, electrodes disconnected and needles taken out.

2.1.4 Sham acupuncture protocol Disposable, single-use, sterilized needles made of stainless steel, 0.20 x 20 mm (Hwoto, Suzhou Medical Appliance Fact.215005 Suzhou, China) will be inserted superficially to a depth of \<5 mm, one in each shoulder and on in each upper arm at non-acupuncture points. Placement of needles is unlikely to affect ovulation and IR in women with PCOS. 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 protocol. No manual stimulation of the needles will be performed. An intended adjustment of the intensity after 10 minutes, 20 minutes and again after 30 minutes when stimulator is turned off and needles removed.

2.1.5 True and sham acupuncture treatment

1. Time of the day and acupuncturist name when the patient receives acupuncture will be recorded.
2. The intensity of stimulation (mA) is noted. It may vary between different electrodes. Note the range e.g. 1.2 - 3.0 mA.
3. Note any other events that may affect the treatment (positive or negative).
4. Note concomitant medications.
5. Collect menstrual logs at the end of every cycle. 2.2 Metformin and placebo Metformin (Kombiglyze XR) and placebo metformin will be packed and tested by a commercial pharmacy supply company (Squibb Company, Shanghai, China) specifically for this study. Metformin or placebo will be started 2 days after baseline visit including OGTT. Subjects will take 0.5 g/times, 3 times one day for up to 6 cycles.

2.3 Monitoring and examination during the treatment Physical examination will be performed monthly. Every menstruation should be recorded, including the date, volume and duration of menstruation during the entire study and follow-up. The condition of physical exercise and diet will be recorded for every cycle. OGTT will be repeated in the third month during the treatment.

2.4 End of treatment visit

During the end of treatment visit will all baseline measures be repeated as listed below:

1. Perform physical examination, including vital signs, height, weight, hip and waist measurements as well as repeating hirsutism and acne assessments after the end of treatment or pregnancy.
2. Repeat the serum levels of sex hormone steroids and metabolic profile.
3. Repeat transvaginal ultrasound of ovarian morphology.
4. Repeat OGTT.
5. Collect 20ml blood, and distributed store 10ml blood after serum separation. Other 10ml blood is for determination of DNA and sphingolipid.
6. Repeat QOL, sleeping, IPAQ anxiety/depression questionnaires, and the quantization table of TCM.
7. Collect menstrual logs.
8. Record adverse events and concomitant medications.
9. Answer the two questions about acupuncture treatment. 2.5 Follow-up visit Baseline and end of treatment visit will be repeated 3 months after last treatment (see point 1-8 under End of treatment visit). All the participants will be followed up with visiting the acupuncturists monthly for 3 month. The condition of physical exercise and diet will be record every month.

2.6 Safety analysis Adverse events will be categorized and percentage of patients experiencing adverse events and serious adverse events during the treatment period and follow up period will be documented. Chi-square tests will be performed to examine differences in the proportion of total and categories of adverse events.

2.7 Statistics One sample of the Kolmogorov-Smirnov test will be used to test the normal distribution of continuous variables. Continuous variables will be presented as means ± standard deviations if they are normally distributed or as medians with interquartile ranges if they are not normally distributed. Statistical comparison will be carried out according to the intention to treat by Student's t-test, Mann-Whitney U-test, and Wilcoxon signed ranks test for continuous variables and by χ2 tests for categorical variables where appropriate. All statistical analyses of the data will be performed using the SPSS program version 21.0 (SPSS Inc., Chicago, IL, USA), and a P-value \< 0.05 will be considered statistically significant.

Eligibility criteria: Inclusion Criteria:

1. Chinese women aged from 18 to 40 years.
2. BMI ≥18.5kg/m2.
3. Confirmed diagnosis of PCOS according to modified Rotterdam criteria in 2003 including at least two of the following three features: ①Oligo-(an intermenstrual interval \>35 days or \<8 cycles in the past year), amenorrhea (an intermenstrual interval\>90 days) and/or; ② polycystic ovarian morphology, i.e. presence of \>12 antral follicles (≤ 9mm) and/or ovarian volume \>10 ml on transvaginal scanning and/or; ③clinical and/or biochemical hyperandrogenism. Clinical hyperandrogenism in China Mainland is defined as a Ferriman-Gallwey (FG) score ≥5 ; biochemical hyperandrogenism is total testosterone (T) \> 2.6 nmol/l and free testosterone ≥6.0 pg/ml.
4. Presence of IR as defined by the homeostatic model assessment (HOMA-IR: \[fasting insulin (μU/mL) × fasting glucose (mmol/L)\] / 22.5). A value ≥ 2.14 will be considered to be indicative of IR.
5. No immediate fertility wish and willingness to use barrier methods to contraception for one year.
6. Willingness to sign the consent form.

Exclusion Criteria:

1. Exclusion of other endocrine disorders:

   ① 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.

   ② Poorly controlled of Type I or Type II diabetes (defined as a HbA1c 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 (extended release) for a diagnosis of Type I or Type II diabetes or for PCOS are alsoexcluded.
   * Cushing's syndrome (define as an archetype of MetS. High glucocorticoid levels lead to muscle, liver and adipocyte insulin resistance. 17-OHCS\>55umol/24h or UFC\>304nmol/24h) ④ Congenital adrenal hyperplasia (define as patients with known 21-hydroxylase deficiency or other enzyme deficiency leading to the phenotype of congenital adrenal hyperplasia. 17-OHP\>10 ng/ml in ACTH 1-24 h excited test (after 60 min)) ⑤ Suspected androgen secreting adrenal or ovarian tumor.
2. Use of hormonal or other medication including Chinese Herbal prescriptions which may affect the outcome the last 2 months.
3. Receiving acupuncture in the past 2 months.
4. Within 6 weeks pregnancy.
5. Post-abortion or postpartum within the past 6 weeks.
6. Breastfeeding within the last 4 months.
7. Not willing to give written consent to the study.
8. Having a bariatric surgery procedure within the past 12 months or being in a period of acute weight loss.
9. Additional exclusion criteria including:

   * 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.

     * Heart disease ③ Patients with a history of, or suspected cervical carcinoma, endometrial carcinoma, or breast carcinoma.

       * Patients enrolled into other studies that require medications. ⑤ Patients taking longer than a one month break during the protocol should not be enrolled.

Primary outcomes:
measure: Changes of HOMA-IR
timeFrame: Change from Baseline Systolic Blood Pressure at 4 months and 7 months
Secondary outcomes:
measure: HOMA-B
timeFrame: 4 months and 7 months
measure: AUCglu
timeFrame: 4 months and 7 months
measure: Menstrual frequency
timeFrame: 4 months and 7 months
measure: Body composition（a composite）
timeFrame: 4 months and 7 months
measure: Metabolic profile（a composite）
timeFrame: 4 months and 7 months
measure: Hormonal profile（a composite）
timeFrame: 4 months and 7 months
measure: Questionnaires（a composite）
timeFrame: 4 months and 7 months
measure: Side effect profile
timeFrame: 4 months and 7 months
measure: Expectation and credibility of treatment（questionnaire, 6 questions，4grades，0-24scores)
timeFrame: 1 week and 4 months
measure: AUCins
timeFrame: 4 months and 7 months
measure: Ovulation rate
timeFrame: 4 months and 7 months
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: The First Affiliated Hospital of Guangzhou Medical University
state: Guangdong
Study officials:
affiliation: The First Affiliated Hospital of Guangzhou Medical University
name: Hongxia Ma
role: STUDY_CHAIR
affiliation: The First Affiliated Hospital of Guangzhou Medical University
name: Juan Li, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: The First Affiliated Hospital of Guangzhou Medical University
name: Maohua Lai, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: The First Affiliated Hospital of Guangzhou Medical University
name: Hua Liu, Master
role: PRINCIPAL_INVESTIGATOR
affiliation: The First Affiliated Hospital of Guangzhou Medical University
name: Wanting Wu, Master
role: PRINCIPAL_INVESTIGATOR
affiliation: The University of Hong Kong
name: Ernest HY NG, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Karolinska Institutet
name: Elisabet Stener-Victorin, PhD
role: STUDY_DIRECTOR
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