The RCT of Acupuncture on PCOS Combined With IR
Condition: Polycystic Ovary Syndrome; Insulin Resistance
MeSH terms: Polycystic Ovary Syndrome; Insulin Resistance; Syndrome
Study type: Interventional
Phase: Phase 3

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.
    

Intervention name(s): true acupuncture; sham acupuncture; metformin; Placebo metformin
Intervention type(s): Other; Other; Drug; Drug
Intervention description(s): True 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 48 treatment sessions during 4 month.; 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 48 treatment sessions during 4 month.; Metformin will be given at 0.5g/times, 3 times one day and for 4 month.; Placebo metformin will be given at 0.5g/times, 3 times one day and for 4 month.
Other intervention name(s): Dimethylbiguanide; placebo Dimethylbiguanide
Intervention MeSH terms: Metformin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: polycystic ovary syndrome; acupuncture; insulin resistance; HOMA-IR; metformin