Clinical trial NCT02647827: Acupuncture or Metformin for Insulin Resistance in Women With PCOS
Official title: Acupuncture or Metformin for Insulin Resistance in Women With Polycystic Ovary Syndrome: A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Polycystic Ovary Syndrome
Insulin Resistance
Hyperandrogenism
Keywords: Acupuncture
Metformin
Glucose metabolism
Hba1c
Lead sponsor: Karolinska Institutet
Sponsor class: OTHER
Collaborators: name: Karolinska University Hospital
name: Peking University
First posted: 2016-01-06
Enrollment: 303
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The hypothesis is that acupuncture is equally effective as metformin (both treatments combined with lifestyle management) in improving whole body glucose homeostasis in insulin resistant women with polycystic ovary syndrome (PCOS), and that both are superior to lifestyle management alone. The investigators hypothesize that acupuncture and metformin induce ovulation and improve hyperandrogenism, as well as health related quality of life (HRQoL) and symptoms of anxiety and depression. Although equally effective (acupuncture and metformin), the investigators hypothesize that acupuncture is associated with less negative side-effects. The investigators also hypothesize that these treatments have the potential to restore epigenetic and molecular alterations in target tissues (endometrial-, adipose-, and skeletal muscle tissue) and thus have the potential to prevent the development of type 2 diabetes (T2D).

Detailed description: Specific Aims The purpose of the study is to perform a randomized controlled trial of women with PCOS, comparing the effectiveness of lifestyle management alone, and in combination with acupuncture or metformin treatment on whole body glucose homeostasis, with the ultimate goal to prevent the development of type 2 diabetes.

Primary aim

1. To determine the clinical effectiveness of 4 months of 1) electroacupuncture + lifestyle management and 2) metformin + lifestyle management, compared to 3) lifestyle management only, for improvement of insulin sensitivity as measured by HOMA-IR, by the insulin response to glucose assessed by calculating the area under the curve (AUCinsulin) during the oral glucose tolerance test (OGTT), and by glucose regulation (assessed by analyzing Hba1c levels).

Secondary aims

1. To evaluate changes in secondary metabolic measures, including fasting insulin, c-peptide, glucose, and adipokines, calculation of HOMA-B (i.e. the Islet β-cell function) and the c-peptide index, assessment of the adipokines and lipid profile, body size and proportions and body fat distribution.
2. To determine changes in genome-wide gene expression and DNA methylation profiles related to insulin sensitivity in fat, muscle and endometrial tissue biopsies, and biomarkers in whole blood.
3. To evaluate endocrine measures including menstrual pattern and ovulation frequency, circulating hormones (sex steroids, AMH, gonadotropins), and excretion of metabolites of sex steroids in urine.
4. To determine changes in women's HRQoL, symptoms of anxiety and depression, dieting and eating patterns, and negative side-effects.
5. To evaluate the cost-effectiveness of the different treatments.

Eligibility criteria: Inclusion criteria - women with PCOS:

1. Age 18 to 40 years
2. Body mass index (BMI) ≥25 to ≤40 given that 95% of all women with PCOS with a BMI ≥25 are insulin resistant (71,72).
3. PCOS diagnosis according to Rotterdam criteria 2003 (73), with at least two of the following three symptoms: Clinical signs of hyperandrogenism (hirsutism or acne); oligo/amenorrhea; and/or polycystic ovaries (PCOS). Hirsutism is defined as a self-reported Ferriman-Gallwey (FG) score ≥8 (≥5 Asian) (74,75). Acne is defined by a positive response to the question Do you have acne? Oligomenorrhea is defined as an intermenstrual interval \>35 days and \<8 menstrual bleedings in the past year. Amenorrhea as \<3 cycles per year. PCO is defined by transvaginal ultrasound with ≥12 follicles 2-9 mm and/or ovarian volume ≥10 ml in one or both ovaries.
4. Willing to sign the consent form.

Inclusion criteria - controls:

Controls should have BMI \>25 to \<40, regular cycles with 28 days ± 2 days, and no signs of hyperandrogenism. They are excluded if they have menstrual irregularities, signs of hyperandrogenism (FG \>4), or evidence of PCO morphology on ultrasound.

Exclusion criteria for all women

1. Age \>40
2. Exclusion of other endocrine disorders such as non-classic congenital adrenal hyperplasia (17-hydroxyprogesterone \< 3nmol/L), androgen secreting tumors or suspected Cushing's syndrome.
3. Having known renal disease (creatinine clearance \< 60 mL/min), hepatic insufficiency, autoimmune disorders or cancer.
4. Any acute condition with potential to alter renal function or cause tissue hypoxia.
5. Type I diabetes.
6. Pharmacological treatment (cortizon, antidepressant, other antidiabetic treatment such as insulin and acarbose, hormonal contraceptives, hormonal ovulation induction or other drugs judged by discretion of investigator) within 12 weeks. Depo Provera or similar within 6 months.
7. Hypersensitivity to metformin hydrochloride or to any of the excipients.
8. Blood pressure \>160 / 100 mmHg
9. Pregnancy or breastfeeding the last 6 months
10. Acupuncture the last 2 months
11. Daily smoking and alcoholic intake
12. Language barrier or disabled person with reduced ability to understand the information given.

In total 50 controls will be matched at baseline (age, weight and BMI) to women with PCOS. Controls will undergo screening and baseline visit, but will not be randomized to any treatment.

Primary outcomes:
measure: Changes from baseline to after 4 months in HOMA-IR [fasting insulin (μU/mL) × fasting glucose (mmol/L)] / 22.5)
timeFrame: 4 months
measure: Changes from baseline to after 4 months of treatment in HbA1c
timeFrame: 4 months
measure: Changes from baseline to after 4 months of treatment in insulin response to glucose during the oral glucose tolerance test (OGTT)
timeFrame: 4 months
Secondary outcomes:
measure: Changes from baseline to after 4 months and again 4 months after last treatment in secondary metabolic measures
timeFrame: 8 months
measure: Changes from baseline to after 4 months and again 4 months after last treatment gene expression and DNA methylation profiles related to insulin sensitivity in fat, muscle and endometrial tissue biopsies, and biomarkers in whole blood.
timeFrame: 8 months
measure: Changes from baseline to after 4 months and again 4 months after last treatment in menstrual pattern.
timeFrame: 8 months
measure: Changes from baseline to after 4 months and again 4 months after last treatment in circulating reproductive hormones.
timeFrame: 8 months
measure: Changes from baseline to after 4 months and again 4 months after last treatment in women's HRQoL.
timeFrame: 8 months
measure: Changes from baseline to after 4 months and again 4 months after last treatment in women's symptoms of anxiety and depression.
timeFrame: 8 months
measure: Changes from baseline to after 4 months and again 4 months after last treatment in women's dieting and eating patterns.
timeFrame: 8 months
measure: Cost-effectiveness of the different treatments throughout the study.
timeFrame: 8 months
Other outcomes:
Locations:
city: Beijing
country: China
facility: Peking University
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
Study officials:
affiliation: Karolinska Institutet
name: Elisabet Stener-Victorin, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Stener-Victorin E, Zhang H, Li R, Friden C, Li D, Wang W, Wang H, Chang C, Li S, Huo Z, Zhang H, Ji X, Linden-Hirschberg A, Qiao J. Acupuncture or metformin to improve insulin resistance in women with polycystic ovary syndrome: study protocol of a combined multinational cross sectional case-control study and a randomised controlled trial. BMJ Open. 2019 Jan 4;9(1):e024733. doi: 10.1136/bmjopen-2018-024733.