Acupuncture or Metformin for Insulin Resistance in Women With PCOS

NCT ID: NCT02647827

Last Updated: 2024-10-09

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 303 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-12-31
• Study Completion Date: 2026-06-30

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.

Conditions

Polycystic Ovary Syndrome; Insulin Resistance; Hyperandrogenism

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Lifestyle management

All women will receive lifestyle management instructions at the baseline visit, before randomization.

Group Type: ACTIVE_COMPARATOR

Lifestyle management

Intervention Type: OTHER

All women will receive lifestyle management instructions at the baseline visit, before randomization. The lifestyle management involves one initial counselling session in connection with the baseline visit, which includes information about the importance of weight management, healthy diet and physical activity.

Acupuncture + lifestyle management

Three treatment per week (4 weeks) and thereafter 2 times per week during 12 weeks.

Group Type: ACTIVE_COMPARATOR

Lifestyle management

Intervention Type: OTHER

All women will receive lifestyle management instructions at the baseline visit, before randomization. The lifestyle management involves one initial counselling session in connection with the baseline visit, which includes information about the importance of weight management, healthy diet and physical activity.

Acupuncture

Intervention Type: DEVICE

Disposable, single-use, sterilized CE marked needles made of stainless steel, 0.25 x 30 mm and 0.30 x 40/50 mm will be inserted to a depth of 15-40 mm in segmental acupuncture points located in abdominal and leg muscles, with innervations corresponding to the ovaries and the pancreas. Two sets of acupuncture points will be alternated every second treatment.

Metformin + lifestyle management

Oral metformin 500 mg three times daily, in total 1500 mg per day.

Group Type: ACTIVE_COMPARATOR

Lifestyle management

Intervention Type: OTHER

All women will receive lifestyle management instructions at the baseline visit, before randomization. The lifestyle management involves one initial counselling session in connection with the baseline visit, which includes information about the importance of weight management, healthy diet and physical activity.

Metformin

Intervention Type: DRUG

Oral metformin 500 mg three times daily, in total 1500 mg per day. To reduce gastrointestinal side-effects of metformin, the dose will be slowly escalated starting with 500 mg daily during the first week, increasing to 500 mg twice per day during the second the week, and 500 mg three times daily, morning, lunch and dinner from the third week in total 16 weeks including the 3 weeks step-up phase (i.e. 4 months).

Interventions

Lifestyle management

All women will receive lifestyle management instructions at the baseline visit, before randomization. The lifestyle management involves one initial counselling session in connection with the baseline visit, which includes information about the importance of weight management, healthy diet and physical activity.

Intervention Type: OTHER

Acupuncture

Disposable, single-use, sterilized CE marked needles made of stainless steel, 0.25 x 30 mm and 0.30 x 40/50 mm will be inserted to a depth of 15-40 mm in segmental acupuncture points located in abdominal and leg muscles, with innervations corresponding to the ovaries and the pancreas. Two sets of acupuncture points will be alternated every second treatment.

Intervention Type: DEVICE

Metformin

Oral metformin 500 mg three times daily, in total 1500 mg per day. To reduce gastrointestinal side-effects of metformin, the dose will be slowly escalated starting with 500 mg daily during the first week, increasing to 500 mg twice per day during the second the week, and 500 mg three times daily, morning, lunch and dinner from the third week in total 16 weeks including the 3 weeks step-up phase (i.e. 4 months).

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

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.

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

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Karolinska University Hospital

OTHER

Sponsor Role: collaborator

Peking University

OTHER

Sponsor Role: collaborator

Karolinska Institutet

OTHER

Sponsor Role: lead

Responsible Party

Elisabet Stener-Victorin

PhD, Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Elisabet Stener-Victorin, PhD

Role: PRINCIPAL_INVESTIGATOR

Karolinska Institutet

Locations

Peking University

Beijing, , China

Site Status: RECRUITING

Karolinska University Hospital

Stockholm, , Sweden

Site Status: RECRUITING

Countries

China; Sweden

Central Contacts

Elisabet Stener-Victorin, PhD

Role: CONTACT

elisabet.stener-victorin@ki.se

+46705643655

Berit Legerstam, Study nurse

Role: CONTACT

berit.legerstam@karolinska.se

+46851773782

Facility Contacts

Jie Qiao, Professor

Role: primary

jie.qiao@263.net

+8615611908108

Haolin Zhang, PhD

Role: backup

zoe@bjmu.edu.cn

+8613911533466

Liselott Blomberg, Study nurse

Role: primary

liselott.blomberg@regionstockholm.se

+46851773782

Anna Cockin, Study nurse

Role: backup

anna.cockin@regionstockholm.se

+46851773782

References

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.

Reference Type: DERIVED

PMID: 30612112 (View on PubMed)

Other Identifiers

2015-004250-18

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

EudraCT: 2015-004250-18

Identifier Type: -

Identifier Source: org_study_id