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Acupuncture or Metformin for Insulin Resistance in Women With PCOS (PIAII)

Primary Purpose

Polycystic Ovary Syndrome, Insulin Resistance, Hyperandrogenism

Status

Recruiting

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Lifestyle management

Acupuncture

Metformin

About this trial

This is an interventional treatment trial for Polycystic Ovary Syndrome focused on measuring Acupuncture, Metformin, Glucose metabolism, Hba1c

Eligibility Criteria

18 Years - 40 Years (Adult)FemaleAccepts Healthy Volunteers

Inclusion criteria - women with PCOS:

Age 18 to 40 years
Body mass index (BMI) ≥25 to ≤40 given that 95% of all women with PCOS with a BMI ≥25 are insulin resistant (71,72).
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.
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

Age >40
Exclusion of other endocrine disorders such as non-classic congenital adrenal hyperplasia (17-hydroxyprogesterone < 3nmol/L), androgen secreting tumors or suspected Cushing's syndrome.
Having known renal disease (creatinine clearance < 60 mL/min), hepatic insufficiency, autoimmune disorders or cancer.
Any acute condition with potential to alter renal function or cause tissue hypoxia.
Type I diabetes.
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.
Hypersensitivity to metformin hydrochloride or to any of the excipients.
Blood pressure >160 / 100 mmHg
Pregnancy or breastfeeding the last 6 months
Acupuncture the last 2 months
Daily smoking and alcoholic intake
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.

Sites / Locations

Peking UniversityRecruiting
Karolinska University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Arm Label

Lifestyle management

Acupuncture + lifestyle management

Metformin + lifestyle management

Arm Description

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

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

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

Outcomes

Primary Outcome Measures

Changes from baseline to after 4 months in HOMA-IR [fasting insulin (μU/mL) × fasting glucose (mmol/L)] / 22.5)

Changes from baseline to after 4 months of treatment in HOMA-IR [fasting insulin (μU/mL) × fasting glucose (mmol/L)] / 22.5) between 1) acupuncture + lifestyle management and 2) metformin + lifestyle management compared to 3) lifestyle management only.

Changes from baseline to after 4 months of treatment in HbA1c

Changes from baseline to after 4 months of treatment in HbA1c between 1) acupuncture + lifestyle management and 2) metformin + lifestyle management compared to 3) lifestyle management only.

Changes from baseline to after 4 months of treatment in insulin response to glucose during the oral glucose tolerance test (OGTT)

Changes from baseline to after 4 months of treatment in insulin response to glucose during the OGTT (AUC using the trapezoidal rule) between 1) acupuncture + lifestyle management and 2) metformin + lifestyle management compared to 3) lifestyle management only.

Secondary Outcome Measures

Changes from baseline to after 4 months and again 4 months after last treatment in secondary metabolic measures

Changes in secondary metabolic measures with calculation of e.g. HOMA-B

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.

Changes in mRNA gene expression and DNA methylation expression and biomarkers in whole blood.

Changes from baseline to after 4 months and again 4 months after last treatment in menstrual pattern.

Changes in menstrual pattern per month.

Changes from baseline to after 4 months and again 4 months after last treatment in circulating reproductive hormones.

Changes in circulating circulating reproductive hormones.

Changes from baseline to after 4 months and again 4 months after last treatment in women's HRQoL.

Changes in women's HRQoL measured with polycystic ovary syndrome questionnaire (PCOSQ) and short form-36 (SF36) two validated questionnairs.

Changes from baseline to after 4 months and again 4 months after last treatment in women's symptoms of anxiety and depression.

Changes in women's symptoms of anxiety and depression measured with the self-reported version of the Comprehensive Psychopathological Rating Scale for Affective Syndromes (CPRS-S-A).

Changes from baseline to after 4 months and again 4 months after last treatment in women's dieting and eating patterns.

Changes in women's dieting and eating patterns assessed with Three-Factor Eating Questionnaire (TFEQ-R21), and Questionnaire of Eating and Weight Patterns-Revised (QEWP-R).

Cost-effectiveness of the different treatments throughout the study.

Cost-effectiveness of the different treatments by calculation of e.g. treatment visits, time for patient and with EuroQol-5 dimension (EQ-5D).

Full Information

NCT ID

NCT02647827

First Posted

December 23, 2015

Last Updated

October 2, 2023

Sponsor

Karolinska Institutet

Collaborators

Karolinska University Hospital, Peking University

1. Study Identification

Unique Protocol Identification Number

NCT02647827

Brief Title

Acupuncture or Metformin for Insulin Resistance in Women With PCOS

Acronym

PIAII

Official Title

Acupuncture or Metformin for Insulin Resistance in Women With Polycystic Ovary Syndrome: A Randomized Controlled Trial

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

December 2015 (undefined)

Primary Completion Date

December 2024 (Anticipated)

Study Completion Date

December 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Karolinska Institutet

Collaborators

Karolinska University Hospital, Peking University

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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 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. 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. 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. To determine changes in women's HRQoL, symptoms of anxiety and depression, dieting and eating patterns, and negative side-effects. To evaluate the cost-effectiveness of the different treatments.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Polycystic Ovary Syndrome, Insulin Resistance, Hyperandrogenism

Keywords

Acupuncture, Metformin, Glucose metabolism, Hba1c

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

303 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Lifestyle management

Arm Type

Active Comparator

Arm Description

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

Arm Title

Acupuncture + lifestyle management

Arm Type

Active Comparator

Arm Description

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

Arm Title

Metformin + lifestyle management

Arm Type

Active Comparator

Arm Description

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

Intervention Type

Other

Intervention Name(s)

Lifestyle management

Intervention Description

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

Device

Intervention Name(s)

Acupuncture

Intervention Description

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

Drug

Intervention Name(s)

Metformin

Intervention Description

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).

Primary Outcome Measure Information:

Title

Changes from baseline to after 4 months in HOMA-IR [fasting insulin (μU/mL) × fasting glucose (mmol/L)] / 22.5)

Description

Time Frame

4 months

Title

Changes from baseline to after 4 months of treatment in HbA1c

Description

Changes from baseline to after 4 months of treatment in HbA1c between 1) acupuncture + lifestyle management and 2) metformin + lifestyle management compared to 3) lifestyle management only.

Time Frame

4 months

Title

Changes from baseline to after 4 months of treatment in insulin response to glucose during the oral glucose tolerance test (OGTT)

Description

Time Frame

4 months

Secondary Outcome Measure Information:

Title

Changes from baseline to after 4 months and again 4 months after last treatment in secondary metabolic measures

Description

Changes in secondary metabolic measures with calculation of e.g. HOMA-B

Time Frame

8 months

Title

Description

Changes in mRNA gene expression and DNA methylation expression and biomarkers in whole blood.

Time Frame

8 months

Title

Changes from baseline to after 4 months and again 4 months after last treatment in menstrual pattern.

Description

Changes in menstrual pattern per month.

Time Frame

8 months

Title

Changes from baseline to after 4 months and again 4 months after last treatment in circulating reproductive hormones.

Description

Changes in circulating circulating reproductive hormones.

Time Frame

8 months

Title

Changes from baseline to after 4 months and again 4 months after last treatment in women's HRQoL.

Description

Changes in women's HRQoL measured with polycystic ovary syndrome questionnaire (PCOSQ) and short form-36 (SF36) two validated questionnairs.

Time Frame

8 months

Title

Changes from baseline to after 4 months and again 4 months after last treatment in women's symptoms of anxiety and depression.

Description

Changes in women's symptoms of anxiety and depression measured with the self-reported version of the Comprehensive Psychopathological Rating Scale for Affective Syndromes (CPRS-S-A).

Time Frame

8 months

Title

Changes from baseline to after 4 months and again 4 months after last treatment in women's dieting and eating patterns.

Description

Changes in women's dieting and eating patterns assessed with Three-Factor Eating Questionnaire (TFEQ-R21), and Questionnaire of Eating and Weight Patterns-Revised (QEWP-R).

Time Frame

8 months

Title

Cost-effectiveness of the different treatments throughout the study.

Description

Cost-effectiveness of the different treatments by calculation of e.g. treatment visits, time for patient and with EuroQol-5 dimension (EQ-5D).

Time Frame

8 months

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

40 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria - women with PCOS: Age 18 to 40 years Body mass index (BMI) ≥25 to ≤40 given that 95% of all women with PCOS with a BMI ≥25 are insulin resistant (71,72). 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. 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 Age >40 Exclusion of other endocrine disorders such as non-classic congenital adrenal hyperplasia (17-hydroxyprogesterone < 3nmol/L), androgen secreting tumors or suspected Cushing's syndrome. Having known renal disease (creatinine clearance < 60 mL/min), hepatic insufficiency, autoimmune disorders or cancer. Any acute condition with potential to alter renal function or cause tissue hypoxia. Type I diabetes. 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. Hypersensitivity to metformin hydrochloride or to any of the excipients. Blood pressure >160 / 100 mmHg Pregnancy or breastfeeding the last 6 months Acupuncture the last 2 months Daily smoking and alcoholic intake 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Elisabet Stener-Victorin, PhD

Phone

+46705643655

elisabet.stener-victorin@ki.se

First Name & Middle Initial & Last Name or Official Title & Degree

Berit Legerstam, Study nurse

Phone

+46851773782

berit.legerstam@karolinska.se

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Elisabet Stener-Victorin, PhD

Organizational Affiliation

Karolinska Institutet

Official's Role

Principal Investigator

Facility Information:

Facility Name

Peking University

City

Beijing

ZIP/Postal Code

100871

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jie Qiao, Professor

Phone

+8615611908108

jie.qiao@263.net

First Name & Middle Initial & Last Name & Degree

Haolin Zhang, PhD

Phone

+8613911533466

zoe@bjmu.edu.cn

Facility Name

Karolinska University Hospital

City

Stockholm

ZIP/Postal Code

17176

Country

Sweden

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Berit Legerstam, Study nurse

Phone

+46851773782

berit.legerstam@karolinska.se

First Name & Middle Initial & Last Name & Degree

Liselotte Blomberg, Study nurse

Phone

+46851773782

liselott.blomberg@karolinska.se

First Name & Middle Initial & Last Name & Degree

Elisabet Stener-Victorin, PhD

First Name & Middle Initial & Last Name & Degree

Angelica Linden-Hirschberg, Professor

First Name & Middle Initial & Last Name & Degree

Sebastian Gidlöf, PhD

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

30612112

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.

Results Reference

derived

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Acupuncture or Metformin for Insulin Resistance in Women With PCOS

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