Clinical Trials Register

Summary
EudraCT Number:	2015-004250-18
Sponsor's Protocol Code Number:	PIAII
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2015-11-25
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Sweden - MPA

A.2

EudraCT number

2015-004250-18

A.3

Full title of the trial

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

Effekt av metformin och akupunktur på insulinkänslighet hos överviktiga kvinnor med polycystiskt ovariesyndrom

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

The effect of acupuncture or metformin for improvement of insulin sensitivity in women with Polycystic Ovary Syndrome

Effekt av metformin och akupunktur på insulinkänslighet hos överviktiga kvinnor med polycystiskt ovariesyndrom

A.3.2

Name or abbreviated title of the trial where available

PIAII

A.4.1

Sponsor's protocol code number

PIAII

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Karolinska Institutet
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Karolinska Institutet
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Karolinska Institutet
B.5.2	Functional name of contact point	Elisabet Stener-Victorin
B.5.3	Address:
B.5.3.1	Street Address	vonEulersväg 8, 3 tr
B.5.3.2	Town/ city	Stockholm
B.5.3.3	Post code	17177
B.5.3.4	Country	Sweden
B.5.6	E-mail	elisabet.stener-victorin@ki.se

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Metformin
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Metformin
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Metformin
D.3.9.1	CAS number	657-24-9
D.3.9.2	Current sponsor code	PIAII
D.3.9.3	Other descriptive name	METFORMIN HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB03200MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Polycystic ovary syndrome (PCOS) affects 10 to 15% of all women and is the most common female endocrine and metabolic disorder during the reproductive years. PCOS is characterized by anovulation, hyperandrogenism and metabolic dysfunction. Women with PCOS have a 3 to 7-fold increased risk of developing type 2 diabetes (T2D).

Polycystiskt ovariesyndrom (PCOS) kallas även det kvinnliga metabola syndromet och är den vanligaste hormonella och metabola störningen hos kvinnor i fertil ålder. PCOS karaktäriseras av oregelbundna cykler, överskott av manligt könshormon och polycystiska äggstockar. Kvinnor med PCOS har en 3 till 7 faldigt ökad risk att utveckla type 2 diabetes (T2D).

E.1.1.1

Medical condition in easily understood language

Polycystic ovary syndrome (PCOS) affects 10 to 15% of all women and is the most common female endocrine and metabolic disorder during the reproductive years.

Polycystiskt ovariesyndrom (PCOS) kallas även det kvinnliga metabola syndromet och är den vanligaste hormonella och metabola störningen hos kvinnor i fertil ålder.

E.1.1.2

Therapeutic area

Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10012613
E.1.2	Term	Diabetes mellitus non-insulin-dependent
E.1.2	System Organ Class	100000004861

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10065161
E.1.2	Term	Polycystic ovarian syndrome
E.1.2	System Organ Class	100000004872

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary objective
• To determine the clinical effectiveness of 4 months of 1) acupuncture + lifestyle management and 2) metformin + lifestyle management compared with 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).

Primärt syfte
Att studera en kliniska effekten av 4 månaders 1) akupunktur + livsstilsråd elller 2) metformin + livsstilsråd jämfört med enbart livsstilsråd avseende förbättring av insulinkänslighet mätt med glukosbelastningstest, latmanssamt cirkulerande nivåer av Hba1c som reflekterar blodsockernivån över de senaste 3-4 veckorna hos kvinnor med PCOS.

E.2.2

Secondary objectives of the trial

Secondary objectives
• 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 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 health related quality of life (HRQL) and symptoms of anxiety and depression, and negative side-effects.
• To evaluate the cost-effectiveness of the different treatments.

Sekundärt syfte
• Att studera förändingar av faste insulin, c-peptid, glukos, och kalkylering av så kallat HOMA-B (β-cell funktion) och c-peptid index, analys áv adipokiner, kroppskomposition och fettcellsstorlek.
• Att studera förändringar i genexpression och DNA methyleringsprofiler relaterat till insulinkänslighet i endometrie-, fett-, och muskelvävnad samt bimarktörer i helblod.
• Att studera förändringar i reproduktiv och endokrin funktion inkluderat menstruationsmönster, cirkulerande hormoner och metaboliter i urin.
• Att studera förändringar i livskvalitet, symptom av oro och depression, biverkningar av behandling samt kostnadseffektivitet.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria – women with PCOS
1. Age 18 to 40 years
2. BMI ≥25 to ≤40 (≥23 to ≤37.5 Chinese) given that 95% of all women with PCOS with a BMI 25 are insulin resistant (27, 28).
3. PCOS diagnosis according to Rotterdam criteria 2003 with at least two of the following three symptoms (29): 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 Chinese) (30, 31). 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, no signs of hyperandrogenism. They are excluded if they have menstrual irregularities, signs of hyperandrogenism (FG >4), evidence of PCO morphology on ultrasound.

Inklusion och exklusionskriterie för kvinnor med och utan polycystiskt ovariesyndrom (PCOS).
Inklusionskriterie - kvinnor med PCOS
1. Ålder 18 till 40 år
2. BMI >25 till <40
3. PCOS diagnos enligt Rotterdam kriterie 2003 med minst två utav föjande 3 symptom: kliniska tecken på hyperandrogenism; hirsutism skattas med Ferriman-Gallwey (FG) score ≥8 och/eller akne (ja/nej) samt minst ett av följande två kriterier: regelbunden menstruation/ägglossning (>35 dagar mellan), ultraljudsverifierade polycystiska (PCO) äggstockar (≥12 folliklar 2-9 mm och/eller en volym ≥10ml i en eller båda äggstockarna).

Inklusionskriterie - Kontroller
1. Ålder 18 till 40 år
2. BMI >25 till <40
3. Regelbundna cykler: 28 dagar ± 2 dagar och inga kliniska tecken på hypandrogenism. De exkluderas om de har oregelbundna cykler och hyperandrogenism (FG >4), PCO morfologi vid ultraljudsundersökning.

E.4

Principal exclusion criteria

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 kidney disease, autoimmune disorders or cancer.
4. Type I diabetes.
5. 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.
6. Blood pressure >160 / 100 mmHg
7. Pregnancy or breastfeeding the last 6 months
8. Acupuncture last 2 months
9. Daily smoking and alcoholic intake
10. Language barrier or disabled person with reduced ability to understand information.

Exklusionskriterer för alla kvinnor är:
1) Ålder >40
2) Andra endokrina sjukdomar som ex androgen producerande tumörer.
3) Känd njursjukdom/njursvikt, autoimmunsjukdom eller cancer
4) Typ I diabetes
5) Läkemedelsbehandling (kortison, antidepressiva, antidiabetika, hormonella preventivmedel, hormonstimulering eller annan medicinering som kan påverka resultaten) senaste 12 veckorna. P-stav eller liknande senaste 6 månaderna.
6) Blodtryck >160 / 100 mmHg
7) Graviditet eller amning senaste 6 månaderna
8) Akupunktur senaste 2 månaderna
9) Daglig rökning eller dagligt alkoholintag
10) Språkliga hinder, kan inte förstå, tala eller läsa svenska och därmed inte fylla i frågeformulär

E.5 End points

E.5.1

Primary end point(s)

Changes in 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).

Förändring i insulinkänslighet mätt med glukosbelastningstest, latmanssamt cirkulerande nivåer av Hba1c som reflekterar blodsockernivån över de senaste 3-4 veckorna hos kvinnor med PCOS.

E.5.1.1

Timepoint(s) of evaluation of this end point

1. After 4 months of intervention

1. Efter 4 månaders behandling

E.5.2

Secondary end point(s)

• 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.
• Changes in gene expression and DNA methylation profiles related to insulin sensitivity in fat, muscle and endometrial tissue biopsies, and biomarkers in whole blood.
• Changes in endocrine measures including menstrual pattern and ovulation frequency, circulating hormones (sex steroids, AMH, gonadotropins), and excretion of metabolites of sex steroids in urine.
• Changes in women’s health related quality of life (HRQL) and symptoms of anxiety and depression, and negative side-effects and the cost-effectiveness of the different treatments.

• Förändingar av faste insulin, c-peptid, glukos, och kalkylering av så kallat HOMA-B (β-cell funktion) och c-peptid index, analys áv adipokiner, kroppskomposition och fettcellsstorlek.
• Förändingar i genexpression och DNA methyleringsprofiler relaterat till insulinkänslighet i endometrie-, fett-, och muskelvävnad samt bimarktörer i helblod.
• Förändingar i reproduktiv och endokrin funktion inkluderat menstruationsmönster, cirkulerande hormoner och metaboliter i urin.
•Förändingar i livskvalitet, symptom av oro och depression, biverkningar av behandling samt kostnadseffektivitet.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. After 4 months of intervention
2. Follow-up 4 months after last treatment.

1. Efter 4 månaders behandling
2. Uppföljning 4 månader efter sista behandlingen.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Akupunktur och livsstilsförändringar

Acupuncture and lifestyle managment

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

353

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

Yes

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

353

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

Ingen

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-02-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-12-16

P. End of Trial
P.	End of Trial Status	Ongoing

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