Clinical Trials Register

Summary
EudraCT Number:	2012-002073-60
Sponsor's Protocol Code Number:
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-12-04
Trial results	View 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

UK - MHRA

A.2

EudraCT number

2012-002073-60

A.3

Full title of the trial

Liraglutide in PCOS (LIPOS) Study: Evaluation of the Efficacy of Liraglutide on Menstrual Cyclicity in Women with PCOS - a prospective randomised double-blind placebo-controlled study

A.3.1

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

Liraglutide in the treatment of polycystic ovary syndrome (LIPOS study)

A.3.2

Name or abbreviated title of the trial where available

Liraglutide in PCOS

A.4.1

Sponsor's protocol code number

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1126-3292

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	University of Warwick
B.1.3.4	Country	United Kingdom
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	Novo Nordisk Ltd
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Warwick Medical School
B.5.2	Functional name of contact point	Dr Harpal Randeva
B.5.3	Address:
B.5.3.1	Street Address	Gibbet Hill Road
B.5.3.2	Town/ city	Coventry
B.5.3.3	Post code	CV4 7AL
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	024 7657 2552
B.5.5	Fax number	024 7657 4637
B.5.6	E-mail	Harpal.Randeva@warwick.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
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	Victoza
D.2.1.1.2	Name of the Marketing Authorisation holder	Novo Nordisk
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Liraglutide (Victoza)
D.3.4	Pharmaceutical form	Solution for injection in pre-filled pen
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Liraglutide
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6.0
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	Yes
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Injection
D.8.4	Route of administration of the placebo	Subcutaneous use

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).

E.1.1.1

Medical condition in easily understood language

Polycystic ovary syndrome is a condition that affects young women and is characterised by irregular periods, increased weight and unwanted groeth of facial and body hair.

E.1.1.2

Therapeutic area

Body processes [G] - Reproductive physiologi cal processes [G08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
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

The primary objective of this study is to investigate whether adding liraglutide (at a maximum dose of 1.8 mg once daily) to metformin (at a maximum dose of 1000 mg twice daily) for 52 weeks of treatment has a significant benefit in improving the regularity of periods (menstruation) in PCOS women.
All PCOS women participating in the study will initially have either amenorrhoea (absence of menstrual periods in a woman of reproductive age) or less than six menses in the last 12 months (PCOS diagnosis based on the Rotterdam Consensus Group criteria), as opposed to women of reproductive age who have normal menstrual periods (9-12 menstrual periods per year with intervals of 28 to 35 days). All study participants will keep a menstrual cycle diary during the duration of the study which will be evaluated at each study visit and the primary endpoint will be assessed at the end of treatment visit, defined as improved menstrual cyclicity. Menstrual rhythm will be assessed with reference to rec

E.2.2

Secondary objectives of the trial

Additional secondary outcomes will include the effects on: anthropometric measurements (e.g. body mass index); inflammatory and cardio-metabolic markers; glucose and reproductive parameters; improved quality of life.
Ovulation will be also considered as a supportive secondary endpoint in the context of this study. Occurrence of ovulation (luteal serum progesterone level > 3 ng/dl) for all study participants will be assessed by progesterone determination 18-25 days following a spontaneous period.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. PCOS diagnosis defined according to all three criteria of the 2003 Rotterdam Consensus Group: (i) Menstrual disorders, either amenorrhoea or less than six menses in the last 12 months; (ii) Clinical or biochemical hyperandrogenism, once secondary causes such as hyperprolactinaemia, Cushing’s syndrome, congenital adrenal hyperplasia have been excluded; (iii) Polycystic ovaries on ultrasound scan
2. Informed consent obtained before any study related activities
3. Body Mass Index (BMI) > 27 kg/m2 and BMI < 45 kg/m2
4. Stable body weight (less than 5 kg self-reported change) during the previous 3 months
5. Age: ≥ 18 years and < 40 years

E.4

Principal exclusion criteria

1. Any clinically significant disease which in the Investigator's opinion could interfere with the safety of study participants or with the results of the study
2. Diagnosis (already documented diagnosis or new diagnosis based on the OGTT results at study visit 2) of Impaired Fasting Glucose (IFG) or Impaired Glucose Tolerance (IGT) or Type 2 Diabetes Mellitus (diagnosis based on the American Diabetes Association criteria on the diagnosis and classification of diabetes mellitus)
3. Previous treatment with GLP-1 receptor agonists (including liraglutide or exenatide) or drugs that affect gastrointestinal motility or carbohydrate metabolism, or lipid-lowering or anti-obesity drugs within the last 3 months
4. Pregnancy, breast-feeding or intention to become pregnant or not using adequate contraceptive methods (adequate contraceptive measures defined as consistent use of barrier methods or true abstinence).
5. Obesity induced by other endocrinological disorders (e.g. Cushing Syndrome). The presence of other endocrinopathies will have been ruled out at the time of PCOS diagnosis.
6. Current or history of treatment with medications that may cause significant weight gain, within 3 months prior to screening, including systemic corticosteroids (except for a short course of treatment, i.e. 7-10 days), atypical antipsychotic, tricyclic antidepressants, and mood stabilizers (e.g., amitryptiline, imipramine, mirtazapin, phenelzine, paroxetine, thioridazine, clorpromazine, olanzapine, clozapine, lithium and valproic acid and its derivatives,)
7. Participation in a clinical trial of weight control within the last 3 months prior to screening
8. Current participation in an organised diet reduction programme (or within the last 3 months) and/or are currently using or have used within three months before screening: orlistat, pramlintide, zonisamide, topiramate (either by prescription or as part of a clinical trial)
9. Any intervention that would alter weight and therefore interfere with menstrual cyclicity, such as: (i) Diet attempts using herbal supplements or over-the-counter medications within 3 months before screening; (ii) Previous surgical treatment for obesity (excluding liposuction if performed more than one year before this study)
10. Surgery scheduled for the study duration period, except for minor surgical procedures, at the discretion of the Investigator
11. History of major depressive disorder or history of other severe psychiatric disorders, e.g. schizophrenia or bipolar disorder within the last 2 years
12. Untreated or uncontrolled hypothyroidism/hyperthyroidism defined as TSH > 6 mIU/L or < 0.4 mIU/L, respectively
13. Impaired liver function, defined as ALAT ≥2.5 times upper limit of normal
14. Impaired renal function defined as serum-creatinine ≥110 μmol/L (≥ 1.3 mg/dL) or according to local label for metformin use
15. Known clinically significant active cardiovascular disease, including history of unstable angina, acute coronary event, other significant cardiac events (including history of myocardial infarction, arrhythmias, or conduction delays on electrocardiogram), or cerebral stroke within the last 6 months and/or heart failure (New York Heart Association Class III and IV) at the discretion of the Investigator
16. Uncontrolled treated/untreated hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg)
17. Cancer (past or present - including medullary thyroid cancer), which in the Investigator's opinion could interfere with the results of the study
18. Known or suspected hypersensitivity to the study drug(s)
19. Mental incapacity precluding adequate understanding or co-operation including subject not able to read or write
20. Smoking and known or suspected abuse of alcohol, narcotics or illicit drugs
21. Injectable hormonal contraceptive or sex hormones within 6 months
22. History of chronic pancreatitis or acute pancreatitis, including idiopathic
23. The receipt of any investigational drug within four weeks prior to screening for this study

E.5 End points

E.5.1

Primary end point(s)

Improvement in menstrural cycle regularity

E.5.1.1

Timepoint(s) of evaluation of this end point

Menstrual rhythm will be assessed with reference to recording of any menstrual periods during the duration of the study (52 weeks of treatment), and PCOS women with ≥ 6 recorded menstrual periods will be defined as having achieved improved menstrual cyclicity; this will form the primary endpoint for statistical analysis, with proportions of PCOS women in the treatment and placebo group compared.

E.5.2

Secondary end point(s)

Ovulation will be considered as a supportive secondary endpoint in the context of this study. Occurrence of ovulation (luteal serum progesterone level > 3 ng/dl) for all study participants will be assessed by progesterone determination 18-25 days following a spontaneous bleed.
Additional secondary outcomes will include the effects on: anthropometric measurements (e.g. BMI); inflammatory and cardio-metabolic markers; glucose and reproductive parameters; improved quality of life.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary endpoints will be determined at the same time points as the primary endpoint.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

E.8.2.3

Other

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.8.4.1

Number of sites anticipated in 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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1