Clinical Trials Register

Summary
EudraCT Number:	2014-003408-65
Sponsor's Protocol Code Number:
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2014-12-02
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

2014-003408-65

A.3

Full title of the trial

Ulipristal acetate versus conventional management of heavy menstrual bleeding (HMB; including uterine fibroids): a randomised controlled trial and exploration of mechanism of action (UCON trial)

A.3.1

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

Comparison of drug ulipristal acetate with existing treatment of levonorgestrel-releasing intra-uterine system.

A.3.2

Name or abbreviated title of the trial where available

UCON

A.4.1

Sponsor's protocol code number

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN20426843

A.5.4

Other Identifiers

Name:

2014-003408-65

Number:

EudraCT

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 Edinburgh
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Edinburgh
B.5.2	Functional name of contact point	Professor Hilary Critchley
B.5.3	Address:
B.5.3.1	Street Address	47 Little France Crescent
B.5.3.2	Town/ city	Edinburgh
B.5.3.3	Post code	EH16 4TJ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01312426858
B.5.5	Fax number	01312426441
B.5.6	E-mail	hilary.critchley@ed.ac.uk
B.Sponsor: 2
B.1.1	Name of Sponsor	NHS Lothian
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	Esmya
D.2.1.1.2	Name of the Marketing Authorisation holder	Gedeon Richter Plc.
D.2.1.2	Country which granted the Marketing Authorisation	Hungary
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	Ulipristal acetate
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.3.11 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.IMP: 2
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	Mirena
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer plc
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Levonorgestrel-releasing intra-uterine system
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intrauterine use
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Heavy menstrual bleeding

E.1.1.1

Medical condition in easily understood language

Heavy menstrual bleeding

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	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10046784
E.1.2	Term	Uterine fibroids
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10027313
E.1.2	Term	Menorrhagia
E.1.2	System Organ Class	10038604 - Reproductive system and breast disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Is UPA more effective at reducing the burden of HMB symptoms than LNG-IUS after 12 months of treatment?

E.2.2

Secondary objectives of the trial

SECONDARY CLINICAL TRIAL OBJECTIVES:

• Ascertain whether UPA use beyond 3 months and up to 12 months duration is associated with histological changes to the endometrium, and if so, whether this compromises safety.
• Ascertain whether UPA is more effective than LNG-IUS in relation to menstrual blood loss, sexual activity, generic quality of life, satisfaction with treatment, patient reported adverse events, and compliance at 3, 6 and 12 months.
• Determine the response to UPA and LNG-IUS treatment difference in the presence of uterine fibroids in terms of (i) alleviation of HMB and (ii) change in uterine/fibroid volume.

MECHANISTIC SUB-STUDY OBJECTIVES:
• To understand how UPA causes a reduction in menstrual bleeding and uterine/ fibroid volume in women with HMB, we will determine whether:
• Administration of UPA alters endometrial cell function (proliferation, apoptosis, expression of steroid receptors, tumour suppressors or inflammatory mediators).
• UPA reduces blood flo

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

UCON Mechanistic Sub-study:

The sub-study has 2 components (i) MRI and (ii) endometrial biopsy.

(i) MRI Sub-study:

The aim of the 3T MRI substudy is to investigate the hypothesis that UPA will reduce blood flow and blood volume in the endometrium and myometrium in women with HMB. The research questions to be addressed will be:
a. Does UPA reduce blood flow and blood volume, as measured by DCEMRI, in the endometrium, junctional zone, outer myometrium and fibroid tissue?
b. Does UPA alter the volume fraction of the extracellular matrix in the above tissues, as measured by DCEMRI?
c. Does UPA reduce uterine and fibroid volume, as measured by high resolution structural Magnetic Resonance Imaging (MRI).

In particular, dynamic contrast EME enhanced MRI (DCEMRI) and high resolution structural MRI will be obtained in a subgroup of 20 women treated with UPA. DCEMRI, combined with pharmacokinetic modeling, yields quantitative estimates of physiological parameters, including tissue blood flow, blood volume fraction and endothelial permeability, as well as volume fraction of the extracellular extravascular space. The technique is well established as a marker of microvascular physiology in a wide range of pathologies and has recently been used, in a number of other studies, to measure regional and cyclical variation in the uterine tissue of 85 women with a range of uterine disorders.

These data, in addition to those from our own unpublished pilot work confirm the feasibility of this technique in the uterus and provide a promising route to monitoring treatment response. Semiquantitative DCEMRI without pharmacokinetic modelling has previously been used for assessment of other fibroid treatments. Structural MRI provides high resolution images suitable for structural segmentation and radiological evaluation that, when combined with design based stereological analysis, yield accurate and precise measurements of uterine and fibroid volume for early assessment of treatment response.

T2 weighted structural and DCEMRI using our established dynamic uterine acquisition protocol will be obtained using a dedicated research 3T clinical scanner (Magnetom Verio, Siemens AG) in a subgroup of 20 women in the UPA treatment group. Scanning will be performed at baseline, and at 6 and 12 months following commencement of treatment. Scans will take place during the secretory phase of the menstrual cycle. Structural images will be evaluated clinically by an experienced radiologist, and stereological analysis performed to determine the volumes of the uterus and of any fibroids. DCEMRI data will be analysed using the well-established adiabatic approximation to tissue homogeneity (AAHT) model, to generate pharmacokinetic maps of blood flow, blood volume and extracellular extravascular volume fraction; these will be used to extract representative values for endometrium, junctional zone, outer myometrium and fibroid tissue.

(ii) Endometrial Biopsies Sub-Study:
Analysis will be conducted on endometrial biopsies collected from women during the proliferative phase of a cycle prior to starting treatment and at 6 and 12 months, taken in a purposive sample of women (Edinburgh site; n=20). Endometrial tissue samples will be collected with a pipelle endometrial sampler. Our extensive experience of this method of endometrial sampling allows us to subdivide each tissue sample for detailed analysis. We will undertake the following analyses:
a) Histology/cell specific protein expression. The tissue sample will be fixed in 70% neutral buffered formalin for 24 hours, and processed into paraffin wax using standardprotocols . Biopsy tissue may also be snap frozen for protein extraction for Western blotting.

b) Gene analyses. Tissue will be collected in RNAlater for subsequent extraction of RNA and downstream analysis using qRTPCR (Taqman) or Illumina arrays.

E.3

Principal inclusion criteria

• Aged 18 years or over
• Menstrual bleeding at intervals of 21-42 days that she perceives to be heavy and troublesome
• Willing to receive medical treatment with either UPA or LNG-IUS
• Willing to undergo two pelvic ultrasounds
• If allocated to UPA, willing and eligible to undergo two endometrial biopsies with the possibility of a third and fourth (i.e. up to four biopsies)
• If allocated to UPA mechanistic sub-study, willing and eligible to undergo three biopsies with the possibility of a fourth and fifth (i.e. up to five biopsies). If ‘No’ may be randomised to RCT if UPA endometrial biopsy consent given
• Willing to use barrier contraception if allocated to UPA
• Given written informed consent
• Willing and eligible to undergo up to three magnetic resonance imaging scans? If allocated to UPA, mechanistic sub-study only. If ‘No’ may still be randomised to RCT

E.4

Principal exclusion criteria

• Post-menopausal
• A >14 week fibroid uterus and/or cavity length >11 cm confirmed by ultrasound scan
• Submucosal fibroids >2cm diameter confirmed by ultrasound scan
• Contraindications to UPA or LNG-IUS
• Intention to continue current use of current use of Cytochrome P450 (CYP3A4) inhibitors
• Intention to continue current use of current use of Cytochrome P450 (CYP3A4) inducers (e.g. Phenytoin, carbamazepine, rifampicin, St John’s Wort)
• Intention to continue current use of P-glycoprotein substrates (e.g. digoxin)
• A past, current or suspected diagnosis of endometrial hyperplasia or neoplasia
• Severe hepatic impairment
• Epilepsy managed with carbamazepine, phenytoin
• Significant renal impairment
• Pregnant
• Current plans to become pregnant within 12 months
• Currently breastfeeding
• Severe asthma that is not sufficiently controlled by oral glucocorticoids
• Past or current known history of with uterine, cervical, ovarian or breast cancer.
• Current use of progestagen-releasing intrauterine device (except if allocated within UCON)
• Intention to continue regular use of Mefenamic acid
• Intention to continue regular use of Tranexamic acid
• Intention to continue regular use of GnRH analogues
• Intention to continue regular use of Progestagen-only contraceptive
• Intention to continue regular use of any combined oral contraceptive pills
• Intention to continue regular use of hormonal replacement therapy

E.5 End points

E.5.1

Primary end point(s)

The primary outcome measure is the conditon-specific Menorrhagia Multi-Attribute Scale (MMAS) designed and validated to capture the impact of HMB on women’s day-to-day life.Summary scores range from 0 (not affected) to 100 (worst affected). The primary time point for analysis will be at 12 months.

E.5.1.1

Timepoint(s) of evaluation of this end point

Validated Menorrhagia Multi-attribute Assessment Scale (MMAS)
to assess impact of HMB on women’s life, measured at 12 months. This is now an accepted primary outcome for randomised trials of interventions to improve HMB.

E.5.2

Secondary end point(s)

SECONDARY CLINICAL OUTCOMES INCLUDE:
Satisfaction, Surgical intervention (hysterectomy or endometrial ablation), menstrual blood loss, menstrual regularity, pain, fibroid symptom and quality of life, sexual activity and compliance will be assessed at 3, 6 and 12 months. Endometrial biopsy at 12 months for exclusion of pre-malignant or other pathology.

MECHANISTIC OUTCOMES (subset of UPA group only):
Study of impact of UPA on cell fate including markers of steroid responsiveness, inflammation, survival and proliferation and complemented with imaging of the uterus using high resolution Magnetic Resonance Imaging (MRI) of the uterine matrix and fibroids and Dynamic Contrast Enhanced (DCE-MRI) to measure uterine perfusion.

E.5.2.1

Timepoint(s) of evaluation of this end point

Satisfaction, menstrual blood loss, menstrual regularity, pain, fibroid symptom and quality of life, sexual activity and compliance will be assessed at 3, 6 and 12 months. Endometrial biopsy at 12 months for exclusion of pre-malignant or other pathology.

MECHANISTIC OUTCOMES (subset of UPA group only):
Study of impact of UPA on cell fate including markers of steroid responsiveness, inflammation, survival and proliferation and complemented with imaging of the uterus using high resolution Magnetic Resonance Imaging (MRI) of the uterine matrix and fibroids and Dynamic Contrast Enhanced (DCE-MRI) to measure uterine perfusion. Measured up to 18 months.

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

Yes

E.6.13.1

Other scope of the trial description

Mechanistic sub-study

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Medication: levonorgestrel-releasing intra-uterine system

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

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

Yes

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

For UPA, satisfactory resolution of any PAEC changes confirmed by endometrial biopsy, at 15 or 18 months post-randomisation. For LNG-IUS, completion of the 12 months follow-up questionnaire by last patient. Whilst women may retain the LNG-IUS for up to 5 years - this is beyond the end of the trial participation.

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