Clinical Trials Register

Summary
EudraCT Number:	2017-005120-16
Sponsor's Protocol Code Number:	62638
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Restarted
Date on which this record was first entered in the EudraCT database:	2018-08-20
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

Netherlands - Competent Authority

A.2

EudraCT number

2017-005120-16

A.3

Full title of the trial

Ulipristal versus standard surgical treatment in symptomatic uterine fibroids

Ulipristal versus standaard chirurgie in de behandeling van symptomatische uterine myomen

A.3.1

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

Ulipristal versus surgery for symptomatic uterine fibroids

Ulipristal (een medicijn) versus operatieve behandeling bij symptomatische vleesbomen in de baarmoeder.

A.3.2

Name or abbreviated title of the trial where available

MYOMEX-2

A.4.1

Sponsor's protocol code number

62638

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	Amsterdam UMC, Location VUmc
B.1.3.4	Country	Netherlands
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	ZonMW
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Amsterdam UMC, Location VUmc
B.5.2	Functional name of contact point	Mei-An Middelkoop
B.5.3	Address:
B.5.3.1	Street Address	De Boelelaan 1117
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1081 HV
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	00310204441851

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	Esmya
D.2.1.1.2	Name of the Marketing Authorisation holder	Gedeon Richter
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Esmya
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.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

Uterine fibroids are very common during reproductive years in women. Minimally invasive treatments are emerging. Myomectomy is the gold standard, preferably laparoscpically, because it removes the fibroids entirely. Ulipristal, a selective progesterone receptor modulator, was introduced in 2012 as a new revolutionary (long-term) treatment for symptomatic uterine fibroids. It claims to make invasive treatment unnecessary.

Myomen van de uterus komen veel voor. (Laparoscopische) myomectomie is de gouden standaard, gezien het feit dat de myomen in geheel wordt verwijderd. Ulipristal, een selectieve progesteron receptor modulator, is in 2012 op de markt gekomen als een nieuwe, revolutionaire (lange termijn) behandeling voor symptomatische uterine myomen. Het claimt invasieve behandeling te kunnen voorkomen.

E.1.1.1

Medical condition in easily understood language

Uterine fibroids are very common. Sometimes surgical removal is necessary. However, ulipristal, a new medicine for treatment of symptomatic fibroids, claims to make invasive treatment unnecessary.

Myomen (vleesbomen) van de baarmoeder komen veel voor. Soms is chirugische verwijdering noodzakelijk. Ulipristal is een nieuw medicijn dat beweert chirurgische behandeling te kunnen voorkomen.

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	21.1
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.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary outcomes with regard to patient:
1) Fibroid-specific quality-of-life, measured by the Uterine Fibroid Symptom-questionnaire (UFS-QOL) and symptom severity scores. Outcome at 24 months after randomization.

Primary outcomes with regard to costs (using internet medical consumption questionnaires; iMCQ):
1) Direct healthcare costs
2) Costs due to loss of productivity (absenteeism from work)
3) Patient costs (informal care, other care services paid for by patients themselves)

Primaire uitkomstmaten t.o.v. de patiënt:
1. Myoom-specifieke kwaliteit van leven, gemeten via de Uterine Fibroid Symptom-questionnaire (UFS-QOL) en de ernst van de myoomgerelateerde symptomen, gemeten via Symptom Severity Scores. Uitkomst wordt geëvalueerd, 24 maanden na randomisatie.

Primaire uitkomstmaten t.o.v. kosten (waarbij gebruik wordt gemaakt van internet medical consumption questionnaires, iMCQ):
1) Directe zorgkosten
2) Kosten door verlies aan productiviteit (door ziekteverlof)
3. Patiëntkosten (informele zorg, andere zorgkosten, betaald door de patiënt zelf).

E.2.2

Secondary objectives of the trial

Secondary outcomes with regard to patient:
1) What is the effect of the intervention on quality of life parameters, such as pain, societal participation and sexual functioning?
2) What is the effect of the intervention on fibroid specific complaints such as volume reduction (UPA group); amount of menstrual bleeding (PBAC-score) and Hemoglobin level.
3) What is the re-intervention rate in both treatment groups and how many patients choose for an intervention after treatment with UPA?
4) What is the effect on patient preference and satisfaction?
5) Which complications/side-effects occur?
6) What is the effect of UPA-usage on the blood results, regarding liver function?
7) Which sub-groups benefit most within the study group (subgroup-analysis)

Secundaire uitkomstmaten t.o.v. de patiënt:
1. Wat is het effect van de interventie op kwaliteit van leven, pijn, sociale participatie en seksuele functie?
2. Wat is het effect van de interventie op myoomgerelateerde klachten zoals volume reductie (UPA groep), hoeveelheid bloedverlies en Hb?
3. wat is het re-interventie ratio in beide behandel groepen en hoeveel patiënten kiezen voor een interventie na behandeling met UPA?
4. Wat is het effect op de voorkeur en tevredenheid van de patiënt?
5. Welke complicaties/bijwerkingen ontstaan er?
6. Wat is het effect van UPA-gebruik op de bloedresultaten, m.b.t. de leverfunctie?
7. Welke sub-groep(en) hebben het meeste baat binnen de onderzoekspopulatie?

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Women visiting the gynaecological outpatient clinic with symptomatic fibroids will be screened for eligibility. In order to be eligible to participate in this trial, a subject must meet all of the following criteria:
- Symptomatic fibroids warranting surgical treatment, either hysterectomy, myomectomy or uterine artery embolization
- Conservative treatment failed or is undesired
- Pre-menopausal
- >18 years of age

Vrouwen met symptomatische myomen, gezien op de polikliniek gynaecologie worden gescreend op geschiktheid. Inclusie criteria voor deelname aan het onderzoek zijn:
- Symptomatische myomen waarvoor chirurgische behandeling nodig is, middels hysterectomie, myomectomie of embolisatie van de arteria uterina.
- Conservatieve behandeling heeft gefaald, of is onwenselijk
- pre-menopauzaal
- >18 jaar

E.4

Principal exclusion criteria

A potential subject who meets any of the following criteria will be excluded from participation in this study:
- Asymptomatic fibroids
- Current pregnancy or unwillingness to use contraception
- Suspicion of malignancy
- Current use of ulipristal
- Contra-indication for the use of ulipristal
o History of, or present liver disease or hepatic impairment;
o Transaminases (alanine transaminase (ALT) or aspartate aminotransferase (AST) and/or total bilirubin exceeds 2 times the upper limit of
normal (performed within a month prior to inclusion).
o Medication that interacts with ulipristal:
 Moderate CYP3A4 inhibitors (e.g. erythromycin, grapefruit juice, verapamil)
 Potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, nefazodone, itraconazole, clarithromycine)
 Potent CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s wort, efavirenz)
- Not willing or able to give written informed consent

Voornaamste exclusie criteria:
- asymptomatische myomen
- Zwangerschap of onwil om te starten met anticonceptie
- verdenking op maligniteit
- Huidig gebruik van Ulipristal
- Contra-indicatie voor het gebruik van Ulipristal:
o In de voorgeschiedenis of momenteel bekend met leveraandoeningen of een verminderde leverfunctie;
o Transaminases (alanine transaminase (ALAT) of aspartate aminotransferase (ASAT) en/of totaal bilirubine is 2x zo hoog als de normaal waarde
(gemeten binnen een maand voorafgaande aan inclusie).
o Huidig gebruik van medicatie dat interacties heeft met Ulipristal:
 Matige CYP3A4 inhibitoren (bijv. erythromycine, grapefruitsap, verapamil)
 Sterke CYP3A4 inhibitoren (bijv. ketoconazol, ritonavir, nefazodon, itraconazol, clarithromycine)
 Sterke CYP3A4 inductor (e.g. rifampicine, carbamazepine, phenytoine, phenobarbital, St. Janskruid, efavirenz)
- Niet mogelijk of bereid tot geschreven informed consent.

E.5 End points

E.5.1

Primary end point(s)

In this study it will be investigated if treatment with Ulipristal is non-inferior to surgical treatment (Hysterectomy, myomectomy or uterine artery emblisation), with regard to Quality of Life, Symptom Severity scores (SSS) and costs. In our study populations we expect comparable baseline SSS in both the UPA and surgery group. If we look at the relative difference (in previous studies) we expect a 63% and 68% reduction in the conservative and surgery group, respectively. Our power calculation is based on previous studies, we will therefore assume a 5 point delta between both groups, with a non-inferiority marge of 15 points with α=0.025, β=0.2, and a standard deviation of 20 points. We estimate that 143 participants (95 patients in the conservative group and 48 patients in the surgery group) will be required to test for comparative efficacy between the two treatments with a non-inferiority margin of 15 points change in UFS-QOL Symptom Severity scores from baseline. Anticipating a 20% lost-to-follow-up we need to include 119 patients in the conservative group and 60 patients in the surgery group, respectively.

The aim of the economic evaluation is to relate the incremental costs of Ulipristal in comparison with surgical treatment to the incremental health effects. Both a cost-effectiveness analysis (CEA) and a cost-utility analysis (CUA) will be performed from a societal and healthcare perspective according to Dutch guidelines with a time horizon of 24 months. Because the time horizon of the economic evaluation is more than 12 months, discounting will be applied to costs (4%) and effects (1.5%).

Dit onderzoek wordt uitgevoerd om te beoordelen of behandeling met ulipristal non-inferior is ten opzichte van chirurgische behandeling (hysterectomie, myomectomie of embolisatie van de arteria uterina), in termen van Kwaliteit van Leven, ernst van symptomen en kosten. In onze studie populatie verwachten we vergelijkbare baseline SSS in zowel de UPA als de chirurgie groep. Als we kijken naar vorige studies, was het relatieve verschil, 63% en 68% vermindering in de conservatie, respectievelijk de chirurgische groep. Onze power calculatie is gebaseerd op vorige studies waarbij we uitgaan van een delta van 5 punten tussen beide groepen, met een non-inferiority marge van 15 punten, α=0.025, β=0.2, en een standaard deviatie van 20 punten. We schatten dat 143 deelnemers (95 patiënten in de conservatieve en 49 patiënten in de chirurgische groep) nodig zijn om vergelijkbare doelmatigheid tussen beide groepen met een non-inferiority marge van 15 punten verschil in de UFS-QOL Symptom Severity Score vanaf baseline. Als we een 20% lost-to-follow-up anticiperen komt dit neer op 119 patiënten in de conservatieve groep en 60 patiënten in de chirurgie groep.

Het doel van de economische evaluatie is om de incrementele kosten van ulipristal in vergelijking met de kosten van de chirurgische behandeling , te relateren aan de incrementele gezondheidseffecten. Zowel een kosten-effect analyse (KEA), als een kosten utiliteits analyse (KUA) worden uitgevoerd vanuit sociale en gezondheidsperspectieven, in overeenkomst met de Nederlandse richtlijnen, met een tijdspanne van 24 maanden. Aangezien de tijdspanne van de economische evaluatie meer is dan 12 maanden, wordt er een korting van kosten (4%) en effect (1.5%) toegepast.

E.5.1.1

Timepoint(s) of evaluation of this end point

The last endpoint will be obtained with the last questionnaire, 24 months after start treatment. It is also necessary to perform an ultrasound and bloodcollection to determine Hb-levels in the Ulipristal-group and in te patients who underwent myomectomy or Uterine Artery Embolisation.

Het laatste eindpunt zal 24 maanden na start behandeling worden verkregen door een vragenlijst. Daarnaast moet een echo zijn gemaakt en wordt een Hb-bepaling uitgevoerd in de Ulipristal-groep en in de patiënten die een myomectomie of embolisatie van de arteria uterina hebben ondergaan.

E.5.2

Secondary end point(s)

Secondary study parameters with regard to the patient are:
- The effect of the intervention on quality of life parameters such as pain (UFS-QOL questionnaire), quality-adjusted life-years (questionnaire ‘EuroQol’: EQ-5D-5L), societal participation and sexual function (questionnaire Female Sexual Function Index (FSFI))
- the effect of the intervention on fibroid specific complaints such as volume reduction (UPA group; measured by ultrasounds), amount of menstrual bleeding (PBAC) and haemoglobin level (lab results).
- re-intervention rate in both treatment groups and how many patients choose for an intervention after treatment with UPA
- satisfaction and patient preference (Likert scale, recommend to a friend)
- complications/side-effects
- effect of UPA-usage on blood results, regarding liver function (lab-results)

These will be described descriptively and between-group differences will be compared and expressed as mean differences with 95% confidence intervals. For standardised questionnaires overall and subscores will be calculated. Therefore we can also calculate a subgroup analysis to see which sub-groups benefit most within the study group.

Secundaire studieparameters met betrekking tot de patiënt zijn:
- Het effect van de interventie op kwaliteit van leven parameters zoals pijn (UFS-QOL vragenlijst), quality-adjusted life-years (vragenlijst 'EuroQoL': Eq-5D-5L), sociale participatie en seksualiteit (vragenlijst Female Sexual Function Index (FSFI))
- Het effect van de interventie op myoomspecifieke klachten zoals volume reductie van het myoom (ulipristal groep), de hoeveelheid menstrueel bloedverlies (PBAC score), Hemoglobine level (labresultaten)
- reinterventie ratio in beide groepen en het aantal patiënten dat kiest voor een interventie na behandeling met UPA
- tevredenheid en patiënt voorkeur (Likert scale, of patiënte de behandeling zou aanraden aan een vriendin)

Deze zullen worden beschreven en verschillen tussen de groepen worden vergeleken en uitgedrukt als een gemiddeld verschil met 95% betrouwbaarheidsintervallen. Voor de gestandardiseerde vragenlijsten zullen algehele en subscores berekend worden. Op deze manier kunnen we ook subgroep analyse verrichten om te analyseren welke subgroep het meeste voordeel heeft binnen deze studie.

E.5.2.1

Timepoint(s) of evaluation of this end point

The last endpoint will be obtained with the last questionnaire and bloodsample collection, 24 months after start treatment. It is also necessary to perform an ultrasound in the Ulipristal-group and in the patients who underwent myomectomy or Uterine Artery Embolisation.

Het laatste eindpunt zal 24 maanden na start behandeling worden verkregen door een vragenlijst en het uitvoeren van labbepaling. Daarnaast moet een echo zijn gemaakt in de Ulipristal-groep en in de patiënten die een myomectomie of embolisatie van de arteria uterina hebben ondergaan.

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

2:1 randomization in favour of the ulipristal (conservative) group

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

Standaard chirurgische behandeling (hysterectomie, myomectomie of embolisatie van de arteria uterina

standard surgical treatment (Hysterectomy, myomectomy or uterine artery embolization)

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

The trial is officially ended when the last questionnaire for the hysterectomy group or the last questionnaire, Hb-level and ultrasound is returned at 24 months for the Ulipristal, myomectomie and uterine artery embolisation group.

De studie is beëindigd wanneer de laatste vragenlijst voor de hysterectomie group, of de laatste vragenlijst, Hb-level en echo zijn gemaakt en teruggestuurd na 24 maanden voor de Ulipristal, myomectomie en embolisatie van de arteria uterina groep.

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:

179

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

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

179

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)

When bleeding complaints increase after finishing this study and the patient was satisfied with UPA, after consultation with patients’ gynaecologist, a new cycle of maximally 4 cycles of 12 weeks can be started (outside the MYOMEX-2 trial). It is advised to perform an ultrasound to check the endometrial thickness, sampling should be done in case of increased thickness. Also liver function should be tested. Important to note is that there is limited experience with additional treatment courses.

Wanneer bloedingsklachten verergeren na voltooien van deze studie en de patiënt was tevreden met UPA, kan in samenspraak met de behandelend gynaecoloog een nieuwe cyclus van maximaal 4 cycli van 12 weken worden gestart (dit is buiten de MYOMEX-2 trial). Een echo wordt geadviseerd om de endometriumdikte te controleren, indien afwijkend wordt endometriumsampling geadviseerd. Ook de leverfunctie dient gecontroleerd te worden. Belangrijk is dat er weinig ervaring is met aanvullende behandelkuren.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	NVOG Consortium 2.0
G.4.3.4	Network Country	Netherlands

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-08-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-11-02

P. End of Trial
P.	End of Trial Status	Restarted

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