Clinical Trials Register

Summary
EudraCT Number:	2013-000934-36
Sponsor's Protocol Code Number:	E5501-G000-311
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-12-04
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2013-000934-36

A.3

Full title of the trial

A Randomized, Global, Double-blind, Placebo-controlled, Parallel-group
Study to Evaluate the Efficacy and Safety of Once-daily Oral
Avatrombopag for the Treatment of Adults with Thrombocytopenia
Associated with Liver Disease Prior to an Elective Procedure

Studio randomizzato, mondiale, in doppio cieco, controllato con placebo, a gruppi paralleli per valutare l’efficacia e la sicurezza di avatrombopag somministrato oralmente una volta al giorno per il trattamento di adulti affetti da trombocitopenia associata a malattia epatica prima di una procedura elettiva

A.3.1

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

A study to investigate the effectiveness of avatrombopag in increasing the amount of platelets (a type of cell found in the blood) in patients with chronic liver disease who need to have a planned procedure but have thrombocytopenia (low platelet counts) related to the chronic liver disease.

Uno studio per indagare l'efficacia di avatrombopag nell’aumentare la quantità di piastrine (un tipo di cellula presente nel sangue) nei pazienti con malattia epatica cronica che necessitano una procedura pianificata, ma hanno trombocitopenia (bassa conta piastrinica) legata a malattia epatica cronica.

A.3.2

Name or abbreviated title of the trial where available

ADAPT II

A.4.1

Sponsor's protocol code number

E5501-G000-311

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01976104

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

P/309/2011

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Eisai Limited
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Eisai Incorporation
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Eisai Limited
B.5.2	Functional name of contact point	Medical Information
B.5.3	Address:
B.5.3.1	Street Address	European Knowledge Centre, Mosquito Way
B.5.3.2	Town/ city	Hatfield, Hertfordshire
B.5.3.3	Post code	AL10 9SN
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+4408456761400
B.5.5	Fax number	+4408456761401
B.5.6	E-mail	LmedInfo@eisai.net

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	No
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	Avatrombopag
D.3.2	Product code	E5501
D.3.4	Pharmaceutical form	Film-coated 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	Avatrombopag maleate
D.3.9.1	CAS number	1254322-84-3
D.3.9.2	Current sponsor code	E5501
D.3.9.3	Other descriptive name	AKR-501, YM-477
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	20
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
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Thrombocytopenia in Patients with Chronic Liver Disease

Trombocitopenia in pazienti con malattia epatica cronica

E.1.1.1

Medical condition in easily understood language

Low platelet counts in patients with chronic liver disease

Basso numero di piastrine in pazienti con malattia del fegato cronica

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	HLGT
E.1.2	Classification code	10035534
E.1.2	Term	Platelet disorders
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10043554
E.1.2	Term	Thrombocytopenia
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	SOC
E.1.2	Classification code	10005329
E.1.2	Term	Blood and lymphatic system disorders
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10039884
E.1.2	Term	Secondary thrombocytopenia
E.1.2	System Organ Class	10005329 - Blood and lymphatic system 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

The primary objective of the study is to confirm that avatrombopag (60 mg avatrombopag for subjects with platelet count <40 × 109/L and 40 mg avatrombopag for subjects with platelet count from 40 to <50 × 109/L) is superior to placebo in removing the need for platelet transfusions or any rescue procedure for bleeding after randomization and up to 7 days following an elective procedure in subjects with chronic liver disease who have thrombocytopenia.

Confermare che avatrombopag (60 mg di avatrombopag per soggetti con conta piastrinica < 40 × 109/l e 40 mg di avatrombopag per soggetti con conta piastrinica tra 40 e < 50 × 109/l) è superiore al placebo nell’eliminare la necessità di trasfusioni piastriniche o di qualsiasi procedura di emergenza per il sanguinamento dopo la randomizzazione e fino a 7 giorni dopo la procedura elettiva in soggetti con malattia epatica cronica che presentano trombocitopenia.

E.2.2

Secondary objectives of the trial

To confirm that avatrombopag is superior to placebo in achieving a platelet count of ≥50 x 109/L on Procedure Day in the proposed target population

To confirm that avatrombopag is superior to placebo in elevating platelet counts from baseline on Procedure Day in the proposed target population

To evaluate whether the observed incidence of bleeding in subjects treated with avatrombopag is noninferior to placebo in those subjects expected to receive a platelet transfusion prior to their procedure

To evaluate the safety of avatrombopag in the proposed target population

•Confermare che avatrombopag è superiore al placebo nel raggiungere una conta piastrinica di ≥ 50 x 109/l al Giorno della procedura nella popolazione bersaglio proposta
•Confermare che avatrombopag è superiore al placebo nell’aumentare la conta piastrinica dal basale al Giorno della procedura nella popolazione bersaglio proposta
•Valutare se l’incidenza osservata di sanguinamento nei soggetti trattati con avatrombopag non sia inferiore al placebo nei soggetti che si prevede debbano ricevere una trasfusione piastrinica prima della loro procedura
•Valutare la sicurezza di avatrombopag nella popolazione bersaglio proposta.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subjects ≥18 years of age at Screening with chronic liver disease
2. Subjects who have a mean baseline platelet count of <50 × 109/L. Platelet counts must be measured on 2 separate occasions, during the Screening Period and at Baseline, and must be performed at least one day apart with neither platelet count >60 × 109/L. The mean of these 2 platelet counts (mean baseline platelet count) will be used for entry criteria and for assignment to the low or high baseline platelet count cohort.
3. Subjects scheduled to undergo a permitted elective procedure and who, in the opinion of the investigator, will otherwise require a platelet transfusion to address a risk of bleeding associated with the procedure
4. Model For End-stage Liver Disease (MELD) score ≤24 at Screening
5. If taking inhibitors of P glycoprotein (P-gp), except for verapamil, dose must be stable for 7 days prior to Screening (see Appendix 2 for the list of P-gp Inhibitors)
6. Provide written informed consent
7. Willing and able to comply with all aspects of the protocol

1.Soggetti di età ≥ 18 anni allo screening con malattia epatica cronica
2.Soggetti con una conta piastrinica media al basale di < 50 × 109/l. Le conte piastriniche devono essere misurate in 2 occasioni separate, durante il periodo di screening e al basale, e devono essere eseguite ad almeno un giorno di distanza con nessuna conta piastrinica pari a > 60 × 109/l. La media di queste 2 conte piastriniche (conta piastrinica media al basale) sarà utilizzata per i criteri di inclusione e per l’assegnazione alla coorte della conta piastrinica al basale bassa o alta.
3.Soggetti programmati per essere sottoposti a procedura elettiva permessa che, a giudizio dello sperimentatore, richiederanno una trasfusione piastrinica per rischio di sanguinamento associato alla procedura
4.Punteggio del modello per la malattia epatica allo stadio terminale (Model For End-stage Liver Disease, MELD) ≤ 24 allo screening
5.Se il/la paziente sta assumendo inibitori della glicoproteina P (P-gp), fatta eccezione per verapamil, la dose deve essere stabile per 7 giorni prima dello screening
6.Consegna del consenso informato scritto
7.Paziente disposto/a e in grado di agire in conformità a tutti gli aspetti del protocollo.

E.4

Principal exclusion criteria

1. Any history of arterial or venous thrombosis, including partial or complete thrombosis
2. Evidence of thrombosis (partial or complete) in the main portal vein, portal vein branches, or any part of the splenic mesenteric system at Screening
3. Portal vein blood flow velocity rate <10 cm/second at Screening
4. Hepatic encephalopathy that cannot be effectively treated
5. Subjects with HCC and Barcelona Clinic Liver Cancer (BCLC) staging classification C or D
6. Platelet transfusion or receipt of blood products containing platelets within 7 days of Screening. However packed red blood cells are permitted
7. Heparin, warfarin, nonsteroidal anti-inflammatory drugs (NSAID), aspirin, verapamil, and antiplatelet therapy with ticlopidine or glycoprotein IIb/IIIa antagonists (eg, tirofiban) within 7 days of Screening
8. Use of erythropoietin stimulating agents within 7 days of Screening
9. Interferon (IFN) use within 14 days of Screening
10. Estrogen-containing hormonal contraceptive or hormone replacement therapy use within 30 days of Screening
11. Active infection requiring systemic antibiotic therapy within 7 days of Screening. However, prophylactic use of antibiotics is permitted.
12. Alcohol abuse, alcohol dependence syndrome, drug abuse, or drug dependence within 6 months of the study start (unless participating in a controlled rehabilitation program) or acute alcoholic hepatitis (chronic alcoholic hepatitis is allowed) within 6 months of the study start
13. Elective procedure performed prior to Visit 4 (Procedure Day)
14. Known to be human immunodeficiency virus (HIV) positive
15. Any clinically significant acute or active bleeding(gastrointestinal, central nervous system, etc.)
16. Known history of any primary hematologic disorder (eg, ITP, myelodysplastic syndrome, etc.)
17. Known medical history of genetic prothrombotic syndromes (eg, Factor V Leiden; prothrombin G20210A; ATIII deficiency etc.) (revised per Amendment 01)
18. Subjects with a history of significant cardiovascular disease (eg, congestive heart failure New York Heart Association Grade III/IV, arrhythmia known to increase the risk of thromboembolic events [eg, atrial fibrillation], coronary artery stent placement, angioplasty, and coronary artery bypass graft [CABG])
19. Females of childbearing potential who have had unprotected sexual intercourse within 30 days before study entry and who do not agree to use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a double-barrier method[such as condom plus diaphragm with spermicide], a progesterone-only contraceptive implant/injection, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. If currently abstinent, the subject must agree to use a double-barrier method as described above if she becomes sexually active during the study period or for 30 days after study drug discontinuation. All females will be considered to be of childbearing potential unless they are postmenopausal (at least 12 months consecutive amenorrhea in the appropriate age group and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, hysterectomy, or bilateral oophorectomy) at least 1 month before dosing.
20. Females who are lactating or pregnant at Screening or Baseline (as documented by a positive serum beta-human chorionic gonadotropin [β-hCG]test with a minimum sensitivity 25 IU/L or equivalent units of β-hCG). A separate baseline ssessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
21. Post liver transplant subjects
22. Any subject who has previously received avatrombopag
23. Hypersensitivity to avatrombopag maleate or any of its excipients
24. Hemoglobin levels ≤8.0 or ≥16.0 g/dL at Screening
25. White blood cell count ≤1.5 × 109/L or ≥15.0 × 109/L at Screening
26. Serum sodium level ≤130 mEq/L at Screening
27. Current malignancy including solid tumors and hematologic malignancies (except HCC)
28. Any history of or concomitant medical condition that, in the opinion of the investigator(s), would compromise the subject’s ability to safely complete the study
29. Currently enrolled in another clinical trial or used any investigational drug or device within 30 days of Screening

1.Qualsiasi anamnesi di trombosi arteriosa o venosa, compresa trombosi parziale o completa
2.Evidenza di trombosi (parziale o completa) nel tronco principale della vena porta, nei rami della vena porta o in qualsiasi parte del sistema mesenterico splenico allo screening
3.Velocità del flusso di sangue della vena porta < 10 cm/secondo allo screening
4.Encefalopatia epatica che non può essere trattata in modo efficace
5.Soggetti con HCC con classificazione C o D secondo la stadiazione BLCL (Barcelona Clinic Liver Cancer)
6.Trasfusione piastrinica o somministrazione di prodotti ematici contenenti piastrine entro 7 giorni dallo screening. Sono tuttavia consentiti globuli rossi concentrati.
7.Eparina, warfarin, farmaci anti-infiammatori non steroidei (FANS), aspirina, verapamil e terapia antipiastrinica con ticlopidina o antagonisti della glicoproteina IIb/IIIa (ad es. tirofiban) entro 7 giorni dallo screening
8.Uso di agenti stimolanti l’eritropoietina entro 7 giorni dallo screening
9.Uso di interferone (IFN) entro 14 giorni dallo screening
10.Contraccettivi ormonali contenenti estrogeni o terapia ormonale sostitutiva entro 30 giorni dallo screening

E.5 End points

E.5.1

Primary end point(s)

Proportion of subjects who do not require a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following an elective procedure

Percentuale di soggetti che non richiedono una trasfusione piastrinica o qualsiasi procedura di emergenza per il sanguinamento dopo la randomizzazione e fino a 7 giorni dopo una procedura elettiva

E.5.1.1

Timepoint(s) of evaluation of this end point

Between randomisation and 7 days post procedure.

tra la randomizzazione e 7 giorni dopo la procedura.

E.5.2

Secondary end point(s)

Proportion of subjects who achieve platelet counts of ≥50 × 109/L on Procedure Day (ie, prior to receiving a platelet transfusion or undergoing the elective procedure)

Change from baseline in platelet count on Procedure Day (ie, prior to receiving a platelet transfusion or undergoing the elective procedure)

Proportion of subjects with a WHO bleeding score ≥2 after randomization and up to 7 days following an elective procedure

•Percentuale di soggetti che raggiungono conte piastriniche di ≥ 50 × 109/l al Giorno della procedura (cioè prima di ricevere una trasfusione piastrinica o di sottoporsi alla procedura elettiva)
•Variazione dal basale della conta piastrinica al Giorno della procedura (cioè prima di ricevere una trasfusione piastrinica o di sottoporsi alla procedura elettiva)
•Percentuale di soggetti con un punteggio di sanguinamento secondo l’OMS pari a ≥ 2 dopo la randomizzazione e fino a 7 giorni dopo una procedura elettiva

E.5.2.1

Timepoint(s) of evaluation of this end point

On procedure day and between randomisation and 7 days post procedure

il giorno della procedura e tra la randomizzazione e 7 giorni dopo la procedura.

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

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)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Belgium

Brazil

Canada

China

France

Germany

Israel

Italy

Philippines

Mexico

Romania

Russian Federation

Czech Republic

Spain

Taiwan

Thailand

United Kingdom

United States

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

Clinical data base lock is the definition of the end of the trial as provided in the protocol. For the patients the end of the trial is the LVLS

chiusura del database dei dati clinici come da protocollo. Per i pazienti il termine dello studio corrisponde alla 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 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.1.1.1

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:

285

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

300

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)

Standard of care

terapia standard

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

2013-12-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-03-18

P. End of Trial
P.	End of Trial Status	Completed

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