Clinical Trials Register

Summary
EudraCT Number:	2009-015002-19
Sponsor's Protocol Code Number:	VTI-206
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2009-09-01
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2009-015002-19

A.3

Full title of the trial

EFFICACY AND SAFETY OF ELAD IN SUBJECTS WITH ACUTE ON CHRONIC HEPATITIS (AOCH)

A.3.1

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

This study examines the safety and efficacy of using ELAD therapy as a continuous liver support to a subject with compromised liver function, allowing time for the subject’s native liver to regenerate to a healthy state, or to stabilize the subject until a suitable donor organ can be found for transplantation.

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

VTI-206

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	VITAL THERAPIES INCORPORATED
B.1.3.4	Country	United States
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	VITAL THERAPIES, INC.
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	PREMIER RESEARCH GROUP LIMITED
B.5.2	Functional name of contact point	CLINICAL TRIAL MANAGER
B.5.3	Address:
B.5.3.1	Street Address	1st Floor, Rubra 2, Mulberry Business Park,
B.5.3.2	Town/ city	Fishponds Road, Wokingham
B.5.3.3	Post code	RG41 2GY
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	441189364000
B.5.5	Fax number	441189364001
B.5.6	E-mail	Jar.Lan@premier-research.com

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	ELAD
D.3.2	Product code	ELAD SYSTEM
D.3.4	Pharmaceutical form	Living tissue equivalent
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Hemodialysis
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Human C3A hepatoblastoma cells
D.3.9.2	Current sponsor code	ELAD
D.3.9.3	Other descriptive name	Extracorporeal Liver Assist system
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
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)	Yes
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Yes
D.3.11.3.5.1	CAT classification and reference number	Somatic cell therapy medicinal product [Art. 2(1)(a) of Regulation (EC) No 1394/2007] and a combined ATMP as defined in Art. 2(1)(d) of Regulation (EC) No 1394/2007. EMA/463750/2010, 19 July 2010.
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

Acute on Chronic Hepatitis (AOCH)

E.1.1.1

Medical condition in easily understood language

Liver disease

E.1.1.2

Therapeutic area

Body processes [G] - Metabolic Phenomena [G03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	13.1
E.1.2	Level	PT
E.1.2	Classification code	10019755
E.1.2	Term	Hepatitis chronic active
E.1.2	System Organ Class	10019805 - Hepatobiliary 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 objective of this study is to evaluate the efficacy and safety of ELAD to stabilize liver function during the acute phase of AOCH. Stabilization is measured using the time to progression (TTP) with progression defined as the earlier of death or an increase of 5 points or more in MELD score at defined times post-baseline. Differences between treatment groups in time to progression will be analyzed based on the time of the death or the first observed increase of at least 5 points from Baseline MELD score at least 24 hours following the end of the Treatment Period, then at least on Study Days 7, 14, 21, 28, 63 and 91.

E.2.2

Secondary objectives of the trial

Secondary efficacy analyses will evaluate the proportion of Progression Free Survivors using a chi-square test to compare the proportion of subjects who survived without MELD-based progression (as defined in the Primary Endpoint) at Study Day 28 (27 days following Baseline) and Study Day 91 (90 days following Baseline). Two-tailed alpha will be set at 0.05. In addition these secondary efficacy analyses will be performed using a Cochran-Mantel-Haenszel test stratified by subject classification (AAH or non-AAH) to compare the proportion of subjects who have survived without MELD-based progression (as defined in the Primary Endpoint) at Study Day 28 and Study Day 91 (27 and 90 days following Baseline respectively). Two-tailed alpha will be set at 0.05.

Safety will be evaluated through monitoring of adverse events (AEs), physical examinations, vital signs, and laboratory test results.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects must meet ALL inclusion criteria to be eligible for the study at baseline:

1) Age ≥18 ≤67 years; AND
2) Acute decompensation of chronic liver disease over the preceding 28 days; AND
3) MELD score between 18 and 35, inclusive; AND
4) Diagnosis of AOCH (AAH or non-AAH); AND
5) Subject or designated representative must provide Informed Consent.

E.4

Principal exclusion criteria

Subjects must NOT meet any of the following exclusion criteria:

1) Platelets <50,000/mm3 at Baseline; OR
2) Evidence of chronic renal failure as defined by a serum creatinine ≥2.5 mg/dL during the 1 – 6 month period prior to study entry (unless creatinine ≥2.5mg/dL is documented as due to type-1 hepato-renal syndrome or isolated episodes of acute renal failure); OR
3) Contraindication to renal replacement therapy (hemodialysis or hemofiltration); OR
4) International Normalization Ratio (INR) > 3.5; OR
5) Septic shock as defined by a positive blood culture and two or more of the following:
a. Systolic blood pressure < 90 mmHg OR mean arterial pressure (MAP) < 60 mmHg;
b. Tachypnea > 20 breaths per minute OR a PaCO2 < 32 mmHg;
c. White blood cell count < 4000 cells/mm3 OR > 12000 cells/mm3 (< 4 x 109 or > 12 X 109 cells/L); OR
6) Evidence of major hemorrhage as indicated by:
• requiring ≥ 4 units packed red blood cells within a 48 hour period, OR
• hemodynamic instability (sustained pulse >120 beats/min AND systolic blood pressure <100 mmHg over one hour).
Subjects with a recent history of gastrointestinal hemorrhage who have been successfully treated and remain hemodynamically stable for a period of 48 hours before randomization will be eligible for the study if the investigator determines the subject to be at low risk for rebleeding; OR
7) Evidence (by physical exam, history, or laboratory evaluation) of significant concomitant disease including chronic congestive heart failure, vascular disease, emphysema, AIDS, hepatitis due to herpes virus, Wilson’s disease, or Budd-Chiari syndrome; OR
8) Known history of hepatocellular carcinoma beyond the Milan criteria and/or occlusive portal vein thrombosis impairing hepatopedal flow; OR
9) Evidence of spontaneous bacterial peritonitis associated with an uncontrolled systemic infection; OR
10) Evidence of brain death as determined by blood flow studies positive for herniation AND/OR absence of pupillary reflex; OR
11) Systolic blood pressure < 85 mmHg OR MAP < 50 mmHg at Baseline; OR
12) Requirement for escalating doses of vasopressor support OR of an alpha-adrenergic agent for one hour or longer AND evidence of hemodynamic instability; OR
13) Subject at maximum vasopressor dose at Screen; OR
14) Clinical or radiographic evidence of a new stroke or intracerebral bleeding; OR
15) Seizures uncontrolled by medication; OR
16) Acute myocardial infarction based on clinical and/or electrocardiographic evidence; OR
17) Lung disease defined by a PaO2 <60 mm Hg on room air, acute respiratory distress syndrome (ARDS), or a history of severe COPD or interstitial lung disease; OR
18) Pregnancy as determined by β-human chorionic gonadotropin (HCG) results, or lactation; OR
19) Participation in another investigational drug, biologic, or device study within one month of enrollment. Subjects who are enrolled in an observational study will be eligible for this trial; OR
20) Previous liver transplant; OR
21) Previous participation in a clinical trial involving ELAD®; OR
22) Have either a Do Not Resuscitate or a Do Not Intubate (DNR/DNI) directive (or such local equivalent) in place.

E.5 End points

E.5.1

Primary end point(s)

The primary study objective is to establish that treatment with the ELAD system results in stabilized liver function for patients during the acute phase of AOCH.

E.5.1.1

Timepoint(s) of evaluation of this end point

A Kaplan-Meier analysis will be used to evaluate differences between treatment groups in time to progression (TTP) based on death or the first observed increase of at least 5 points from Baseline MELD score at least 24 hours after the ELAD Treatment Period is ended and up to Study Day 91 (90 days following Baseline). This analysis will be stratified based on the classification of a subject as either AAH or non-AAH diagnosis. A stratified log-rank test will be used to compare the Kaplan-Meier curves with 2-tail alpha set at 0.05.

E.5.2

Secondary end point(s)

Safety will be evaluated through monitoring of adverse events (AEs), physical examinations, vital signs, and laboratory test results.

E.5.2.1

Timepoint(s) of evaluation of this end point

Continuously through out treatment period and posat treatment study days 14, 21, 63 and 91

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

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

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

Standard medical therapy

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

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

Last visit of the last patient.
Subsequent long-term (life-long) follow-up of patients will be carried out through establishment of a registry.

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