Clinical Trials Register

Summary
EudraCT Number:	2009-013795-44
Sponsor's Protocol Code Number:	NCHECR-ENCORE1
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-04-08
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

Germany - BfArM

A.2

EudraCT number

2009-013795-44

A.3

Full title of the trial

A randomised, double-blind, placebo-controlled, clinical trial to compare the safety and efficacy of reduced dose efavirenz (EFV) with standard dose EFV plus two nucleotide reverse transcriptase inhibitors (N(t)RTI) in antiretroviral-naïve HIV-infected individuals over 96 weeks

A.3.1

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

A 96 week study comparing the standard dose (600mg) to the reduced dose (400mg) efavirenz with the combination of Truvada for HIV-infected participants who have not taken any anti-HIV medication.

A.3.2

Name or abbreviated title of the trial where available

Encore1

A.4.1

Sponsor's protocol code number

NCHECR-ENCORE1

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01011413

A.5.4

Other Identifiers

Name:

Australian New Zealand Clinical Trials Registry

Number:

12610001097033

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	The Kirby Institute (formerly National Centre in HIV Epidemiology and Clinical Research (NCHECR)), University of New Sou
B.1.3.4	Country	Australia
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	Bill and Melinda Gates foundation
B.4.2	Country	United States
B.4.1	Name of organisation providing support	University of New South Wales
B.4.2	Country	Australia
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	EFAMAT 200
D.2.1.1.2	Name of the Marketing Authorisation holder	Matrix Laboratories
D.2.1.2	Country which granted the Marketing Authorisation	India
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	Efavirenz
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	EFAVIRENZ
D.3.9.1	CAS number	154598-52-4
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	200
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	Yes
D.3.11.13.1	Other medicinal product type	Non-nucleoside reverse transcriptase inhibitor
D.IMP: 2
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	Truvada
D.2.1.1.2	Name of the Marketing Authorisation holder	Gilead Sciences Inc
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
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	Truvada
D.3.2	Product code	J05AF30
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	TENOFOVIR DISOPROXIL FUMARATE
D.3.9.1	CAS number	202138-50-9
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	300
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EMTRICITABINE
D.3.9.1	CAS number	143491-57-0
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	200
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	Yes
D.3.11.13.1	Other medicinal product type	nucleotide analogue reverse transcriptase inhibitors

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

Human Immunodeficiency Virus infection

E.1.1.1

Medical condition in easily understood language

HIV infection

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

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	10070257
E.1.2	Term	Human immunodeficiency virus test positive
E.1.2	System Organ Class	10022891 - Investigations

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	10020161
E.1.2	Term	HIV infection
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To compare the safety and efficacy of standard (600mg qd) versus reduced dose (400mg qd) EFV as part of initial combination antiretroviral therapy (ART).

E.2.2

Secondary objectives of the trial

To conduct a range of analyses to examine:
• Virological response to therapy
• Changes in CD4+ T cell numbers
• Incidence and type of SAEs
• Incidence and type of AEs
• Changes from baseline in fasted lipid, glucose and selected serum biochemical parameters
• Adherence to therapy
• Quality of life
• Neurocognitive function
• Dry Blood Spot to measure viral loads
• Measurement of EFV concentration in dried blood spot and plasma samples

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

Title: The EFV central nervous system exposure sub-study
Date: 10-Nov-2009
Version: 1.0
Objectives: To investigate the central nervous system exposure of efavirenz when dosed at 600 mg and 400 mg once daily

Title: Pharmacogenetics and Population Pharmacokinetics Sub-Study
Date: 28-Sep-2009
Version: 0.2
Objectives:
1.To investigate the relationship between drug plasma exposure (PK) and drug disposition genes (PGx)
2.To investigate the relationship between drug plasma exposure (PK) and virological response (PD, achieving and maintaining of undetectable viral load)

E.3

Principal inclusion criteria

• HIV-1 positive by licensed diagnostic test
• aged >16 years of age (or minimum age as determined by local regulations or as legal requirements dictate)
• 50 < CD4 <500 cells/µL
• No prior AIDS-defining illness, using the CDC 1993 case definition (except pulmonary tuberculosis)
• HIV RNA ≥1000 copies/mL
• no prior exposure to ART (including short course ARVs for preventing MTCT)
• calculated creatinine clearance (CLCr) ≥ 50 mL/min (Cockcroft-Gault formula)
• provision of written informed consent.

E.4

Principal exclusion criteria

• the following laboratory values:
- absolute neutrophil count (ANC) <500 cells/μL
- hemoglobin <7.0 g/dL
- platelet count <50,000 cells/μL
- AST and/or ALT >5 x ULN
• pregnant women or nursing mothers
• active opportunistic or malignant disease not under adequate control
• use of immunomodulators within 30 days prior to screening
• use of any prohibited medications
• current alcohol or illicit substance use that might adversely affect study participation.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the comparison between treatment groups of proportions of patients with HIV RNA <200 copies/mL 48 weeks after randomisation.

E.5.1.1

Timepoint(s) of evaluation of this end point

48 weeks

E.5.2

Secondary end point(s)

Virologic endpoints
•Proportion of participants with plasma HIV RNA <400 copies/mL and <50 copies/mL
•Time to virological failure (HIV RNA ≥200 copies/mL)
•Time to loss of virological response (TLOVR), as defined by virological failure, permanent randomized treatment discontinuation, new AIDS-defining illness, death and withdrawal from study
•Mean changes from baseline in log plasma HIV RNA copies/mL
•Frequency of plasma HIV RNA blips (defined as a plasma viral load result >200 copies/mL on randomised therapy following a previous result <200 copies/mL, with a follow-up result <200 copies/mL at least one week following the >200 copies/mL reading in the absence of a change of any component of the ART regimen).

Immunologic endpoints
•Mean change from baseline in CD4+ T cell count/µL.

Clinical endpoints
•Rate of opportunistic disease or death
•Rates of serious non-AIDS-defining illness and non-AIDS-related mortality.

Metabolic endpoints
•Mean/median change from baseline in fasted lipids (TC, LDL-c, HDL-c and TG)
•Mean/median change from baseline in fasted glucose
•Rates of initiation or changes in existing lipid-lowering therapies.
Safety
•Mean/median change from baseline in selected serum biochemical parameters
•Rates and types of serious adverse events (SAEs)
•Rates, types and severity of adverse events (AEs).

Adherence
•Median scores of self-reported adherence to randomised study medications.

Quality of Life
•Change from baseline health status scores.

Neurological endpoints
•Change from baseline in questionnaire scores.

Resistance endpoints
•Patterns of genotypic resistance at virological failure.

Pharmacokinetic endpoints
•Steady state EFV concentrations measured by plasma and dried blood spot samples.

Exploratory endpoints
•Relationship between dried blood spot and plasma samples when measuring viral load.
•Relationship between dried blood spot and plasma samples when measuring EFV concentrations.

E.5.2.1

Timepoint(s) of evaluation of this end point

96 weeks

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

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

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.8.3

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

Yes

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

Chile

Germany

Hong Kong

India

Israel

Malaysia

Mexico

Nigeria

Peru

Singapore

South Africa

Taiwan

Thailand

United Kingdom

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 Sponsor and the Protocol Steering Committee also has the power to stop the study at any time should they deem it in the trial participants best interests to do so. There will be two early interim analyses reviewed by an independent data safety monitoring board who may make a recommendation to stop the study in the event that the experimental arm was considered inferior (by pre-defined terms of reference finalised immediately prior to study commencement).

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

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:

630

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

630

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

100

F.4.2.2

In the whole clinical trial

630

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)

Consistent with normal care

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

2012-06-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-03-31

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-03-31

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