Clinical Trials Register

Summary
EudraCT Number:	2011-006187-47
Sponsor's Protocol Code Number:	AI424-494
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-11-20
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

Denmark - DHMA

A.2

EudraCT number

2011-006187-47

A.3

Full title of the trial

A 48-Week, Randomized, Open-Label Phase 3b Study Comparing the Antiviral Efficacy and Safety of ATV/RTV Plus 3TC with ATV/RTV plus TDF/FTC in HIV-1-Infected, Treatment-Naive Subjects, Followed by a 48-Week Period on ATV/RTV Plus 3TC.

A.3.1

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

Open- Label Randomized Study Comparing Efficacy and Safety of ATV/RTV+3TC with ATV/RTV+TDF/FTC in HIV- Infected, Treatment Naïve Subjects, Followed by Treatment with ATV/RTV+3TC

A.4.1

Sponsor's protocol code number

AI424-494

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01620944

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	Bristol-Myers Squibb International Corporation
B.1.3.4	Country	Belgium
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	Bristol-Myers Squibb International Corporation
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Bristol-Myers Squibb International Corporation
B.5.2	Functional name of contact point	EU Study Start-Up Unit
B.5.3	Address:
B.5.3.1	Street Address	Parc de l'Alliance - Avenue de Finlande, 8
B.5.3.2	Town/ city	Braine-l'Alleud
B.5.3.3	Post code	1420
B.5.3.4	Country	Belgium
B.5.6	E-mail	clinical.trials@bms.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	Yes
D.2.1.1.1	Trade name	Reyataz
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Company
D.2.1.2	Country which granted the Marketing Authorisation	United States
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.3.4	Pharmaceutical form	Capsule, hard
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	ATAZANAVIR SULFATE
D.3.9.1	CAS number	229975-97-7
D.3.9.3	Other descriptive name	ATAZANAVIR SULFATE
D.3.9.4	EV Substance Code	SUB20595
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.3.11 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	Norvir
D.2.1.1.2	Name of the Marketing Authorisation holder	Abbott Laboratories Limited, Abbott House,Vanwall Business Park,Berkshire,United Kingdom
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.4	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	RITONAVIR
D.3.9.1	CAS number	155213-67-5
D.3.9.4	EV Substance Code	SUB10342MIG
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	100
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: 3
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	Epivir
D.2.1.1.2	Name of the Marketing Authorisation holder	ViiV Healthcare UK Limited, 980 Great West Road, Brentford, Middlesex, United Kingdom
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.4	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	LAMIVUDINE
D.3.9.1	CAS number	134678-17-4
D.3.9.4	EV Substance Code	SUB08392MIG
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.3.11 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

HIV

E.1.1.1

Medical condition in easily understood language

HIV

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	10068341
E.1.2	Term	HIV-1 infection
E.1.2	System Organ Class	100000004862

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 response rate (proportion of subjects with HIV-1 RNA < 40 c/mL) at Week 48 of a QD regimen of ATV/RTVHS 300/100 mg combined with either one additional drug (3TC 300 mg QD) or two additional drugs (TDF/FTC 300/200 mg QD).

E.2.2

Secondary objectives of the trial

To assess efficacy by determining:
− The proportion of subjects with HIV-1 RNA < 40 c/mL at Week 96.
− The proportion of subjects with HIV-1 RNA < 400 c/mL at Weeks 48 and 96.
• To assess safety, as measured by:
− Incidence of SAEs and AEs leading to discontinuation through Weeks 48 and 96.
− Changes from baseline in renal function [using estimated glomerular filtration rate (eGFR)] and BMD at Weeks 48 and 96.
• To assess the incidence of newly emergent genotypic substitutions and phenotypic resistance to study drugs among subjects with virologic failure through Weeks 48 and 96.

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

PK sub-study

E.3

Principal inclusion criteria

1) Signed Written Informed Consent
a) Freely given informed consent must be obtained from subjects prior to clinical trial participation, including informed consent for any screening procedures conducted to establish subject eligibility for the trial.
b) A freely given PK sub-study consent form must be obtained from the subset of
subjects participating in the intensive PK sub-study.
2) Target Population
a) Treatment-naive HIV-1-infected subjects (< 48 hours of any ARV is allowed)
b) Subjects who have an HIV-1 RNA level ≥ 1000 c/mL at screening
c) Subjects who have a CD4+ cell count > 100 cells/mm3.
3) Age and Reproductive Status
a) Men and women, 18 years of age or older (or minimum age as determined by local regulatory or legal requirements)
b) Women of childbearing potential (WOCBP) must use method(s) of contraception based on the tables in Appendix 2. For a teratogenic study drug and/or when there is insufficient information to assess teratogenicity (preclinical studies have not been done), a highly effective method(s) of contraception (failure rate of less than 1% per year) is required. The individual methods of contraception should be determined in consultation with the investigator. WOCBP must follow instructions for birth control for a period of 30 days after the last dose of investigational product.
c) Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product.
d) Women must not be breastfeeding
e) Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men that are sexually active with WOCBP must follow instructions for birth control for a period of 90 days aftert the last dose of investigational product.
f) Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile--see Section 3.3.3 for the definition of WOCBP) and azoospermic men do not require contraception.

E.4

Principal exclusion criteria

1) Target Disease Exceptions
a) Subjects who have an HIV-1 RNA level ≥ 500,000 c/mL at screening
b) Screening HIV genotype showing resistance to any component of the study regimen (ATV, RTV, 3TC, TDF/FTC) or primary resistance mutations to HIV protease inhibitors (see Appendix 4)
c) Previously documented HIV-2 infection
2) Medical History and Concurrent Diseases
a) Acute or chronic hepatitis B virus (HBV)
b) Acute hepatitis C virus (HCV) co-infection.
Note: Chronic co-infection with hepatitis C is not an exclusion criteria. Subjects with acute hepatitis C may have the option to be screened after the event has evolved into a chronic infection.
c) Presence of a newly diagnosed HIV-related opportunistic infection or any medical condition requiring acute therapy at the time of enrollment. Subjects on stable maintenance therapy for an opportunistic infection may be enrolled
d) Primary HIV infection
e) History or current cardiac disease, defined by presence of arrhythmias, ischemic disease, or a conduction abnormality including left bundle branch block (LBB) or left anterior fascicular block (LAFB), 2nd- or 3rd-degree atrioventricular block (AVB), or any cardiac abnormality deemed clinically significant by the investigator. In addition, the following ECG findings are exclusionary:
i) PR Interval > 260 msec (severe 1st degree AV Block)
ii) QRS Interval > 120 msec
f) Moderate-to-severe hepatic insufficiency
g) Obstructive liver disease
h) Recent therapy with agents having significant systemic myelosuppressive, neurotoxic, pancreatotoxic, hepatotoxic or cytotoxic potential within 3 months of study start or the expected need for such therapy at the time of enrollment, or therapy with methadone or ribavirin/interferons or treatment with neurotoxic drugs or drugs that affect CYP3A4
i) Concomitant administration of a proton pump inhibitor (PPI) or H2 blocker or any other drug with potential interaction with the investigational productsj) Life expectancy < 1 year according to the judgment of the investigator
k) Active alcohol or substance use sufficient, in the investigator’s opinion, to prevent adequate compliance with study therapy or to increase the risk of developing pancreatitis or chemical hepatitis
l) History or ongoing psychiatry disorder
3) Physical and Laboratory Test Findings
a) Screening laboratory analysis showing any of the following abnormal laboratory
results:
i) Grade IV glucose
ii) Grade IV electrolytes
iii) Grade IV transaminases
iv) Grade IV hematology
v) Calculated creatinine clearance < 60 mL/min as estimated by the Cockcroft- Gault equation.
4) Allergies and Adverse Drug Reaction
a) Hypersensitivity to any component of the study drug formulations.
5) Sex and Reproductive Status
a) Women with a positive pregnancy test on enrollment or prior to study drug administration
6) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness (eg, infectious disease)

E.5 End points

E.5.1

Primary end point(s)

Proportion of subjects with HIV-1 RNA < 40 c/mL at Week 48

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 48

E.5.2

Secondary end point(s)

• Proportion of subjects with HIV-1 RNA < 400 c/mL at Week 48, and proportion of subjects with HIV-1 RNA < 40 c/mL and < 400 c/mL at Week 96.
• Incidence rates of SAEs and AEs leading to discontinuation through Weeks 48 and 96; percent change from baseline in eGFR and bone mineral density at Weeks 48 and 96.
• Incidence rates of newly emergent genotypic substitutions and phenotypic resistance to study drugs for virologic failures through Week 48 and 96.

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 48 and 96

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

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

E.6.10

Pharmacogenetic

Yes

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

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

All patients will continue/swith to experimental regimen of ATZ/RTV + 3TC

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

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

Denmark

France

Italy

Portugal

Spain

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

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 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.1.1.1

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:

400

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

372

F.4.2.2

In the whole clinical trial

420

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)

Subjects who have successfully completed participation in this trial and who are medically stable on the current regimen at study completion and who do not have access to the marketed drug may be eligible to continue to receive the medication.
The drugs provided will be limited to the marketed drugs made available in the clinical trial in which the subject was treated. If a newer formulation of marketed product is not available, an earlier formulation will be provided.

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

2012-11-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-11-14

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2012-12-05

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