Clinical Trials Register

Summary
EudraCT Number:	2011-001635-23
Sponsor's Protocol Code Number:	TMC114IFD3003
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-07-12
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2011-001635-23

A.3

Full title of the trial

PROTEAse inhibitor (DRV/rtv) in mono- or triple therapy in suppressed HIV-1 infected subjects

A.3.1

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

PROTEA: A clinical trial comparing the efficacy of darunavir/ritonavir 800/100 mg monotherapy versus a triple combination therapy containing darunavir/ritonavir 800/100 mg and 2 nucleoside/nucleotide reverse transcriptase inhibitors in patients with
undetectable plasma HIV-1 RNA on current treatment

A.4.1

Sponsor's protocol code number

TMC114IFD3003

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	Janssen Cilag International N.V.
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	Janssen Medical Affairs
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	Janssen Biologics
B.5.2	Functional name of contact point	Clinical Registry Group
B.5.3	Address:
B.5.3.1	Street Address	Archimedesweg 29
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333CM
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31 071 524 21 66
B.5.5	Fax number	+31 071 524 21 10
B.5.6	E-mail	ClinicaltrialsEU@its.jnj.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	Prezista
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen-Cilag International N.V.
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.3.1	Product name	darunavir-film coated tablet-400mg (F030)
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	DARUNAVIR
D.3.9.1	CAS number	206361-99-1
D.3.9.2	Current sponsor code	Darunavir ethanolate (formerly known as TMC114 ethanolate)
D.3.9.3	Other descriptive name	DRV (formerly known as TMC114)
D.3.9.4	EV Substance Code	SUB25394
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	400
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	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	Norvir®
D.2.1.1.2	Name of the Marketing Authorisation holder	Abbott Laboratories limited
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.3.1	Product name	ritonavir
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.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-1 infection

E.1.1.1

Medical condition in easily understood language

HIV-1 infection

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.0
E.1.2	Level	LLT
E.1.2	Classification code	10020192
E.1.2	Term	HIV-1
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

The primary objective is to demonstrate non-inferiority in terms of the percentage of subjects who have plasma HIV-1 RNA levels <50 copies/mL after 48 weeks of follow-up after switching to DRV/rtv monotherapy versus triple therapy containing DRV/rtv (FDA Snapshot method).

E.2.2

Secondary objectives of the trial

1. the correlation of plasma HIV-1 RNA, cerebrospinal fluid (CSF) HIV-1 RNA, and neurocognitive function of DRV/rtv monotherapy versus triple therapy containing DRV/rtv at week 48
2. change in neurocognitive function of DRV/rtv monotherapy versus triple therapy containing DRV/rtv over 48 and 96 weeks
3. the rate of plasma HIV-1 RNA suppression after 48 and 96 weeks of follow-up to DRV/rtv monotherapy versus triple therapy containing DRV/rtv, using the time to loss of virologic response (TLOVR) method.
4. the correlation of plasma HIV-1 RNA and neurocognitive function of DRV/rtv monotherapy versus triple therapy containing DRV/rtv
at Weeks 48 and 96
5. the loss of treatment options as defined by treatment-emergent phenotypic drug resistance
6. the viral genotype of subjects
7. To evaluate and compare safety and tolerability

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

a lumbar puncture (extraction of cerebrospinal fluid [CSF] from the spinal canal) for laboratory testing (antiviral effectiveness, pharmacokinetic analysis, biochemistry and immune markers) and an additional blood sample for pharmacokinetic analysis (to measure the drug level in blood) will be taken. The study hypothesis is that, after 48 weeks of randomised treatment, DRV/rtv monotherapy is as effective as the triple therapy containing DRV/rtv plus plus 2 nucleoside analogues

E.3

Principal inclusion criteria

1. Have documented HIV-1 infection.
2. Be male or female aged 18 or over 18 years old.
3. Criterion deleted per amendment.
4. Criterion modified per amendment.
4.1 Currently be receiving HAART for at least 48 weeks.
5. Criterion modified per amendment.
5.1 Have at least 2 documented plasma HIV-1 RNA <50 copies/mL, and no HIV-1 RNA 50 or over 50 copies/mL in the 48 weeks prior to the screening visit.
6. Be taking the same ARV combination for at least 8 weeks before screening.
7. Have the preference, together with the physician, to change the current HAART regimen for reasons of simplification and/or toxicity (examples of toxicities include but are not limited to: CNS, gastrointestinal disturbances, jaundice, anemia, nausea, neuropathy, paresthesia, hyperlipidemia, glucose intolerance or diabetes, nephrolithiasis, lipodystrophy, hepatotoxicity, rash and skin related events, any other AE or intolerability or laboratory abnormalities caused by current HAART).
8. Criterion modified per amendment.
8.1 Have no CD4+ cell counts below 100 cells/mm3, from the time of first known HIV infection to the start of HAART, and >200 cells/mm3 at screening or a maximum of 4 weeks prior to screening.
9. Be able to comply with the protocol requirements. In particular, subjects should be willing to be followed up to Week 96 even if they discontinue randomized treatment.
10. If heterosexually active, a female of childbearing potential and a non-vasectomized male subject who has a female partner of childbearing potential must agree to use effective contraceptives from screening onwards until 30 days after completion of study treatment.
11. If a woman of childbearing potential, she must have a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test at screening; and a negative serum or urine pregnancy test before the first dose of study medication to ensure they are not pregnant at the time of starting treatment.
12. Criterion modified per amendment.
12.1 Have voluntarily signed and dated an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.

E.4

Principal exclusion criteria

1. Criterion modified per amendment.
1.1 Has a history of virologic failure defined as 2 consecutive plasma HIV-1 RNA >500 copies/mL after initial viral suppression while on previous or current antiretroviral therapy.
2. Has a history of any primary PI mutations as defined by the IAS-USA guidelines 2010.24
3. Has clinical or laboratory evidence of significantly decreased hepatic function or decompensation, irrespective of liver enzyme levels (liver insufficiency).
4. Is diagnosed with acute viral hepatitis at screening or before Baseline 1.
5. Is co-infected with hepatitis B.
6. Has documented hepatic cirrhosis.
7. Has a grade 3 or 4 laboratory abnormality as defined by the Division of AIDS (DAIDS) grading table (see Attachment 1: DAIDS AE grading table), with the following exceptions unless clinical assessment foresees an immediate health risk to the subject:
* Subjects with pre-existing diabetes or with asymptomatic glucose grade 3 or 4 elevations.
* Subjects with asymptomatic triglyceride or cholesterol elevations of grade 3 or 4.
* Subjects taking atazanavir with asymptomatic hyperbilirubinemia of grade 3 or 4.
8. Has presence of any currently active AIDS defining illness (Category C conditions according to the Centers for Disease Control (CDC) Classification System for HIV Infection 1993) with the following exceptions:
* Stable cutaneous Kaposi's Sarcoma (ie, no internal organ involvement other than oral lesions) that is unlikely to require any form of systemic therapy during the study.
* Wasting syndrome due to HIV infection.
9. Is a woman who is pregnant or breastfeeding.
10. Is an active drug abuser, including alcohol or recreational drugs.
11. Has any active clinically significant disease (eg, tuberculosis, cardiac dysfunction, pancreatitis, acute viral infections) or life threatening disease or findings during screening of medical history or physical examination that, in the investigator's opinion, would compromise the subject's safety or outcome of the study.
12. Has any medical or psychiatric condition which, in the opinion of the investigator, could compromise the subject's safety or adherence to the study protocol.
13. Is on anti-psychotic drugs.
14. Criterion modified per amendment.
14.1 Has a severe depression (based on test results from the BDI: scoring between 30 and 63).
15. Has previously demonstrated clinically significant allergy or hypersensitivity to any of the excipients of the investigational medication (DRV).
16. Is hypersensitive to ritonavir or to any of the other ingredients found in the ritonavir tablet.
17. Uses disallowed concomitant therapy (see Section 8 and DRV Summary of Product Characteristics [SPC]25).
18. Is currently enrolled in an investigational drug study or has participated in such study within 30 days before screening.

E.5 End points

E.5.1

Primary end point(s)

the percentage of patients who have
plasma human immunodeficiency virus type-1 (HIV-1) ribonucleic acid (RNA) levels <50 copies/mL after 48 weeks of follow-up after switching to DRV/ritonavir (rtv) monotherapy versus triple therapy containing DRV/rtv

E.5.1.1

Timepoint(s) of evaluation of this end point

48 weeks

E.5.2

Secondary end point(s)

the correlation of plasma HIV-1 RNA, cerebrospinal fluid (CSF) HIV-1 RNA, and
neurocognitive function of DRV/rtv monotherapy versus triple therapy containing DRV/rtv at
week 48

change in neurocognitive function of DRV/rtv monotherapy versus
triple therapy containing DRV/rtv over 48 and 96 weeks

the rate of plasma HIV-1 RNA suppression after 48 and 96 weeks of follow-up to DRV/rtv monotherapy versus triple therapy containing DRV/rtv, using the time to loss of virologic response (TLOVR) method.

the correlation of plasma HIV-1 RNA and neurocognitive function of DRV/rtv monotherapy versus triple therapy containing DRV/rtv at Weeks 48 and 96

the loss of treatment options of DRV/rtv monotherapy versus triple therapy containing DRV/rtv at Weeks 48 and 96, as defined by treatment-emergent phenotypic drug resistance

the viral genotype of subjects treated with DRV/rtv monotherapy versus triple therapy containing DRV/rtv over 48 and 96 weeks

To evaluate and compare safety and tolerability of DRV/rtv monotherapy versus triple therapy containing DRV/rtv over 48 and 96 weeks

E.5.2.1

Timepoint(s) of evaluation of this end point

48 weeks en 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

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

Yes

E.6.13.1

Other scope of the trial description

Tolerability

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

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

monotherapy vs triple combination 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

Israel

Switzerland

E.8.7

Trial has a data monitoring committee

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

Number of subjects for this age range:

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:

255

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

215

F.4.2.2

In the whole clinical trial

260

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)

see protocol

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

2011-08-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-01-17

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

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