Clinical Trials Register

Summary
EudraCT Number:	2018-000177-72
Sponsor's Protocol Code Number:	208090
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-05-21
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

France - ANSM

A.2

EudraCT number

2018-000177-72

A.3

Full title of the trial

A Phase III, randomized, multicenter, open-label, non-inferiority study evaluating the efficacy, safety and tolerability of switching to dolutegravir/lamivudine fixed dose combination in HIV-1 infected adults who are virologically suppressed

A.3.1

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

To determine the efficacy, safety and tolerability of two approved medicines, dolutegravir (DTG) plus lamivudine (3TC) taken together as a single tablet, compared with subjects taking their current antiretroviral therapy regimen (CAR) for the treatment of HIV-1 infected adults in whom the HIV-1 virus is currently suppressed.

A.4.1

Sponsor's protocol code number

208090

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	ViiV Healthcare UK 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	ViiV Healthcare UK (No.3) Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	PPD
B.5.2	Functional name of contact point	Project Manager
B.5.3	Address:
B.5.3.1	Street Address	27-35 rue Victor Hugo
B.5.3.2	Town/ city	Ivry-sur-Seine Cedex
B.5.3.3	Post code	94853
B.5.3.4	Country	France
B.5.4	Telephone number	+33(0) 9 71 59 15 09
B.5.6	E-mail	Marie.Schyns@ppdi.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	GSK3515864
D.3.2	Product code	DTC/3TC Bilayer Tablets, 50 mg/300 mg
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	DOLUTEGRAVIR
D.3.9.1	CAS number	1051375-19-9
D.3.9.2	Current sponsor code	GSK1349572A
D.3.9.3	Other descriptive name	DTG
D.3.9.4	EV Substance Code	SUB31300
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	50
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.3.9.2	Current sponsor code	GR109714X
D.3.9.3	Other descriptive name	3TC
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

Human Immunodeficiency Virus-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	20.1
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 demonstrate the non-inferior antiviral activity of switching to DTG/3TC FDC once daily compared to continuation of CAR over 48 weeks in virologically suppressed adults living with HIV-1

E.2.2

Secondary objectives of the trial

To demonstrate the antiviral activity of switching to DTG/3TC FDC once daily compared to continuation of CAR over 48 weeks
To evaluate the antiviral activity of switching to DTG/3TC FDC once daily compared to continuation of CAR over 24 weeks
To evaluate the immune effects of DTG/3TC FDC once daily compared to continuation of CAR
To evaluate the safety and tolerability of DTG/3TC FDC once daily compared to CAR over time
To evaluate the safety and tolerability of DTG/3TC FDC once daily in those with creatinine clearance of between 30-49 mL/min/1.73m2 compared to those with a creatinine clearance of ≥50 mL/min/1.73m2
To evaluate the effects of DTG/3TC FDC once daily on fasting lipids over time compared to CAR
To assess viral resistance in participants meeting Confirmed Virologic Withdrawal (CVW) Criteria
To assess health related quality of life for participants treated with DTG/3TC FDC compared to CAR

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 sub-study of Virologic Response to Subsequent ART after Discontinuation from 208090 for Meeting CVW or PVW Criteria will be conducted. This sub-study will evaluate and determine the virologic response to subsequent regimens of participants who have virologic failure to DTG/3TC FDC. The evaluation period will start from the time the participant is discontinued from the 208090 study for confirmed virologic withdrawal (CVW) or precautionary virologic withdrawal (PVW) criteria while on DTG/3TC FDC, and will last for up to 12 months. The results of this study may provide information that will help guide treatment decisions for people living with HIV who virologically fail a DTG/3TC FDC regimen.
Objectives:
To determine the drug regimens that are used after CVW or PVW with DTG/3TC FDC.
To determine the proportion of participants with CVW or PVW with DTG/3TC FDC who achieve virologic suppression with the subsequent regimen at the end of 12 months of follow up.
To describe the reasons for discontinuation of/switching from subsequent treatment regimen and reason for virologic failure

E.3

Principal inclusion criteria

1. Aged 18 years or older (or older, if required by local regulatory agencies), at the time of signing the informed consent
2. Adults living with HIV
3. Documented evidence of at least two plasma HIV-1 RNA measurements <50 c/mL in the 12 months prior to Screening: one within the 6 to 12 month window, and one within 6 months prior to Screening.
4. Plasma HIV-1 RNA <50 c/mL at Screening.
5. Must be on uninterrupted current regimen (either the initial or second cART regimen) for at least 3 months prior to Screening.
Any prior switch, defined as a change of a single drug or multiple drugs simultaneously, must have occurred due to tolerability and/or safety concerns or access to medications, or convenience/simplification and must NOT have been done for suspected or established treatment failure. The following switches, if they are the only switches, would not be considered a change in regimen;
a. A switch from a PI boosted with RTV to the same PI boosted with cobicistat is allowed (and vice versa).
b. A switch from lamivudine (3TC) to emtricitabine (FTC) (and vice versa)
c. A switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) (and vice versa).
Acceptable stable cART regimens prior to Screening include 2 NRTIs plus:
- INI (either the initial or second cART regimen)
- NNRTI (either the initial or second cART regimen)
- Boosted PI (or atazanavir [ATV] unboosted) (either the initial or second PI-based cART regimen)
6. Male and Female
a. A female participant is eligible to participate if she is not pregnant [as confirmed by a negative serum human chorionic gonadotrophin test at screen and a negative urine hCG test at Randomization (a local serum hCG test at Randomization is allowed if it can be done, and results obtained, within 24 hours prior to randomization)], not breastfeeding, and at least one of the following conditions applies:
- Not a woman of childbearing potential
OR
- A WOCBP who agrees to follow the contraceptive guidance during the treatment period from 28 days prior to the first dose of study medication and for at least 2 weeks after the last dose of study medication.
The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
The investigator is responsible for ensuring that participants understand how to properly use these methods of contraception.
All participants in the study should be counselled on safer sexual practices including the use and benefit/risk of effective barrier methods (e.g., male condom) and on the risk of HIV transmission to an uninfected partner.
The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
7. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol.
8. Participants enrolled in France must be affiliated to, or a beneficiary of, a social security category.

E.4

Principal exclusion criteria

1. Women who are pregnant or breastfeeding or plan to become pregnant or breastfeed during the study
2. Any evidence of an active CDC Stage 3 disease, EXCEPT cutaneous Kaposi’s sarcoma not requiring systemic therapy. Historical or current CD4 cell counts less than 200 cells/mm3 are NOT exclusionary.
3. Participants with severe hepatic impairment (Class C) as determined by Child-Pugh classification.
4. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
5. Evidence of Hepatitis B virus (HBV) infection based on the results of testing at Screening for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (anti-HBc), Hepatitis B surface antigen antibody (anti-HBs) and HBV DNA as follows:
- Participants positive for HBsAg are excluded.
- Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and positive for HBV DNA are excluded.
Note: Participants positive for anti-HBc (negative HBsAg status) and positive for anti-HBs (past and/or current evidence) are immune to HBV and are not excluded. Anti-HBc must be either total anti-HBc or anti-HBc immunoglobulin G (IgG), and NOT anti-HBc IgM. Participants with a documented history of chronic HBV and current undetectable HBV DNA while on a TAF/TDF regimen are excluded.
6. Anticipated need for any HCV therapy during the randomized phase of the study, or anticipated need for HCV therapy with a potential for adverse drug-drug interactions with DTG/3TC.
7. Untreated syphilis infection (positive rapid plasma reagin [RPR] at Screening without clear documentation of treatment). Participants who are at least 7 days post
completed treatment are eligible.
8. History or presence of allergy or intolerance to the study interventions or their components or drugs of their class.
9. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or penile intraepithelial neoplasia.
10. Participants who in the investigator’s judgment, poses a significant suicidality risk
11. Any pre-existing physical or mental condition which, in the opinion of the Investigator, may interfere with the participant’s ability to comply with the dosing schedule and/or protocol evaluations or which may compromise the safety of the participant.
12. Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or excretion of the study interventions or render the participant unable to take oral medication.
13. Use of any regimen consisting of single or dual ART (peri-partum treatment with single dose nevirapine is allowed).
14. Current use of stavudine, didanosine, or nelfinavir
15. Participants receiving any prohibited medication and who are unwilling or unable to switch to an alternate medication
16. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening;
17. Treatment with any of the following agents within 28 days of Screening (radiation therapy, cytotoxic chemotherapeutic agents, any systemic immune suppressant)
18. Exposure to an experimental drug or experimental vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of IP.
19. Any evidence of major NRTI mutation or presence of any DTG resistance-associated mutation in any available prior resistance genotype assay test result, if known. Refer to the most recent version of IAS Guidelines, SRM, and Section 8 (Screening Assessments) for more information. All resistance reports with HIV-1 reverse transcriptase or integrase genotypic data must be provided to ViiV after screening and before randomization for review by ViiV virology.
20. Any verified Grade 4 laboratory abnormality. A single repeat test is allowed during the Screening period to verify a result.
21. Alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN) or ALT ≥3xULN and bilirubin ≥1.5xULN (with >35% direct bilirubin).
22. Creatinine clearance of <30 mL/min/1.73m2 via CKD-EPI method. Participants with creatinine clearance between 30 – 49 mL/min/1.73m2 are eligible after the medical monitor has provided approval after reviewing participant’s current ART regimen.
23. Any acute laboratory abnormality at Screening, which, in the opinion of the investigator, would preclude the participant’s participation in the study of an investigational compound.
24. Within the 12 month window prior to Screening and after confirmed suppression to <50 c/mL, any plasma HIV-1 RNA measurement >200 c/mL.

E.5 End points

E.5.1

Primary end point(s)

Virologic failure endpoint as per FDA snapshot category 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 participants with plasma HIV-1 RNA <50 c/mL at Week 48 using the Snapshot algorithm for the ITT-E population
- Virologic failure endpoint as per FDA snapshot category at Week 24
- Proportion of participants with plasma HIV-1 RNA <50 c/mL at Week 24 using the Snapshot algorithm for the ITT-E population
- Change from Baseline in CD4+ cell count and in CD4+/CD8+ cell counts ratio at Weeks 24 and 48
- Incidence of disease progression (HIVassociated conditions, AIDS, and death) through Weeks 24 and 48
- Incidence and severity of adverse events (AEs) and laboratory abnormalities
- Proportion of participants who discontinue treatment due to AEs
- Change from Baseline in fasting lipids at Weeks 24 and 48
- Incidence of observed genotypic and phenotypic resistance to ARVs for participants meeting CVW Criteria
- Change from Baseline in health status using HIV TSQ and SDM at Weeks 24 and 48 (or Withdrawal from the study) and SDM at Weeks 24, 48 and every 24 weeks during the continuation phase
(or Withdrawal from the study)

E.5.2.1

Timepoint(s) of evaluation of this end point

Weeks 24 and 48

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)

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

non-inferiority switch study

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

CAR (Current Antiretroviral therapy regimen)

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

Belgium

Brazil

Canada

China

Denmark

France

Germany

Italy

Mexico

Russian Federation

South Africa

Spain

Sweden

Taiwan

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

LPLV

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

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:

540

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

220

F.4.2.2

In the whole clinical trial

600

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)

At the end of the study all subjects will transition to locally approved and available DTG + 3TC FDC and be managed as per standard of care at their study site. Prior to completion, sites will need to have confirmation that DTG + 3TC FDC is locally available for study subjects. If DTG + 3TC FDC is not yet approved and available locally, ViiV Healthcare will continue to provide study drug in a Continuation Phase until local availability.

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

2019-08-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-07-02

P. End of Trial
P.	End of Trial Status	Ongoing

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