Regimen Switch to Dolutegravir + Rilpivirine From Current Antiretroviral Regimen in Human Immunodeficiency Virus Type 1 Infected and Virologically Suppressed Adults (SWORD-2)

NCT ID: NCT02422797

Last Updated: 2024-09-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 518 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-04-21
• Study Completion Date: 2023-05-25

Brief Summary

The aim of this study was to determine if virologically suppressed, human immunodeficiency virus type 1 (HIV-1) infected adults on an antiretroviral regimen (including 2 nucleoside reverse transcriptase inhibitors [NRTIs] plus a third agent) remain suppressed upon switching to a two-drug regimen with dolutegravir (DTG) + rilpivirine (RPV). The study primarily assessed the non-inferiority antiviral activity of switching to DTG + RPV once daily compared to the continuation of current antiretroviral regimen (CAR) up to Week 48 with a switch visit for eligible subjects in the CAR group to initiate DTG + RPV therapy at Week 52. CAR included 2 NRTIs plus 1 HIV-1 integrase inhibitor (INI), or 1 non-nucleoside reverse transcriptase inhibitor (NNRTI), or 1 protease inhibitor (PI). The study included a 148-week open-label treatment phase, comprising of an Early Switch Phase (Day 1 to Week 52) and a Late Switch Phase (Week 52 to Week 148). The participants fulfilling the study eligibility criteria participated in the Early Switch Phase where they either switched from their CAR to DTG + RPV, or continued taking their CAR, until Week 52. At the end of Early Switch Phase, eligible participants proceeded to the Late Switch Phase where all participants in both DTG + RPV and CAR treatment groups received DTG + RPV therapy until Week 148. After Week 148, subjects could have been eligible to continue to receive DTG +RPV in the Continuation Phase.

Conditions

HIV Infections

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Current antiretroviral regimen (CAR)

Participants continued to receive their current antiretroviral regimen (two nucleoside reverse transcriptase inhibitor \[NRTIs\] + a third agent). A third agent included either an: integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). CAR was administered according to the approved labeling in an open-label fashion up to Week 52 during early switch phase. At Week 52, participants with human immunodeficiency virus-1 (HIV-1) ribonucleic acid (RNA) \<50 copies per milliliter (c/mL), switched to DTG 50 mg + RPV 25 mg once daily and were followed-up through the Late Switch Phase, at Week 148 and through the Continuation Phase, after Week 148.

Group Type: ACTIVE_COMPARATOR

CAR

Intervention Type: DRUG

CAR included the following combinations: 2 NRTIs + 1 INI, 2 NRTIs + 1 NNRTI, or 2 NRTIs + 1 PI.

DTG + RPV

Participants received DTG 50 milligrams (mg) + RPV 25 mg together once daily at approximately the same time, with a meal, in an open-label fashion up to Week 52 during early switch phase. Participants continued to receive DTG 50 mg + RPV 25 mg up to Week 148 during the Late Switch Phase.

Participants who successfully completed 148 weeks of treatment were given the opportunity to continue to receive DTG + RPV once daily in the Continuation Phase (after Week 148).

Group Type: EXPERIMENTAL

DTG 50 mg

Intervention Type: DRUG

Participants received one oral tablet of 50 mg DTG daily administered concomitantly with RPV. Each DTG tablet contained 52.62 mg dolutegravir sodium salt, which was equivalent to 50 mg dolutegravir free acid.

RPV 25 mg

Intervention Type: DRUG

Participants received DTG 50 milligrams (mg) + RPV 25 mg together once daily at approximately the same time, with a meal, in an open-label fashion up to Week 52 during early switch phase. Participants continued to receive DTG 50 mg + RPV 25 mg up to Week 148 during the Late Switch Phase.

Participants who successfully completed 148 weeks of treatment were given the opportunity to continue to receive DTG + RPV once daily in the Continuation Phase (after Week 148), one oral tablet of 25 mg RPV daily administered concomitantly with DTG along with a meal. Each RPV tablet contained 27.5 mg of rilpivirine hydrochloride, which was equivalent to 25 mg of RPV.

Interventions

DTG 50 mg

Participants received one oral tablet of 50 mg DTG daily administered concomitantly with RPV. Each DTG tablet contained 52.62 mg dolutegravir sodium salt, which was equivalent to 50 mg dolutegravir free acid.

Intervention Type: DRUG

RPV 25 mg

Participants received DTG 50 milligrams (mg) + RPV 25 mg together once daily at approximately the same time, with a meal, in an open-label fashion up to Week 52 during early switch phase. Participants continued to receive DTG 50 mg + RPV 25 mg up to Week 148 during the Late Switch Phase.

Participants who successfully completed 148 weeks of treatment were given the opportunity to continue to receive DTG + RPV once daily in the Continuation Phase (after Week 148), one oral tablet of 25 mg RPV daily administered concomitantly with DTG along with a meal. Each RPV tablet contained 27.5 mg of rilpivirine hydrochloride, which was equivalent to 25 mg of RPV.

Intervention Type: DRUG

CAR

CAR included the following combinations: 2 NRTIs + 1 INI, 2 NRTIs + 1 NNRTI, or 2 NRTIs + 1 PI.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Participants must have been able to understand and comply with protocol requirements, instructions, and restrictions.
• Participants must have been likely to complete the study as planned.
• Participants must have been considered appropriate candidates for participation in an investigative clinical trial with oral medication (e.g., no active substance abuse, acute major organ disease, or planned long-term work assignments out of the country, etc.).
• HIV-1 infected men or women of greater than or equal to (>=)18 years of age.
• Must have been on uninterrupted current regimen (either the initial or second combination antiretroviral therapy [cART] regimen) for at least 6 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. Acceptable stable cART regimens prior to screening include 2 NRTIs plus INI (either the initial or second cART regimen), or an NNRTI (either the initial or second cART regimen), or a Boosted PI (or atazanavir unboosted) (either the initial or second PI-based cART regimen).
• 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;
• Plasma HIV-1 RNA <50 c/mL at Screening;
• A female may have been eligible to enter and participate in the study if she was of : Non-child-bearing potential either defined as post-menopausal (12 months of spontaneous amenorrhea and >=45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy or, Child-bearing potential with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the following methods of contraception to avoid pregnancy: Complete abstinence from intercourse from 2 weeks prior to administration of study drug, throughout the study, and for at least 2 weeks after discontinuation of all study medications and completion of the Follow-up visit; Any intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year (not all IUDs meet this criterion); Male partner sterilization with documentation of azoospermia prior to the female participant's entry into the study and this male is the sole partner for that participant; The documentation on male sterility could come from the site personnel's review of participant's medical records, medical examination, and/or semen analysis, or medical history interview provided by her or her partner; Approved hormonal contraception for participants randomly assigned to DTG + RPV arm (and for participants randomly assigned to CAR following switch to DTG + RPV at Week 52) or approved hormonal contraception plus a barrier method for participants assigned to CAR through Week 52; Approved hormonal contraception included: Combined estrogen and progestogen oral contraceptive, Contraceptive subdermal implant, Injectable progestogen, Contraceptive vaginal ring, Percutaneous contraceptive patches. Any other method with published data showing that the expected failure rate is <1% per year. Any contraception method must have been used consistently, in accordance with the approved product label during treatment with study drug and for at least 2 weeks after discontinuation of study drug and completion of the Follow-Up Visit. The investigator was responsible for ensuring that participants understand how to properly use these methods of contraception. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal were not acceptable methods of contraception.
• Participants who were willing and able to understand requirements of study participation and provided signed and dated written informed consent prior to screening.
• For participants enrolled in France: participants were eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Exclusion Criteria

Exclusionary Criteria prior to screening or Day 1:

• Within 6 months prior to Screening and after confirmed suppression to <50 c/mL on current ART regimen, any plasma HIV-1 RNA measurement >=50 c/mL.
• Within the 6 to 12 month window prior to screening and after confirmed suppression to <50 c/mL, any plasma HIV-1 RNA measurement >200 c/mL.
• Within the 6 to 12 month window prior to screening and after confirmed suppression to <50 c/mL, 2 or more plasma HIV-1 RNA measurements >=50 c/mL.
• Any drug holiday during the window between initiating first HIV ART and 6 months prior to screening, except for brief periods (less than 1 month) where all ART was stopped due to tolerability and/or safety concerns.
• Any switch to a second line regimen, defined as change of a single drug or multiple drugs simultaneously, due to virologic failure to therapy (defined as a confirmed plasma HIV 1 RNA measurement >=400 c/mL after initial suppression to <50 c/mL while on first line HIV therapy regimen).

Exclusionary medical conditions:

• Women who were pregnant, breastfeeding or planned to become pregnant or breastfeed during the study.
• Any evidence of an active Centers for Disease Control and Prevention Category C disease. Exceptions included cutaneous Kaposi's sarcoma not requiring systemic therapy and historic CD4+ lymphocyte counts of <200 cells per cubic millimeter (cells/mm^3).
• Participants with severe hepatic impairment (Class C) as determined by Child-Pugh Classification.
• Unstable liver disease (as defined by the presence of any of the following: ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• 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), and Hepatitis B surface antibody (HBsAb) as follows: Participants positive for HBsAg were excluded; Participants positive for anti-HBc (negative HBsAg status) and negative for HBsAb were excluded.
• Participants with an anticipated need for any Hepatitis C virus (HCV) therapy during the Early Switch Phase and for interferon-based therapy for HCV throughout the entire study period.
• History or presence of allergy to the study drugs or their components or drugs of their class;
• Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial neoplasia; other localized malignancies require agreement between the investigator and the Study medical monitor for inclusion of the participant prior to randomization;
• Participants who in the investigator's judgment posed a significant suicidality risk. Participant's history of suicidal behavior and/or suicidal ideation should have been considered when evaluating for suicide risk;
• Any pre-existing physical or mental condition which, in the opinion of the Investigator, could have interfered with the participant's ability to comply with the dosing schedule and/or protocol evaluations or which could have compromised the safety of the participants;
• Any condition which, in the opinion of the Investigator, could have interfered with the absorption, distribution, metabolism or excretion of the study drugs or render the participant unable to take oral medication;

Exclusionary Treatments prior to Screening or Day 1:

• Use of medications which were associated with Torsades de Pointes.
• Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.
• Treatment with any of the following agents within 28 days of Screening: radiation therapy; cytotoxic chemotherapeutic agents; any immunomodulators that alter immune responses.
• 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 Day 1 of this study.
• Participants who were participating or anticipated to be selected to participate in any other interventional study, with the exception of the DEXA sub-study 202094, after randomization
• A history of use of any regimen consisting of only single NNRTI therapy (even if only for peri-partum treatment), or only single or dual NRTI therapy prior to starting cART.
• Current or prior history of etravirine (ETR) use.
• Current use of tipranavir/ritonavir or fosamprenavir/ritonavir.
• Participants receiving any prohibited medication and who were unwilling or unable to switch to an alternate medication.

Exclusionary Laboratory Values or Clinical Assessments at Screening:

• Evidence of viral resistance based on the presence of any resistance associated major PI, INI, NRTI, or NNRTI mutation and integrase (IN) resistance associated substitution R263K in any available prior resistance genotype assay results.
• Any verified Grade 4 laboratory abnormality, with the exception of Grade 4 lipid abnormalities. A single repeat test was allowed during the Screening period to verify a result.
• 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.
• Alanine aminotransferase (ALT) >=5 × upper limit of normal (ULN), or ALT >=3 × ULN and bilirubin >=1.5 × ULN (with greater than [>] 35% direct bilirubin).
• Corrected QT interval (QTc [Bazett]) >450 milliseconds or QTc (Bazett) >480 milliseconds for participants with bundle branch block. The QTc was the QT interval corrected for heart rate according to Bazett's formula (QTcB).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Janssen Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

GlaxoSmithKline

INDUSTRY

Sponsor Role: collaborator

ViiV Healthcare

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

ViiV Healthcare

Locations

GSK Investigational Site

Bakersfield, California, United States

GSK Investigational Site

Washington D.C., District of Columbia, United States

GSK Investigational Site

Washington D.C., District of Columbia, United States

GSK Investigational Site

Fort Lauderdale, Florida, United States

GSK Investigational Site

Vero Beach, Florida, United States

GSK Investigational Site

West Palm Beach, Florida, United States

GSK Investigational Site

Macon, Georgia, United States

GSK Investigational Site

Southfield, Michigan, United States

GSK Investigational Site

Omaha, Nebraska, United States

GSK Investigational Site

Chapel Hill, North Carolina, United States

GSK Investigational Site

Austin, Texas, United States

GSK Investigational Site

Buffalo, Texas, United States

GSK Investigational Site

Seattle, Washington, United States

GSK Investigational Site

Buenos Aires, , Argentina

GSK Investigational Site

Buenos Aires, , Argentina

GSK Investigational Site

Rosario, , Argentina

GSK Investigational Site

Darlinghurst, , Australia

GSK Investigational Site

Sydney, , Australia

GSK Investigational Site

Montreal, , Canada

GSK Investigational Site

Montreal, , Canada

GSK Investigational Site

Montreal, , Canada

GSK Investigational Site

Montreal, , Canada

GSK Investigational Site

Regina, , Canada

GSK Investigational Site

Toronto, , Canada

GSK Investigational Site

Vancouver, , Canada

GSK Investigational Site

Bordeaux, , France

GSK Investigational Site

Lyon, , France

GSK Investigational Site

Marseille, , France

GSK Investigational Site

Paris, , France

GSK Investigational Site

Saint-Denis, , France

GSK Investigational Site

Tourcoing, , France

GSK Investigational Site

Berlin, , Germany

GSK Investigational Site

Berlin, , Germany

GSK Investigational Site

Bonn, , Germany

GSK Investigational Site

Cologne, , Germany

GSK Investigational Site

Hanover, , Germany

GSK Investigational Site

Bergamo, , Italy

GSK Investigational Site

Milan, , Italy

GSK Investigational Site

Barnaul, , Russia

GSK Investigational Site

Krasnodar, , Russia

GSK Investigational Site

Saint Petersburg, , Russia

GSK Investigational Site

Saratov, , Russia

GSK Investigational Site

A Coruña, , Spain

GSK Investigational Site

Alicante, , Spain

GSK Investigational Site

Badalona, , Spain

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Cartagena, , Spain

GSK Investigational Site

Madrid, , Spain

GSK Investigational Site

Madrid, , Spain

GSK Investigational Site

Móstoles, , Spain

GSK Investigational Site

Murcia, , Spain

GSK Investigational Site

Oviedo, , Spain

GSK Investigational Site

Santa Cruz La Laguna, , Spain

GSK Investigational Site

Santiago de Compostela, , Spain

GSK Investigational Site

Valencia, , Spain

GSK Investigational Site

Kaohsiung City, , Taiwan

GSK Investigational Site

Kaohsiung City, , Taiwan

GSK Investigational Site

New Taipei City, , Taiwan

GSK Investigational Site

Taichung, , Taiwan

GSK Investigational Site

London, , United Kingdom

Countries

United States; Argentina; Australia; Canada; France; Germany; Italy; Russia; Spain; Taiwan; United Kingdom

References

Llibre JM, Hung CC, Brinson C, et al. Efficacy, safety, and tolerability of dolutegravir plus rilpivirine for the maintenance of virologic suppression in HIV-1-infected adults: the phase III, randomized, open-label, active-controlled, noninferiority SWORD-1 and SWORD-2 studies. Lancet [epublished ahead of print] 6 January 2018.

Reference Type: BACKGROUND

Aboud M, Orkin C, Podzamczer D, Bogner JR, Baker D, Khuong-Josses MA, Parks D, Angelis K, Kahl LP, Blair EA, Adkison K, Underwood M, Matthews JE, Wynne B, Vandermeulen K, Gartland M, Smith K. Efficacy and safety of dolutegravir-rilpivirine for maintenance of virological suppression in adults with HIV-1: 100-week data from the randomised, open-label, phase 3 SWORD-1 and SWORD-2 studies. Lancet HIV. 2019 Sep;6(9):e576-e587. doi: 10.1016/S2352-3018(19)30149-3. Epub 2019 Jul 12.

Reference Type: DERIVED

PMID: 31307948 (View on PubMed)

Llibre JM, Hung CC, Brinson C, Castelli F, Girard PM, Kahl LP, Blair EA, Angelis K, Wynne B, Vandermeulen K, Underwood M, Smith K, Gartland M, Aboud M. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018 Mar 3;391(10123):839-849. doi: 10.1016/S0140-6736(17)33095-7. Epub 2018 Jan 6.

Reference Type: DERIVED

PMID: 29310899 (View on PubMed)

McComsey GA, Lupo S, Parks D, Poggio MC, De Wet J, Kahl LP, Angelis K, Wynne B, Vandermeulen K, Gartland M, Cupo M, Aboud M; 202094 Sub-Study Investigators. Switch from tenofovir disoproxil fumarate combination to dolutegravir with rilpivirine improves parameters of bone health. AIDS. 2018 Feb 20;32(4):477-485. doi: 10.1097/QAD.0000000000001725.

Reference Type: DERIVED

PMID: 29239893 (View on PubMed)

Other Identifiers

2014-005148-16

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

201637

Identifier Type: -

Identifier Source: org_study_id