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

NCT02422797 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: 2016372014-005148-16
• Study Type: interventional
• Target: 518
• Locations: 11 countries
• Sites: 61

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

Keywords

HIV; NNRTI-sparing; two-drug regimen; nucleoside reverse transcriptase inhibitors; protease inhibitor; integrase inhibitor; non-nucleoside reverse transcriptase inhibitor; dolutegravir plus rilpivirine; virologically-suppressed

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 48 Using Snapshot Algorithm

  Percentage of participants with plasma HIV 1 RNA \< 50 c/mL at Week 48 using the Food and Drug Administration (FDA) snapshot algorithm was assessed to demonstrate the non-inferior antiviral activity of switching to DTG+RPV once daily compared to continuation of CAR over 48 weeks in HIV-1 infected antiretroviral therapy (ART)-experienced participants. Virologic success or failure was determined by the last available HIV-1 RNA assessment while the participant was on-treatment within the window of the visit of interest. Plasma samples were collected for quantitative analysis of HIV-1 RNA.

  Week 48

Secondary Outcomes (49)

• Changes From Baseline in Cluster Designation (CD)4+ Lymphocyte Count at Weeks 24 and 48

  At Weeks 24 and 48

• Percentage of Participants With Plasma HIV 1 RNA <50 c/mL at Week 24 Using Snapshot Algorithm

  Week 24

• Number of Participants With Common Non-serious Adverse Event (AE), Any Serious AE (SAE), AE of Maximum Toxicity Grade 1, 2, 3 or 4 and AE Leading to Discontinuation (AELD)

  Up to Week 410 or study discontinuation

• Number of Participants With Maximum Post-baseline Emergent Chemistry Toxicities Over 48 Weeks

  Up to 48 weeks

• Number of Participants With Maximum Post-baseline Emergent Hematology Toxicities Over 48 Weeks

  Up to 48 weeks

Other Outcomes (4)

• Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Weeks 100 and 148 Using the Snapshot Algorithm-DTG+RPV Group Through Early and Late Switch Phase

  Weeks 100 and 148

• Change From Baseline in CD4+ Lymphocyte Count at Weeks 100 and 148-DTG+RPV Group Through Early and Late Switch Phase

  At Weeks 100 and 148

• Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Weeks 100 and 148 Using the Snapshot Algorithm-CAR Group Through Late Switch Phase

  Weeks 100 and 148

Study Arms (2)

Current antiretroviral regimen (CAR)

ACTIVE COMPARATOR

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.

Drug: CAR

DTG + RPV

EXPERIMENTAL

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).

Drug: DTG 50 mg; Drug: RPV 25 mg

Interventions

DTG 50 mg 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.

DTG + RPV

RPV 25 mg 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.

DTG + RPV

CAR DRUG

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

Current antiretroviral regimen (CAR)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).
• 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;
• 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;

Sponsors & Collaborators

• ViiV Healthcare: lead
• Janssen Pharmaceuticals: collaborator
• GlaxoSmithKline: collaborator

Study Sites (61)

GSK Investigational Site

Bakersfield, California, 93301, United States

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GSK Investigational Site

Washington D.C., District of Columbia, 20007, United States

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GSK Investigational Site

Washington D.C., District of Columbia, 20037, United States

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GSK Investigational Site

Fort Lauderdale, Florida, 33316, United States

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GSK Investigational Site

Vero Beach, Florida, 32690, United States

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GSK Investigational Site

West Palm Beach, Florida, 33407, United States

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GSK Investigational Site

Macon, Georgia, 31201, United States

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GSK Investigational Site

Southfield, Michigan, 48075, United States

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GSK Investigational Site

Omaha, Nebraska, 68198, United States

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GSK Investigational Site

Chapel Hill, North Carolina, 27599-7064, United States

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GSK Investigational Site

Austin, Texas, 78705, United States

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GSK Investigational Site

Buffalo, Texas, 14201, United States

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GSK Investigational Site

Seattle, Washington, 98104, United States

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GSK Investigational Site

Buenos Aires, 1141, Argentina

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GSK Investigational Site

Buenos Aires, C1202ABB, Argentina

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GSK Investigational Site

Rosario, 2000, Argentina

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GSK Investigational Site

Darlinghurst, 2010, Australia

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GSK Investigational Site

Sydney, 2010, Australia

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GSK Investigational Site

Montreal, H2L 4E9, Canada

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GSK Investigational Site

Montreal, H2L 4P9, Canada

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GSK Investigational Site

Montreal, H3A 1T1, Canada

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GSK Investigational Site

Montreal, H4A 3J1, Canada

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GSK Investigational Site

Regina, S4P 0W5, Canada

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GSK Investigational Site

Toronto, M4N 3M5, Canada

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GSK Investigational Site

Vancouver, V6Z 2T1, Canada

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GSK Investigational Site

Bordeaux, 33000, France

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GSK Investigational Site

Lyon, 69317, France

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GSK Investigational Site

Marseille, 13003, France

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GSK Investigational Site

Paris, 75970, France

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GSK Investigational Site

Saint-Denis, 93205, France

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GSK Investigational Site

Tourcoing, 59208, France

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GSK Investigational Site

Berlin, 10243, Germany

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GSK Investigational Site

Berlin, 12157, Germany

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GSK Investigational Site

Bonn, 53127, Germany

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GSK Investigational Site

Cologne, 50937, Germany

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GSK Investigational Site

Hanover, 30625, Germany

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GSK Investigational Site

Bergamo, 24127, Italy

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GSK Investigational Site

Milan, 20157, Italy

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GSK Investigational Site

Barnaul, 656010, Russia

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GSK Investigational Site

Krasnodar, 350015, Russia

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GSK Investigational Site

Saint Petersburg, 190103, Russia

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GSK Investigational Site

Saratov, 410009, Russia

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GSK Investigational Site

A Coruña, 15006, Spain

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GSK Investigational Site

Alicante, 03010, Spain

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GSK Investigational Site

Badalona, 08916, Spain

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GSK Investigational Site

Barcelona, 08035, Spain

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GSK Investigational Site

Barcelona, 08097, Spain

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GSK Investigational Site

Cartagena, 30202, Spain

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GSK Investigational Site

Madrid, 28041, Spain

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GSK Investigational Site

Madrid, 28046, Spain

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GSK Investigational Site

Móstoles, 28935, Spain

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GSK Investigational Site

Murcia, 30003, Spain

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GSK Investigational Site

Oviedo, 33011, Spain

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GSK Investigational Site

Santa Cruz La Laguna, 38320, Spain

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GSK Investigational Site

Santiago de Compostela, 15706, Spain

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GSK Investigational Site

Valencia, 46014, Spain

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GSK Investigational Site

Kaohsiung City, 807, Taiwan

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GSK Investigational Site

Kaohsiung City, 824, Taiwan

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GSK Investigational Site

New Taipei City, 220, Taiwan

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GSK Investigational Site

Taichung, 40705, Taiwan

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GSK Investigational Site

London, NW3 2QG, United Kingdom

Location

Related Publications (4)

• 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.

  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.

  PMID: 31307948 DERIVED

• 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.

  PMID: 29310899 DERIVED

• 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.

  PMID: 29239893 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

dolutegravir; Automobiles

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Motor Vehicles; Transportation; Technology, Industry, and Agriculture

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 9, 2015
• First Posted: April 21, 2015
• Study Start: April 21, 2015
• Primary Completion: September 16, 2016
• Study Completion: May 25, 2023
• Last Updated: September 3, 2024
• Results First Posted: October 24, 2017

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

AU (2); FR (6); DE (5); CA (7); TW (4); IT (2); RU (4); ES (14); GB (1); US (13); AR (3)