'COMBINE-2': Real-world Evidence for Effectiveness of Two Drug Regimen, Antiretroviral Therapy With Integrase Inhibitors Plus a Reverse Transcriptase Inhibitor

Dolutegravir (DTG) is a well-tolerated 2nd generation integrase strand transfer inhibitor (INSTI); rilpivirine (RPV) is a well-tolerated non- nucleoside reverse transcriptase inhibitors (NNRTI) and lamivudine (3TC) is a nucleoside reverse transcriptase inhibitors (NRTIs). This study aims to gather the real-world evidence to evaluate effectiveness of the two-drug regimen (2DR). This is a multi-site observational study in subjects who have started and/or who plan to initiate 2DR with an integrase inhibitor plus a reverse transcriptase inhibitor. The study does not require any changes to the routine standard of care that subjects receive. Approximately 500 eligible subjects will be included from potential investigational sites across Europe and data from them will be collected either retrospectively or prospectively.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Dolutegravir (DTG); Drug: Lamivudine (3TC); Drug: Rilpivirine (RPV)

• Study Type: Observational
• Enrollment (Actual): 1

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08041
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

The study population will consist of HIV positive male or female subjects aged 18 years or over and who have started 2DR with an integrase inhibitor plus a reverse transcriptase inhibitor from 2014 onwards as a first-line treatment among naïve subjects, or a switching option for those with HIV RNA suppression on current treatment (stable switches), or a second-line treatment for those with virological failure on prior treatment.

Description

Inclusion Criteria:

• HIV positive male or female subjects aged 18 years or over and who have started 2DR with an integrase inhibitor plus a reverse transcriptase inhibitor from 2014 onwards as a first-line treatment among naïve subjects, or a switching option for those with HIV RNA suppression on current treatment (stable switches), or a second-line treatment for those with virological failure on prior treatment.

Exclusion Criteria:

• No specific exclusion criteria

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Subjects receiving 2DR treatment; Data will be collected from HIV positive male or female adult subjects who have started 2DR with an integrase inhibitor plus a reverse transcriptase inhibitor from 2014.

Drug: Dolutegravir (DTG); DTG is a 2nd generation integrase strand transfer inhibitor. Subjects receiving DTG as a part of 2DR treatment will be included in the study.; Drug: Lamivudine (3TC); 3TC is a nucleoside reverse transcriptase inhibitor. Subjects receiving 3TC as a part of 2DR treatment will be included in the study.; Drug: Rilpivirine (RPV); RPV is a non-nucleoside reverse transcriptase inhibitor. Subjects receiving RPV as part of 2DR treatment will be included in the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of treatment-naïve subjects with human immunodeficiency virus ribonucleic acid (HIV-RNA) levels <50 copies/milliliter (c/mL) at Week 24	Number of treatment-naïve subjects with human immunodeficiency virus ribonucleic acid (HIV-RNA) levels <50 c/mL at Week 24 will be assessed.	Week 24
Number of treatment-naïve subjects with human immunodeficiency virus ribonucleic acid (HIV-RNA) levels <50 c/mL at Week 48	Number of treatment-naïve subjects with human immunodeficiency virus ribonucleic acid (HIV-RNA) levels <50 c/mL at Week 48 will be assessed.	Week 48
Number of treatment-naïve subjects with human immunodeficiency virus ribonucleic acid (HIV-RNA) levels <50 c/mL at Week 96	Number of treatment-naïve subjects with human immunodeficiency virus ribonucleic acid (HIV-RNA) levels <50 c/mL at Week 96 will be assessed.	Week 96
Number of subjects who lose virologic control within the first 24 weeks after switching to a 2-DR	Virologic control is defined as 2 consecutive HIV RNA levels >50 c/mL or HIV RNA >50c/mL followed by study treatment discontinuation or missing value. Number of subjects who lose virologic control will be assessed using a Kaplan-Meier Method.	Week 24
Number of subjects who lose virologic control within the first 48 weeks after switching to a 2-DR	Virologic control is defined as 2 consecutive HIV RNA levels >50 c/mL or HIV RNA >50c/mL followed by study treatment discontinuation or missing value. Number of subjects who lose virologic control will be assessed using a Kaplan-Meier Method.	Week 48
Number of subjects who lose virologic control within the first 96 weeks after switching to a 2-DR	Virologic control is defined as 2 consecutive HIV RNA levels >50 c/mL or HIV RNA >50c/mL followed by study treatment discontinuation or missing value. Number of subjects who lose virologic control will be assessed using a Kaplan-Meier Method.	Week 96
Number of treatment-experienced subjects with HIV-RNA levels <50 c/mL at Week 24	Number of treatment-experienced subjects with HIV-RNA levels <50 c/mL at Week 24 will be assessed.	Week 24
Number of treatment-experienced subjects with HIV-RNA levels <50 c/mL at Week 48	Number of treatment-experienced subjects with HIV-RNA levels <50 c/mL at Week 48 will be assessed.	Week 48
Number of treatment-experienced subjects with HIV-RNA levels <50 c/mL at Week 96	Number of treatment-experienced subjects with HIV-RNA levels <50 c/mL at Week 96 will be assessed.	Week 96

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of subjects with HIV RNA >200 c/mL after 24 weeks	Subjects will be assessed for HIV RNA >200 c/mL after Week 24.	Week 24
Number of subjects with HIV RNA >200 c/mL after 48 weeks	Subjects will be assessed for HIV RNA >200 c/mL after Week 48.	Week 48
Number of subjects with HIV RNA >200 c/mL after 96 weeks	Subjects will be assessed for HIV RNA >200 c/mL after Week 96.	Week 96
Number of subjects with low level viremia	Low level viremia is defined as virologic load >50 and <200 c/mL. Number of subjects with low level viremia will be assessed at indicated time points.	Up to Week 96
Time to virologic suppression	Virologic suppression is defined as viral load < 50 c/mL at the end of 6months/12months/18 months or as pre-specified.	Up to Week 96
Time to virologic failure	Time to virologic failure in the stable switch Population will be assessed. Subjects with virologic rebound or virologic non-response will be considered as failure.	Up to Week 96
Number of subjects with resistance profile in case of virologic failure	Subjects with virologic rebound or virologic non-response will be considered as failure. Results of all HIV resistance tests performed before and during antiretroviral treatment will be evaluated to analyze resistance profile in case of virologic failure.	Up to Week 96
Number of subjects with stable switch while virologically suppressed	A switching option for those with HIV RNA suppression on current treatment will be called as 'Stable switch'. Number of subjects with stable switch while virologically suppressed will be analyzed.	Up to Week 96
Number of subjects with Switch after Failure	Subjects with virologic rebound or virologic non-response will be considered as failure. Number of subjects with Switch after Failure will be analyzed.	Up to Week 96
Number of subjects switching for safety reasons	Number of subjects switching for safety reasons including tolerability, toxicity and other reasons will be evaluated.	Up to Week 96
Number of subjects with adverse events (AEs) and serious AEs (SAEs)	An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.	Up to Week 96
cluster of differentiation (CD)4+ and CD8+ T cell counts	All available CD4 and CD8 results since first starting 2DR treatment will be collected to analyze CD4+ and CD8+ T cell counts.	Up to Week 96
CD4/CD8 ratio at each time point	All available CD4 and CD8 results since first starting 2DR treatment will be collected to analyze CD4/CD8 ratio at each time point	Up to Week 96
Number of factors associated with plasma HIV-RNA > 50 c/mL	If number of failure allows, analysis to assess factors associated with success at week 96 in naïve and treatment experienced populations and with virologic failure in population switching with HIV RNA suppression will be analyzed.	Up to Week 96

Collaborators and Investigators

• Sponsor: ViiV Healthcare
• Investigators: Study Director: GSK Clinical Trials, ViiV Healthcare

Study record dates

Study Major Dates

• Study Start (Actual): November 18, 2019
• Primary Completion (Actual): January 31, 2023
• Study Completion (Actual): January 31, 2023

Study Registration Dates

• First Submitted: July 19, 2018
• First Submitted That Met QC Criteria: July 12, 2019
• First Posted (Actual): July 15, 2019

Study Record Updates

• Last Update Posted (Estimated): November 13, 2023
• Last Update Submitted That Met QC Criteria: November 10, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: HIV; Lamivudine; Dolutegravir; 2DR; COMBINE-2
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Urogenital Diseases; Genital Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Lamivudine; Dolutegravir; Rilpivirine
• Other Study ID Numbers: 207859

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• IPD Sharing Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No