ANZCTR - Registration

Registration number

NCT02429791

Ethics application status

Date submitted

9/04/2015

Date registered

29/04/2015

Date last updated

4/03/2020

Titles & IDs

Public title

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

Scientific title

A Phase III, Randomized, Multicenter, Parallel-group, Non-inferiority Study Evaluating the Efficacy, Safety, and Tolerability of Switching to Dolutegravir Plus Rilpivirine From Current INI-, NNRTI-, or PI-based Antiretroviral Regimen in HIV-1-Infected Adults Who Are Virologically Suppressed

Secondary ID [1]

2014-005147-40

Secondary ID [2]

201636

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

HIV Infections

Condition category

Condition code

Infection

Acquired immune deficiency syndrome (AIDS / HIV)

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Treatment: Drugs - DTG 50 mg
Treatment: Drugs - RPV 25 mg
Treatment: Drugs - CAR

Active Comparator: Participants receiving CAR - Participants will receive CAR from Day 1 to Week 52 (Early Switch Phase), and eligible participants will switch to DTG 50 milligrams (mg) + RPV 25 mg once daily from Week 52 to 148 (Late Switch Phase).

Experimental: Participants receiving DTG 50 mg + RPV 25 mg - Participants will receive DTG 50 mg + RPV 25 mg once daily from Day 1 through Week 148 (Early and Late Switch Phase).

Treatment: Drugs: DTG 50 mg
Participants will take one oral tablet of 50 mg DTG daily administered concomitantly with RPV. Each DTG tablet will contain 52.62 mg dolutegravir sodium salt, which is equivalent to 50 mg dolutegravir free acid.

Treatment: Drugs: RPV 25 mg
Participants will take one oral tablet of 25 mg RPV daily administered concomitantly with DTG along with a meal. Each RPV tablet will contain 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of RPV.

Treatment: Drugs: CAR
CAR will include following combinations: 2 NRTIs + 1 INI, 2 NRTIs + 1 NNRTI, or 2 NRTIs + 1 PI

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Control group

Outcomes

Primary outcome [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. The Intent-to-Treat Exposed (ITT-E) population consisted of all randomly assigned participants who received at least one dose of study drug.

Timepoint [1]

Week 48

Secondary outcome [1]

Changes From Baseline in Cluster Designation (CD)4+ Lymphocyte Count at Weeks 24 and 48 - Blood samples were collected and CD4+ cell count assessment by flow cytometry was carried out to evaluate the immunological activity of DTG + RPV once daily compared to continuation of CAR. Value obtained at Day 1 was considered as Baseline value. Change from Baseline was calculated as value at indicated time point minus Baseline value.

Timepoint [1]

Baseline (Day 1), Weeks 24 and 48

Secondary outcome [2]

Percentage of Participants With Plasma HIV 1 RNA <50 c/mL at Week 24 Using Snapshot Algorithm - Percentage of participants with plasma HIV 1 RNA < 50 c/mL at Week 24 using the FDA snapshot algorithm was assessed to evaluate the antiviral activity of DTG + RPV once daily compared to continuation of CAR. 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.

Timepoint [2]

Week 24

Secondary outcome [3]

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) - An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to 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, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize participant or may require medical or surgical intervention were categorized as SAE. AEs were graded as per Division of Acquired Immunodeficiency Syndrome (DAIDS) grading. Grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=potentially life-threatening. Common AEs were those with >5% incidence for either treatment. This summary presents results as reported after all participants completed the Early Switch Phase.

Timepoint [3]

Up to Week 52

Secondary outcome [4]

Number of Participants With Maximum Post-Baseline Emergent Chemistry Toxicities Over 48 Weeks - Blood samples were collected to evaluate alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), total bilirubin, chloride, creatinine, glucose, potassium, phosphate, sodium, blood urea nitrogen (BUN), total carbon dioxide, lipase, creatine phosphokinase and creatinine clearance. Value obtained at Day 1 was considered as Baseline value. Number of participants who experienced maximum grade toxicity post-Baseline in clinical chemistry over 48 weeks was summarized. Clinical chemistry toxicities were graded using DAIDS grading table for grading severity of adult and pediatric adverse events. Grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=potentially life-threatening. For all laboratory parameters, one assessment out of range was sufficient to be considered a chemistry toxicity.

Timepoint [4]

Up to 48 weeks

Secondary outcome [5]

Number of Participants With Maximum Post-Baseline Emergent Hematology Toxicities Over 48 Weeks - Blood samples were collected to evaluate hemoglobin, hematocrit, basophils, eosinophils, lymphocytes, monocytes, neutrophils, mean corpuscular volume (MCV), red blood cell (RBC) count, white blood cell (WBC) count and platelet count. Value obtained at Day 1 was considered as Baseline value. Number of participants who experienced maximum grade toxicity post-Baseline in hematology over 48 weeks was summarized. Hematology toxicities were graded using DAIDS grading table for grading severity of adult and pediatric adverse events. Grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=potentially life-threatening. For all laboratory parameters, one assessment out of range was sufficient to be considered a hematology toxicity.

Timepoint [5]

Up to 48 weeks

Secondary outcome [6]

Mean Change From Baseline in High-sensitivity C-reactive Protein (Hs-CRP) at Week 48 - Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess hs-CRP. Change from Baseline was calculated as value at indicated time point minus Baseline value.

Timepoint [6]

Baseline (Day 1) and Week 48

Secondary outcome [7]

Mean Change From Baseline in Cystatin C at Week 48 - Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess cystatin C. Change from Baseline was calculated as value at indicated time point minus Baseline value.

Timepoint [7]

Baseline (Day 1) and Week 48

Secondary outcome [8]

Mean Change From Baseline in D-Dimer at Week 48 - Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess D-Dimer. Change from Baseline was calculated as value at indicated time point minus Baseline value.

Timepoint [8]

Baseline (Day 1) and Week 48

Secondary outcome [9]

Mean Change From Baseline in Fatty Acid Binding Protein 2 (FABP) and Soluble CD14 at Week 48 - Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess FABP and soluble CD14. Change from Baseline was calculated as value at indicated time point minus Baseline value.

Timepoint [9]

Baseline (Day 1) and Week 48

Secondary outcome [10]

Mean Change From Baseline in Soluble CD163 and Oxidized Low Density Lipoprotein (LDL) at Week 48 - Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess soluble CD163 and oxidized LDL. Change from Baseline was calculated as value at indicated time point minus Baseline value.

Timepoint [10]

Baseline (Day 1) and Week 48

Secondary outcome [11]

Mean Change From Baseline in Retinol Binding Protein (RBP), Serum Creatinine and Glucose at Week 48 - Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess RBP, serum creatinine and glucose. Change from Baseline was calculated as value at indicated time point minus Baseline value.

Timepoint [11]

Baseline (Day 1) and Week 48

Secondary outcome [12]

Mean Change From Baseline in Urine Phosphate at Week 48 - Urine biomarker samples were collected at Baseline (Day 1) and Week 48 to assess urine phosphate. Change from Baseline was calculated as value at indicated time point minus Baseline value.

Timepoint [12]

Baseline (Day 1) and Week 48

Secondary outcome [13]

Mean Change From Baseline in Beta-2-microglobulin (B2M) (Blood and Urine), Urine RBP and 25 Hydroxy-vitamin D (Blood) at Week 48 - Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess B2M and 25 hydroxy-vitamin D. Urine samples were collected to assess B2M and RBP. Change from Baseline was calculated as value at indicated time point minus Baseline value. For 25 hydroxy-vitamin D, analysis of changes from Baseline was performed on log-transformed data. Results were transformed back via exponential transformation such that treatment comparisons are assessed via odds ratios.

Timepoint [13]

Baseline (Day 1) and Week 48

Secondary outcome [14]

Mean Change From Baseline in Urine Albumin/Creatinine Ratio and Urine Protein/Creatinine Ratio at Week 48 - Urine biomarker samples were collected at Baseline (Day 1) and Week 48 to assess urine albumin/creatinine ratio and urine protein/creatinine ratio. Change from Baseline was calculated as value at indicated time point minus Baseline value.

Timepoint [14]

Baseline (Day 1) and Week 48

Secondary outcome [15]

Mean Change From Baseline in Bone-specific Alkaline Phosphatase, Procollagen 1 N-terminal Propeptide, Osteocalcin, Type I Collagen C-Telopeptides and Soluble Vascular Cell Adhesion Molecule (sVCAM) at Week 48 - Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess bone-specific alkaline phosphatase, procollagen 1 N-terminal propeptide, osteocalcin, Type I Collagen C-Telopeptides and sVCAM. Change from Baseline was calculated as value at indicated time point minus Baseline value. For bone-specific alkaline phosphatase, procollagen 1-N-propeptide, osteocalcin and type 1 collagen C-telopeptide, analyses of changes from baseline were performed on log-transformed data. Results were transformed back via exponential transformation such that treatment comparisons are assessed via odds ratios.

Timepoint [15]

Baseline (Day 1) and Week 48

Secondary outcome [16]

Mean Change From Baseline in Interleukin 6 (IL-6) at Week 48 - Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess IL-6. Change from Baseline was calculated as value at indicated time point minus Baseline value.

Timepoint [16]

Baseline (Day 1) and Week 48

Secondary outcome [17]

Mean Change From Baseline in Insulin Resistance Based on Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) at Week 48 - Blood biomarker samples were collected at Baseline (Day 1) and Week 48 to assess insulin resistance. Change from Baseline was calculated as value at indicated time point minus Baseline value. The homeostatic model assessment (HOMA) of insulin resistance (HOMA-IR) index, the product of basal glucose and insulin levels divided by 22.5 (1,2), is regarded as a simple, inexpensive, and reliable surrogate measure of insulin resistance.

Timepoint [17]

Baseline (Day 1) and Week 48

Secondary outcome [18]

Mean Change From Baseline in Fasting Lipids at Weeks 24 and 48 - Blood samples were collected at Baseline (Day 1), Week 24 and Week 48 to assess fasting lipids which included total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides. Change from Baseline was calculated as value at indicated time point minus Baseline value.

Timepoint [18]

Baseline (Day 1), Week 24 and Week 48

Secondary outcome [19]

Number of Participants With Genotypic Resistance- Early Switch Phase - Plasma samples were collected for drug resistance testing. Confirmed Virologic Withdrawal (CVW) resistance Population comprised of all participants in the ITT-E Population who met confirmed CVW through the end of visit window (Week 48, Week 100 or Week 148) and had available on-treatment genotypic resistance data at the time CVW criterion was met. Genotypic Resistance data for the following drugs (Rilpivirine [RPV], Dolutegravir [DTG], Emtricitabine [FTC], Tenofovir [TDF], Darunavir/r [DRV/r]) in participants Meeting CVW Criteria has been presented.

Timepoint [19]

Up to Week 48

Secondary outcome [20]

Number of Participants With Genotypic Resistance-DTG+RPV Early Switch Group Through Early and Late Switch Phase - Plasma samples were collected for drug resistance testing. Genotypic Resistance data for the following drugs (DTG, Elvitegravir [EVG], Raltegravir [RAL], Delavirdine [DLV], Efavirenz [EFV], Etravirine [ETR], Nevirapine [NVP], RPV, Lamivudine [3TC], Abacavir [ABC], FTC, TDF, Zidovudine [ZDV], Stavudine [d4T], Didanosine [ddI], Atazanavir/r [ATV/r], DRV/r, Fosamprenavir/r [FPV/r], Indinavir/r [IDV/r], Lopinavir/r [LPV/r], Nelfinavir [NFV], Ritonavir [RTV], Saquinavir/r [SQV/r], Tipranavir/r [TPV/r]) in participants Meeting CVW Criteria has been presented.

Timepoint [20]

Up to Week 148

Secondary outcome [21]

Number of Participants With Genotypic Resistance-CAR Late Switch Group Through Late Switch Phase - Plasma samples were collected for drug resistance testing. Late Switch (LS) CVW resistance Population comprised of all participants in the LS-ITT-E Population who met CVW through the end of visit window (Week 48, Week 100 or Week 148) and had available on-treatment genotypic resistance data at the time CVW criterion was met. Genotypic Resistance data for the following drugs (DTG, EVG, RAL, DLV, EFV, ETR, NVP, RPV, 3TC, ABC, FTC, TDF, ZDV, d4T, ddI, ATV/r, DRV/r, FPV/r, IDV/r, LPV/r, NFV, RTV, SQV/r, TPV/r) in participants Meeting CVW Criteria has been presented.

Timepoint [21]

Post-LS Baseline (Week 52) up to Week 148

Secondary outcome [22]

Number of Participants With Phenotypic Resistance-Early Switch Phase - Plasma samples were collected for drug resistance testing. Phenotypic Resistance data for the following drugs (DTG, RAL, EVG, RPV, ETR, 3TC, ABC, FTC, TDF, d4T, ddI, ATV/r, DRV/r, FPV/r, IDV/r, LPV/r, SQV/r, TPV/r) in participants Meeting CVW Criteria has been presented.

Timepoint [22]

Up to Week 48

Secondary outcome [23]

Number of Participants With Phenotypic Resistance-DTG+RPV Early Switch Group Through Early and Late Switch Phase - Plasma samples were collected for drug resistance testing. Phenotypic Resistance data for the following drugs (DTG, EVG, RAL, DLV, EFV, ETR, NVP, RPV, 3TC, ABC, FTC, TDF, ZDV, d4T, ddI, ATV/r, DRV/r, FPV/r, IDV/r, LPV/r, NFV, RTV, SQV/r, TPV/r) in participants Meeting CVW Criteria has been presented.

Timepoint [23]

Up to Week 148

Secondary outcome [24]

Number of Participants With Phenotypic Resistance-CAR Late Switch Group Through Late Switch Phase - Plasma samples were collected for drug resistance testing. Phenotypic Resistance data for the following drugs (DLV, EFV, ETR, NVP, RPV, 3TC, ABC, FTC, TDF, ZDV, d4T, ddI, ATV/r, DRV/r, FPV/r, IDV/r, LPV/r, NFV, RTV, SQV/r, TPV/r) in participants Meeting CVW Criteria has been presented.

Timepoint [24]

Post-LS Baseline (Week 52) up to Week 148

Secondary outcome [25]

Pre-dose Concentrations of DTG and RPV at Weeks 4, 24, 48, 56, 76 and 100 in Participants Switching to DTG + RPV-DTG+RPV Early Switch Group Through Early and Late Switch Phase - Two separate blood samples for DTG and RPV were collected pre-dose at Weeks 4, 24, 48, 56, 76, and 100. Pre-dose concentrations of DTG and RPV at Weeks 4, 24, 48, 56, 76 and 100 is summarized for the participants switching to DTG + RPV in the early + late switch phase. Pharmacokinetic (PK) Parameter Population consisted of all participants who received DTG +RPV and provided at least one evaluable estimate of predose concentration (C0).

Timepoint [25]

Pre-dose at Week 4, 24, 48, 56, 76 and 100

Secondary outcome [26]

Pre-dose Concentrations of DTG and RPV at Weeks 56, 76 and 100 in Participants Switching to DTG+RPV-CAR Late Switch Group Through Late Switch Phase - Two separate blood samples for DTG and RPV were collected pre-dose at Weeks 56, 76, and 100. Pre-dose concentrations of DTG and RPV at Weeks 56, 76 and 100 is summarized for the participants switching to DTG + RPV in the late switch phase. LS PK Parameter Population comprised of all participants who were randomized to CAR and received DTG + RPV in the Late Switch Phase and provided at least one evaluable estimate of Pre-dose concentration.

Timepoint [26]

Pre-dose at Weeks 56, 76 and 100

Secondary outcome [27]

Pre-dose Concentrations of DTG and RPV at Weeks 2, 4 and 8 in the First 20 Participants Who Switch From Efavirenz (EFV) or Nevirapine (NVP) to DTG + RPV - Two blood samples were collected pre-dose for DTG and RPV at Weeks 2,4 and 8 only for the first 20 participants who switch from EFV or NVP to DTG + RPV. One blood sample was collected pre-dose for EFV or NVP at Week 2 for the first 20 participants who switch from EFV or NVP to DTG + RPV. PK Parameter NNRTI Subset Extra Sampling Population consisted of the first approximately 20 participants in the PK Parameter NNRTI Subset population who have extra PK samples at weeks 2,4 and 8.

Timepoint [27]

Pre-dose at Week 2, 4 and 8

Secondary outcome [28]

Percentage of Participants With Plasma HIV 1 RNA <50 c/mL at Week 48 Using Snapshot Algorithm by Baseline Third Agent Treatment Class - Percentage of participants with plasma HIV 1 RNA < 50 c/mL at Week 48 using the FDA snapshot algorithm was assessed by Baseline third agent class to assess the impact of Baseline third agent class (INI, NNRTI, or PI) on efficacy of DTG +RPV compared to continuation of CAR. Plasma samples were collected for quantitative analysis of HIV-1 RNA. The analysis was done using Cochran-Mantel Haenszel test stratified by current antiretroviral third-agent class and age group.

Timepoint [28]

Week 48

Secondary outcome [29]

Changes From Baseline in Cluster Designation (CD)4+ Lymphocyte Count at Week 48 by Baseline Third Agent Treatment Class - Blood samples were collected for CD4 cell count assessment by flow cytometry was carried out to assess the impact of Baseline third agent class (INI, NNRTI, or PI) on efficacy, safety and tolerability of DTG +RPV compared to continuation of CAR. Value at Day 1 was considered as Baseline. Change from Baseline was calculated as value at indicated time point minus Baseline value.

Timepoint [29]

Baseline (Day 1) and Week 48

Secondary outcome [30]

Number of Participants With Any AE, AELD or AE With Grade 1, 2, 3 or 4 Toxicity Over 48 Weeks by Baseline Third Agent Treatment Class - An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Number of participants with any AE, AELD or AE with maximum grade toxicity experienced by any one participant over 48 weeks by Baseline third agent class (INI, NNRTI, or PI) was summarized. AEs were graded as per DAIDS grading. Grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=potentially life-threatening.

Timepoint [30]

Up to 48 weeks

Secondary outcome [31]

Number of Participants With Maximum Post-baseline Emergent Chemistry Toxicities Over 48 Weeks by Baseline Third Agent Treatment Class - Blood samples were collected to evaluate ALT, albumin, ALP, AST, total bilirubin, chloride, creatinine, glucose, potassium, phosphate, sodium, BUN, total carbon dioxide, lipase, creatine phosphokinase and creatinine clearance. Value at Day 1 was considered as Baseline. Number of participants who experienced maximum toxicity grade post-Baseline in chemistry parameters over 48 weeks by Baseline third agent treatment class (INI, NNRTI, PI) was summarized. Clinical chemistry toxicities were graded using DAIDS grading table for grading severity of adult and pediatric adverse events. Grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=potentially life-threatening.

Timepoint [31]

Up to 48 weeks

Secondary outcome [32]

Number of Participants With Maximum Post-Baseline Emergent Hematology Toxicities Over 48 Weeks by Baseline Third Agent Treatment Class - Blood samples were collected to evaluate hemoglobin, hematocrit, basophils, eosinophils, lymphocytes, monocytes, neutrophils, MCV, RBC count, WBC count and platelet count. Value at Day 1 was considered as Baseline. Number of participants who experienced maximum toxicity grade post-Baseline in hematology parameters over 48 weeks by Baseline third agent treatment class (INSTI, NNRTI, PI) was summarized. Hematology toxicities were graded using DAIDS grading table for grading severity of adult and pediatric adverse events. Grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=potentially life-threatening.

Timepoint [32]

Up to 48 weeks

Secondary outcome [33]

Number of Participants With Observed Genotypic Resistance for Participants Meeting Virologic Withdrawal Criteria by Baseline Third Agent Treatment Class - For all participants who meet virologic withdrawal criteria, plasma samples with HIV-1 RNA level >=200 c/mL were to be analyzed in an attempt to obtain genotype data on as many samples as possible. Samples for drug resistance testing (genotypic) were to be collected at Day 1. Number of participants with genotypic resistance to CAR and to DTG or RPV for those meeting virologic withdrawal criteria in subgroups stratified based on Baseline third agent treatment class (INSTI, NNRTI, PI) were to be summarized. This outcome has not been analyzed as the number of participants was low (1 CVW per arm) and summaries by Baseline third agent were not provided. Therefore, data are not available for this outcome measure due to the insufficient number of participants with events.

Timepoint [33]

Up to Week 48

Secondary outcome [34]

Number of Participants With Observed Phenotypic Resistance for Participants Meeting Virologic Withdrawal Criteria by Baseline Third Agent Treatment Class - For all participants who meet virologic withdrawal criteria, plasma samples with HIV-1 RNA level >=200 c/mL were to be analyzed in an attempt to obtain phenotype data on as many samples as possible. Samples for drug resistance testing (phenotypic) were to be collected at Day 1. Number of participants with phenotypic resistance to CAR and to DTG or RPV for those meeting virologic withdrawal criteria in subgroups stratified based on Baseline third agent treatment class (INSTI, NNRTI, PI) were to be summarized. This outcome was not analyzed as the number of participants was low (1 CVW per arm) and summaries by Baseline third agent were not provided. Therefore, data are not available for this outcome measure due to the insufficient number of participants with events.

Timepoint [34]

Up to Week 48

Secondary outcome [35]

Change From Baseline in Fasting Lipids at Weeks 24 and 48 by Baseline Third Agent Treatment Class - Blood samples were collected at Baseline (Day 1), Weeks 24 and 48 to assess fasting lipids which included total cholesterol (CHO), LDL cholesterol, HDL cholesterol and triglycerides. Change from Baseline was calculated as value at indicated time point minus Baseline value.

Timepoint [35]

Baseline (Day 1), Week 24 and Week 48

Secondary outcome [36]

Change From Baseline in Pre-specified Treatment Symptoms Using the Symptom Distress Module at Weeks 4, 24 and 48-Early Switch Phase - Symptom Distress Module, also called the HIV Symptom Index or Symptoms Impact Questionnaire, is a 20-item self-reported measure that addresses presence and perceived distress linked to symptoms commonly associated with HIV or its treatment. Symptom count is based on which of the 20 symptoms were present in participant. Symptom count is the sum of number of symptoms present and ranges from 0 (none) to 20 (all). Symptom bother score is based on score for each symptom present ranging from 1 (it doesn't bother me) to 4 (it bothers me a lot). Symptom bother score is unweighted sum of the bother item scores for each symptom. Symptom bother score ranges from 0 (minimum bother score) to 80 (maximum bother score). Last observation carried forward (LOCF) was used as primary method of analysis. Change from Baseline was calculated as value at indicated time point minus Baseline value. Day 1 was considered as Baseline value.

Timepoint [36]

Baseline (Day 1), Week 4, Week 24 and Week 48

Secondary outcome [37]

Change From Baseline in Pre-specified Treatment Symptoms Using the Symptom Distress Module at Weeks 56, 76, 100 and 148-DTG+RPV Early Switch Group Through Early and Late Switch Phase - Symptom Distress Module, also called the HIV Symptom Index or Symptoms Impact Questionnaire, is a 20-item self-reported measure that addresses presence and perceived distress linked to symptoms commonly associated with HIV or its treatment. Symptom count is based on which of the 20 symptoms were present in participant. Symptom count is the sum of number of symptoms present and ranges from 0 (none) to 20 (all). Symptom bother score is based on score for each symptom present ranging from 1 (it doesn't bother me) to 4 (it bothers me a lot). Symptom bother score is unweighted sum of the bother item scores for each symptom. Symptom bother score ranges from 0 (minimum bother score) to 80 (maximum bother score). LOCF was used as primary method of analysis. Change from Baseline was calculated as value at indicated time point minus Baseline value. Day 1 was considered as Baseline value.

Timepoint [37]

Baseline (Day 1), Week 56, Week 76, Week 100 and Week 148

Secondary outcome [38]

Change From LS Baseline in Pre-specified Treatment Symptoms Using the Symptom Distress Module at Weeks 56, 76, 100 and 148-CAR Late Switch Group Through Late Switch Phase - Symptom Distress Module, also called the HIV Symptom Index or Symptoms Impact Questionnaire, is a 20-item self-reported measure that addresses presence and perceived distress linked to symptoms commonly associated with HIV or its treatment. Symptom count is based on which of the 20 symptoms were present in participant. Symptom count is the sum of number of symptoms present and ranges from 0 (none) to 20 (all). Symptom bother score is based on score for each symptom present ranging from 1 (it doesn't bother me) to 4 (it bothers me a lot). Symptom bother score is unweighted sum of the bother item scores for each symptom. Symptom bother score ranges from 0 (minimum bother score) to 80 (maximum bother score). LOCF was used as primary method of analysis. Change from LS Baseline was calculated as value at indicated time point minus LS Baseline value. Value at Week 48 was considered as LS Baseline value.

Timepoint [38]

LS Baseline (Week 48), Week 56, Week 76, Week 100 and Week 148

Secondary outcome [39]

Change From Baseline Treatment Satisfaction Using the HIV Treatment Satisfaction Questionnaire (HIV TSQ) at Weeks 4, 24 and 48-Early Switch Phase - HIV TSQ is a 10-item self-reported scale that measures overall satisfaction with treatment and by specific domains e.g., convenience, flexibility. Each item is scored 0 (very dissatisfied, inconvenient) to 6 (very satisfied, convenient). The items are summed up to produce a treatment satisfaction total score (0 to 60) and 2 subscale scores: general satisfaction/clinical and lifestyle/ease subscales (0 to 30). Higher scores indicated greater treatment satisfaction as compared to the past few weeks. The HIV TSQ was administered as a paper questionnaire. Total score, lifestyle/ease score and General satisfaction/CS have been summarized. LOCF was used as primary method of analysis. Value obtained at Day 1 was considered as Baseline value. Change from Baseline was calculated as value at indicated time point minus Baseline value.

Timepoint [39]

Baseline (Day 1), Week 4, Week 24 and Week 48

Secondary outcome [40]

Change From Baseline Treatment Satisfaction Using HIV TSQ at Weeks 56, 76, 100 and 148 - DTG+RPV Early Switch Group Through Early and Late Switch Phase - HIV TSQ is a 10-item self-reported scale that measures overall satisfaction with treatment and by specific domains e.g., convenience, flexibility. Each item is scored 0 (very dissatisfied, inconvenient) to 6 (very satisfied, convenient). The items are summed up to produce a treatment satisfaction total score (0 to 60) and 2 subscale scores: general satisfaction/clinical and lifestyle/ease subscales (0 to 30). Higher scores indicated greater treatment satisfaction as compared to the past few weeks. The HIV TSQ was administered as a paper questionnaire. Total score, lifestyle/ease score and General satisfaction/CS have been summarized. LOCF was used as primary method of analysis. Value obtained at Day 1 was considered as Baseline value. Change from Baseline was calculated as value at indicated time point minus Baseline value.

Timepoint [40]

Baseline (Day 1), Week 56, Week 76, Week 100 and Week 148

Secondary outcome [41]

Change From LS Baseline Treatment Satisfaction Using HIV TSQ at Weeks 56, 76, 100 and 148-CAR Late Switch Group Through Late Switch Phase - HIV TSQ is a 10-item self-reported scale that measures overall satisfaction with treatment and by specific domains e.g., convenience, flexibility. Each item is scored 0 (very dissatisfied, inconvenient) to 6 (very satisfied, convenient). The items are summed up to produce a treatment satisfaction total score (0 to 60) and 2 subscale scores: general satisfaction/clinical and lifestyle/ease subscales (0 to 30). Higher scores indicated greater treatment satisfaction as compared to the past few weeks. The HIV TSQ was administered as a paper questionnaire. Total score, lifestyle/ease score and General satisfaction/CS have been summarized. LOCF was used as primary method of analysis. Value obtained at Week 48 was considered as LS Baseline value. Change from LS Baseline was calculated as value at indicated time point minus LS Baseline value.

Timepoint [41]

LS Baseline (Week 48), Week 56, Week 76, Week 100 and Week 148

Eligibility

Key inclusion criteria

- Participants must be able to understand and comply with protocol requirements,
instructions, and restrictions.

- Participants must be likely to complete the study as planned.

- Participants must be 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 >=18 years of age.

- Must be 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 be eligible to enter and participate in the study if she is 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 can 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 includes: 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 be 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 is 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 are not acceptable methods of
contraception. Note: these contraceptive requirements do not apply to females of
reproductive potential with same sex partners only, when this is their preferred and
usual lifestyle. All participants participating in the study should be counseled 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.

- Participants who are willing and able to understand requirements of study
participation and provide signed and dated written informed consent prior to
screening.

- For participants enrolled in France: participants will be eligible for inclusion in
this study only if either affiliated to or a beneficiary of a social security
category.

Minimum age

18 Years

Maximum age

No limit

Gender

Both males and females

Can healthy volunteers participate?

No

Key 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 are pregnant, breastfeeding or plan to become pregnant or breastfeed during
the study.

- Any evidence of an active Centers for Disease Control and Prevention Category C
disease. Exceptions include 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 are excluded; Participants positive for anti-HBc (negative HBsAg status) and
negative for HBsAb are excluded. Note: Participant positive for anti-HBc (negative
HBsAg status) and positive for HBsAb are immune to HBV and are not 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 pose a significant suicidality risk.
Participant's history of suicidal behavior and/or suicidal ideation should be
considered when evaluating for suicide risk;

- 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
participants;

- Any condition which, in the opinion of the Investigator, may interfere 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 are 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 are currently participating or are anticipated to be selected to
participate in any other interventional study, with the exception of the DEXA
sub-study 202094, after randomization (NOTE: Participants who are already enrolled
into another interventional study at time of screening may be eligible after
consultation with the GlaxoSmithKline study team prior to randomization.
Considerations include participant's ability to attend all visits on schedule, and
possible drug and study procedure compatibility).

- 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 are unwilling or unable to
switch to an alternate medication. Note: Any prohibited medications that decrease DTG
or RPV concentrations should be discontinued for a minimum of four weeks or a minimum
of three half-lives (whichever is longer) prior to the first dose and any other
prohibited medications should be discontinued for a minimum of two weeks or a minimum
of three half-lives (whichever is longer) prior to the first dose.

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. Note: Prior genotypic
resistance testing is not required but if available it must be provided to
GlaxoSmithKline, after screening and before randomization, to provide direct evidence
of no pre-existing exclusionary resistance mutations. You must wait for the study
virologists to confirm the lack of exclusionary resistance mutations, which will be
provided before the screening window closes.

- Any verified Grade 4 laboratory abnormality, with the exception of Grade 4 lipid
abnormalities. A single repeat test is 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 >35% direct bilirubin).

- Corrected QT interval (QTc [Bazett]) >450 milliseconds or QTc (Bazett) >480
milliseconds for participants with bundle branch block. The QTc is the QT interval
corrected for heart rate according to Bazett's formula (QTcB).

Study design

Statistical methods / analysis

Recruitment

Recruitment status

Active, not recruiting

Date of first participant enrolment

Anticipated

Actual

14/04/2015

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

12/08/2021

Actual

Sample size

Target

Accrual to date

Final

510

Recruitment in Australia

Recruitment state(s)

NSW,VIC

Recruitment hospital [1]

GSK Investigational Site - Darlinghurst

Recruitment hospital [2]

GSK Investigational Site - Prahran

Recruitment postcode(s) [1]

2010 - Darlinghurst

Recruitment postcode(s) [2]

3181 - Prahran

Recruitment outside Australia

Country [1]

United States of America

State/province [1]

California

Country [2]

United States of America

State/province [2]

District of Columbia

Country [3]

United States of America

State/province [3]

Florida

Country [4]

United States of America

State/province [4]

Georgia

Country [5]

United States of America

State/province [5]

Missouri

Country [6]

United States of America

State/province [6]

New Jersey

Country [7]

United States of America

State/province [7]

Texas

Country [8]

United States of America

State/province [8]

Virginia

Country [9]

Argentina

State/province [9]

Buenos Aires

Country [10]

Belgium

State/province [10]

Antwerpen

Country [11]

Belgium

State/province [11]

Brussels

Country [12]

Belgium

State/province [12]

Gent

Country [13]

Belgium

State/province [13]

Liege

Country [14]

Canada

State/province [14]

British Columbia

Country [15]

Canada

State/province [15]

Ontario

Country [16]

Canada

State/province [16]

Québec

Country [17]

France

State/province [17]

Garches

Country [18]

France

State/province [18]

Lyon Cedex 03

Country [19]

France

State/province [19]

Paris Cedex 12

Country [20]

France

State/province [20]

Paris Cedex 13

Country [21]

France

State/province [21]

Paris

Country [22]

Germany

State/province [22]

Bayern

Country [23]

Germany

State/province [23]

Hessen

Country [24]

Germany

State/province [24]

Hamburg

Country [25]

Italy

State/province [25]

Lombardia

Country [26]

Italy

State/province [26]

Brescia

Country [27]

Netherlands

State/province [27]

Rotterdam

Country [28]

Russian Federation

State/province [28]

Kazan

Country [29]

Russian Federation

State/province [29]

Moscow

Country [30]

Russian Federation

State/province [30]

Orel

Country [31]

Russian Federation

State/province [31]

Smolensk

Country [32]

Russian Federation

State/province [32]

St. Petersburg

Country [33]

Spain

State/province [33]

Alcala de Henares

Country [34]

Spain

State/province [34]

Barcelona

Country [35]

Spain

State/province [35]

Elche (Alicante)

Country [36]

Spain

State/province [36]

Granada

Country [37]

Spain

State/province [37]

Huelva

Country [38]

Spain

State/province [38]

Madrid

Country [39]

Spain

State/province [39]

Malaga

Country [40]

Spain

State/province [40]

Marbella

Country [41]

Spain

State/province [41]

Palma de Mallorca

Country [42]

Spain

State/province [42]

Sevilla

Country [43]

Spain

State/province [43]

Valencia

Country [44]

Taiwan

State/province [44]

Kaohsiung

Country [45]

Taiwan

State/province [45]

Taipei

Country [46]

United Kingdom

State/province [46]

London

Country [47]

United Kingdom

State/province [47]

Manchester

Funding & Sponsors

Primary sponsor type

Commercial sector/Industry

Name

ViiV Healthcare

Address

Country

Other collaborator category [1]

Commercial sector/Industry

Name [1]

Janssen Pharmaceuticals

Address [1]

Country [1]

Other collaborator category [2]

Commercial sector/Industry

Name [2]

GlaxoSmithKline

Address [2]

Country [2]

Ethics approval

Ethics application status

Summary

Brief summary

The aim of this study is 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 will primarily
assess the non-inferiority antiviral activity of switching to DTG + RPV once daily compared
to 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 will include
2 NRTIs plus 1 HIV-1 integrase inhibitor (INI), or 1 non-nucleoside reverse transcriptase
inhibitor (NNRTI), or 1 protease inhibitor (PI). The study will include 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 will
participate in the Early Switch Phase where they will either switch from their CAR to DTG +
RPV, or continue taking their CAR, until Week 52. At the end of Early Switch Phase, eligible
participants will proceed to the Late Switch Phase where all participants in both DTG + RPV
and CAR treatment groups will receive DTG + RPV therapy until Week 148. After Week 148,
subjects may be eligible to continue to receive DTG +RPV in the Continuation Phase. The study
is planned to be conducted in approximately 476 participants.

Trial website

https://clinicaltrials.gov/show/NCT02429791

Trial related presentations / publications

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.

Public notes

Contacts

Principal investigator

Name

GSK Clinical Trials

Address

ViiV Healthcare

Country

Phone

Fax

Email

Contact person for public queries

Name

Address

Country

Phone

Fax

Email

Contact person for scientific queries

Summary results

Trial Review

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02429791