Phase 3
Completed N=627
Comparative Efficacy and Safety Study of Dolutegravir and Lopinavir/Ritonavir in Second-line Treatment
Source: ClinicalTrials.gov NCT02227238 ↗Enrolled (actual)
627
Serious AEs
8.9%
Results posted
Jul 2019
Primary outcomePrimary: Percentage of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) <50 Copies Per Milliliter (c/mL) at Week 48 — 84; 70 Percentage of participants — p=<.001
◆ Published Evidence
Highly cited
196citations · ~28 / year
Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom first-line therapy has failed (DAWNING): an open-label, non-inferiority, phase 3b trial.
Summary
For treatment of human immunodeficiency virus type 1(HIV-1), publicly funded programmes tend to follow World Health Organization (WHO) guidelines to use a non-nucleoside reverse transcriptase inhibitor (NNRTI) combined with two nucleoside reverse transcriptase inhibitors (NRTIs) for first-line antiretroviral therapy (ART); however, there is a need for further data on the best treatment options for people with HIV-1 who have virological failure with this first-line regimen. The number of patients failing on their first-line regimen is increasing thereby requiring a switch to second-line treatment to reduce accumulation of drug-resistance mutations, disease progression, HIV transmission, and death. WHO guidelines recommend second-line antiretroviral therapy for adults consisting of two NRTIs + a ritonavir-boosted protease inhibitor (PI); atazanavir (ATV) plus ritonavir (RTV) or lopinavir (LPV)/RTV are the preferred boosted PI options. This study is conducted to demonstrate non-inferior antiviral activity at 48 weeks of a dolutegravir (DTG) containing regimen compared to a WHO-recommended standard of care regimen for second line treatment, LPV/RTV + two NRTIs, in HIV-1 infected patients failing first line therapy. This study comprises of a Screening Phase (approximately 28 to 42 days), a Randomized Phase (Day 1 to Week 48 plus a 4-week treatment extension), and a Continuation Phase. Approximately 612 subjects will be randomized 1:1 to receive DTG 50 milligram (mg) once daily or LPV/RTV (800/200 mg once daily or 400/100 mg twice daily, in accordance with investigator decision and local label), each added to an investigator selected background regimen of two NRTIs at least one of which needs to be fully active based on viral resistance testing at Screening. Subjects randomized to the LPV/RTV arm will either (i) continue receiving LPV/RTV and complete the study after the 4-week treatment extension at Week 52, or (ii) switch to the DTG arm prior to study completion at Week 52 and continue to have access to DTG in the Continuation Phase. Subjects randomized to receive DTG who successfully complete 52 weeks of treatment and subjects originally randomized to receive LPV/RTV but switched to DTG prior to Week 52 will continue to have access to DTG until it is either locally approved and commercial supplies are available to patients or the patient no longer derives clinical benefit, or the patient meets a protocol-defined reason for discontinuation.
Linked Publications (2)
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Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom first-line therapy has failed (DAWNING): an open-label, non-inferiority, phase 3b trial.
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Integrase Inhibitor Resistance Mechanisms and Structural Characteristics in Antiretroviral Therapy-Experienced, Integrase Inhibitor-Naive Adults with HIV-1 Infection Treated with Dolutegravir plus Two Nucleoside Reverse Transcriptase Inhibitors in the DAWNING Study.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Percentage of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) <50 Copies Per Milliliter (c/mL) at Week 48 |
84; 70 | <.001 sig |
| SECONDARY Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 24 |
82; 69 | — |
| SECONDARY Percentage of Participants With Plasma HIV-1 RNA <400 c/mL at Weeks 24 and 48 |
90; 84; 88; 77 | — |
| SECONDARY Percentage of Participants Without Virologic or Tolerability Failure at Week 24 and Week 48 |
97.6; 91.9; 96.0; 86.1 | — |
| SECONDARY Time to Viral Suppression at Week 48 |
29.0; 111.0 | — |
| SECONDARY Change From Baseline in Helper-inducer T-lymphocyte Having Surface Antigen Cluster of Differentiation (CD4+) Cell Count at Weeks 24 and 48 |
84.0; 82.0; 120.0; 118.0 | — |
| SECONDARY Number of Participants With Disease Progression-Randomized + Continuation Phase |
10; 7 | — |
| SECONDARY Number of Participants With Treatment-emergent Genotypic Resistance-Randomized Phase |
3; 0; 1; 3; 0; 0 | — |
| SECONDARY Number of Participants With Treatment-emergent Genotypic Resistance-Continuation Phase |
5; 2; 0 | — |
| SECONDARY Number of Participants With Fold Change in Treatment-emergent Phenotypic Resistance From Baseline-Randomized Phase |
5; 18; 2; 5; 1; 0 | — |
| SECONDARY Number of Participants With Fold Change in Treatment-emergent Phenotypic Resistance From Baseline-Continuation Phase |
8; 3; 0; 0; 4 | — |
| SECONDARY Number of Participants With Non-serious Adverse Events (AEs) With >=2% Frequency Threshold and Serious Adverse Events (SAEs)-Randomized Phase |
155; 202; 20; 20 | — |
| SECONDARY Number of Participants With Non-serious AEs With >=2% Frequency Threshold and SAEs-Continuation Phase |
150; 29 | — |
| SECONDARY Number of Participants With Non-serious AEs With >=2% Frequency Threshold and SAEs-Randomized + Continuation Phase |
218; 213; 47; 20 | — |
| SECONDARY Change From Baseline in Glucose, Chloride, Carbon-di-oxide (CO2), Potassium, Phosphate, Sodium, Urea, Cholesterol, High Density Lipoprotein (HDL) Cholesterol, Low Density Lipoprotein (LDL) Cholesterol and Triglycerides |
0.07; 0.01; 0.08; -0.00; 0.07; -0.06 | — |
| SECONDARY Change From Baseline in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Creatine Kinase Values |
-12.24; -14.94; -13.73; -13.46; -13.87; -11.38 | — |
| SECONDARY Change From Baseline in Albumin Values |
-0.39; -0.51; 0.09; -0.67; 0.50; -0.28 | — |
| SECONDARY Change From Baseline in Creatinine and Bilirubin Values |
9.68; 4.69; 10.81; 5.57; 12.46; 5.19 | — |
| SECONDARY Change From Baseline in Lipase Values |
0.17; 1.52; 0.79; 0.58; 2.01; 0.94 | — |
| SECONDARY Number of Participants With Clinical Chemistry Toxicities -Randomized Phase |
32; 27; 10; 15; 4; 1 | — |
| SECONDARY Number of Participants With Clinical Chemistry Toxicities-Continuation Phase |
43; 33; 9; 0; 46; 16 | — |
| SECONDARY Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes |
0.00; 0.00; 0.00; 0.00; 0.00; 0.00 | — |
| SECONDARY Change From Baseline in Hematocrit Values |
-0.00; -0.01; 0.00; -0.01; 0.01; -0.01 | — |
| SECONDARY Change From Baseline in Hemoglobin Values |
-1.33; -4.23; -0.12; -4.41; 2.39; -2.10 | — |
| SECONDARY Change From Baseline in Mean Corpuscular Volume (MCV) |
0.68; 0.46; 1.72; 1.78; 3.91; 3.83 | — |
| SECONDARY Change From Baseline in Erythrocyte Values |
-0.08; -0.16; -0.07; -0.23; -0.06; -0.21 | — |
| SECONDARY Number of Participants With Hematology Toxicities -Randomized Phase |
6; 18; 5; 4; 5; 0 | — |
| SECONDARY Number of Participants With Hematology Toxicities-Continuation Phase |
13; 2; 1; 0; 23; 6 | — |
| SECONDARY Number of Participants Who Discontinued Treatment Due to AEs-Randomized Phase |
8; 18 | — |
| SECONDARY Number of Participants Who Discontinued Treatment Due to AEs-Continuation Phase |
9 | — |
| SECONDARY Change From Baseline in Fasting LDL Cholesterol at Week 24 and Week 48 |
-0.121; 0.050; -0.012; 0.135 | 0.0010 sig |
| SECONDARY Change From Baseline in Fasting Total Cholesterol/HDL Cholesterol Ratio |
-0.237; 0.305; -0.084; 0.275 | <0.0001 sig |
| SECONDARY Number of Participants With Maximum Post-Baseline Emergent Grade 2 or Greater Laboratory Abnormalities in Fasting LDL Cholesterol |
5; 20 | — |
| SECONDARY Number of Participants With Maximum Post-Baseline Emergent Grade 2 or Greater Drug-related Diarrhea |
1; 22; 1; 23 | — |
| SECONDARY Change From Baseline in Gastrointestinal Symptom Rating Scale (GSRS) Score |
0.00; 0.00; 0.00; 0.00; 0.00; 0.00 | — |
| SECONDARY Change From Baseline in Treatment Satisfaction, Using the HIV-Treatment Satisfaction Questionnaire (HIVTSQ) Score |
3.4; 2.0; 5.0; 3.0; 5.0; 3.0 | — |
| SECONDARY Number of Participants Showing Adherence With Treatment, Using the Morisky 8-Item Medication Adherence Scale (MMAS-8) |
70; 75; 102; 100; 137; 137 | — |
Eligibility Criteria
Inclusion Criteria
- HIV-1 infected subjects >=18 years of age.
- A female subject may be eligible to enter and participate in the study if she:
is of non-childbearing potential defined as either 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, is of child-bearing potential, with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the protocol-defined methods of contraception to avoid pregnancy throughout the study and for at least 2 weeks after discontinuation of all study medication.
- HIV-1 infection as documented by HIV-1 RNA >=400 c/mL at Screening.
- Subject has been on a first-line treatment regimen consisting of an NNRTI plus two NRTIs for at least 6 months and is currently experiencing virologic failure to this first-line regimen defined as two consecutive (>=7 days apart) HIV-1 RNA results of >=400 c/mL.
- Subjects must receive at least one fully active agent within the dual-NRTI background regimen for second line treatment. Fully active is defined by the Screening genotypic resistance report of the central laboratory (or a laboratory contracted by the central laboratory) showing no evidence of full or of partial resistance for a given NRTI which will be taken on study.
- Subject is PI-naïve and Integrase inhibitor (INI)-naïve, defined as no prior or current exposure to any PI or INI.
- Subject or the subject's legal representative is willing and able to understand and provide signed and dated written informed consent prior to screening.
Exclusion Criteria
- Women who are breastfeeding.
- Any evidence of an active Centers for Disease Control and Prevention (CDC) Category C disease Exceptions include cutaneous Kaposi's sarcoma not requiring systemic therapy and historic or current CD4+ cell levels =5 times the upper limit of normal (ULN) or ALT >=3xULN and bilirubin >=1.5xULN (with >35% direct bilirubin)
Data sourced from ClinicalTrials.gov (NCT02227238) and the linked publication. Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.