Clinical trial NCT03682848: Safety and Efficacy of Dolutegravir/Lamivudine (DTG/3TC) in Therapy-naive Human Immunodeficiency Virus-1 (HIV-1) Infected Adolescents
Official title: An Open-label, Single Arm Study to Evaluate the Week 48 Efficacy and Safety of a Two-drug Regimen of Dolutegravir/Lamivudine (DTG/3TC) as a Fixed Dose Combination (FDC), in Antiretroviral Therapy (ART)-Naive HIV-1-infected Adolescents, ≥12 to <18 Years of Age Who Weigh at Least 25 kg
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: HIV Infections
Keywords: Viral load
Dolutegravir
Lamivudine
HIV-1
Fixed dose combination
DOVATO
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
First posted: 2018-09-25
Enrollment: 32
Sex: ALL
Minimum age (years): 12
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: All participants will receive the FDC of DTG/3TC (50/300 milligrams) for once daily dosing in this single arm study.
Primary purpose: TREATMENT

Brief summary: First-line antiretroviral regimens are highly efficacious and generally well tolerated. However, as these regimens need to be taken life-long, there is growing concern about long-term toxicities associated with these regimens. Thus, there is great interest from participants and clinicians in unique regimens that might avoid such toxicities by minimizing the number of antiretrovirals without sacrificing long-term antiviral efficacy. DTG plus 3TC is a novel, well-tolerated first-line regimen for HIV-infected treatment- naive participants, limiting the risk of many common adverse reactions associated with other antiretroviral drugs. Thus, this study is designed to evaluate the efficacy and safety of DTG/3TC as a FDC, in ART-naive HIV-1-infected adolescents, who weigh at least 25 kilograms (kg). The study will consists of Screening Phase (up to 28 days prior to the first dose of drug) followed by Treatment Phase (up to 48 weeks). Participants who successfully complete 48 weeks of therapy and who continue to receive benefit from DTG/3TC FDC may enter a 96 weeks study Extension Phase. Study participants who have successfully completed both the Treatment Phase through 48 weeks and the Extension Phase through 144 weeks and continue to receive benefit from this two-drug regimen will continue to receive DTG/3TC FDC in a Continuation Phase (after Week 144) until: DTG and 3TC are both locally approved for use as part of a dual regimen and the single entities of DTG and 3TC are available to participants (e.g. through public health services), or the DTG/3TC FDC tablet, if required by local regulations, is locally approved and available (e.g. commercially or through public health services), or the participant no longer derives clinical benefit or the participant meets a protocol-defined reason for discontinuation. All participants will receive the FDC of DTG/3TC (50/300 milligrams) for once daily. Approximately 30 participants will be enrolled in the study.


Eligibility criteria: Inclusion Criteria:

* HIV-1 infected adolescents \>=12 to \<18 years of age at the time of signing the informed consent form.
* Weight \>=25 kg at the time of signing the informed consent form.
* Screening plasma HIV-1 RNA between 1,000 and \<=500,000 c/mL.
* Antiretroviral-naive (defined as no prior therapy with any antiretroviral agent for the treatment of HIV following a diagnosis of HIV-1 infection). Participants who received ART for prevention of mother to child transmission of HIV in the first 3 months of life are allowed. Participants who received HIV post-exposure prophylaxis (PEP) or pre-exposure prophylaxis (PrEP) in the past are allowed as long as the last PEP/PrEP dose was \>6 months from HIV diagnosis or there is documented HIV seronegativity at least 2 months after the last prophylactic dose and prior to the date of HIV diagnosis.
* Male and female participants will be included. A female participant is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin \[hCG\] test at Screening and negative urine hCG test before Enrollment) and not lactating. Female participants who are of child bearing potential and who are engaging in sexual activity that could lead to pregnancy, must agree to use one of the birth control method from 28 days prior to the first dose of study medication, and until 4 weeks after the last dose of study medication (and completion of the follow-up visit). Condoms are recommended in addition, because their appropriate use is the only contraception method effective for preventing HIV-1 transmission. The investigator is responsible for ensuring that participants understand how to properly use these methods of contraception. All participants participating in the study should also be counselled on safer sexual practices, including the use and benefit/risk of effective barrier methods (example given \[e.g.\] male condom), and on the risk of HIV transmission to an uninfected partner.
* The participant's parent(s) or legal guardian or the participant is capable of giving signed informed consent.

Exclusion Criteria:

* Females who are breastfeeding or plan to become pregnant or breastfeed during the study.
* Any evidence of an active Centers for Disease Control and Prevention (CDC) Stage 3 and/or Category C or World Health Organization (WHO) Stage 4 disease, except cutaneous Kaposi's sarcoma not requiring systemic therapy and historical or current CD4 cell counts less than 200 cells per cubic millimeter (cells/mm\^3) or CD4 percent \<15 percent.
* Participants with severe hepatic impairment (Class C) as determined by Child-Pugh classification.
* Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal 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 HBV surface antigen (HBsAg), HBV core antibody (anti-HBc), HBV surface antibody (anti-HBs or HBsAb), and HBV Deoxyribonucleic acid (DNA) as follows: participants positive for HBsAg are excluded; participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status) and positive for HBV DNA are excluded. Participant's positive for anti-HBc (negative HBsAg status) and positive for anti-HBs (past and/or current evidence) are immune to HBV and are not excluded.
* Anticipated need for any HCV therapy during the first 48 weeks of the study and for HCV therapy based on interferon or any drugs that have a potential for adverse drug: drug interactions with study treatment throughout the entire study period.
* Untreated syphilis infection (positive rapid plasma reagin \[RPR\] at Screening without clear documentation of treatment). Participants who are at least 24 hours post completed treatment are eligible.
* History or sensitivity to any of the study medications or their components or drugs of their class, or a history of drug or other allergy that in the opinion of the Investigator or Medical Monitor contraindicates participation.
* Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or penile intraepithelial neoplasia; other localized malignancies require agreement between the investigator and the Study Medical Monitor for inclusion of the participant.
* Participants who in the investigator's judgment, poses a significant suicidality risk. Recent history of suicidal behavior and/or suicidal ideation may be considered as evidence of serious suicide risk.
* 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 systemic immune suppressant.
* Treatment with any agent with documented activity against HIV-1 in vitro within 28 days of first dose of study treatment.
* Receipt of any prohibited medication and inability or unwillingness to switch to an alternative medication.
* 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 the first dose of study treatment.
* Any evidence of pre-existing viral resistance based on the presence of any major resistance-associated mutation in the Screening result or, if known, in any historical resistance test result.
* Any verified Grade 4 laboratory abnormality. 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.
* ALT \>=5 times the upper limit of normal (ULN) or ALT \>=3 times ULN and bilirubin \>=1.5 times ULN (with \>35 percent direct bilirubin).
* Creatinine clearance of \<50 milliliters per minute per 1.73 square meter (mL/min/1.73 m\^2) using the Schwartz equation method.
* Children who are wards of the state or government.

Primary outcomes:
measure: Percentage of Participants With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Less Than 50 Copies Per Milliliter (c/mL) at Week 48
timeFrame: Week 48
Secondary outcomes:
measure: Percentage of Participants With Plasma HIV-1 RNA <200 c/mL at Week 24
timeFrame: Week 24
measure: Percentage of Participants With Plasma HIV-1 RNA <200 c/mL at Week 96
timeFrame: Week 96
measure: Percentage of Participants With Plasma HIV-1 RNA <200 c/mL at Week 144
timeFrame: Week 144
measure: Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 24
timeFrame: Week 24
measure: Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 96
timeFrame: Week 96
measure: Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 144
timeFrame: Week 144
measure: Percentage of Participants With Plasma HIV-1 RNA <200 c/mL at Week 48
timeFrame: Week 48
measure: Number of Participants With Adverse Events and Serious Adverse Events Through 144 Weeks
timeFrame: Up to 144 weeks
measure: Number of Participants With Severity of Adverse Events Through 144 Weeks
timeFrame: Up to 144 weeks
measure: Number of Participants With Abnormal Findings for Hematology Parameters Through 144 Weeks
timeFrame: Up to 144 weeks
measure: Number of Participants With Abnormal Findings for Clinical Chemistry Parameters Through 144 Weeks
timeFrame: Up to 144 weeks
measure: Number of Participants With Abnormal Findings for Fasting Lipids Through 144 Weeks
timeFrame: Up to 144 weeks
measure: Number of Participants With Abnormal Findings for Urinalysis Parameters Through 144 Weeks
timeFrame: Up to 144 weeks
measure: Number of Participants Who Discontinue Treatment Due to Adverse Events Through 144 Weeks
timeFrame: Up to 144 weeks
measure: Number of Participants With Adverse Events and Serious Adverse Events Through 96 Weeks
timeFrame: Up to 96 weeks
measure: Number of Participants With Severity of Adverse Events Through 96 Weeks
timeFrame: Up to 96 weeks
measure: Number of Participants With Abnormal Findings for Hematology Parameters Through 96 Weeks
timeFrame: Up to 96 weeks
measure: Number of Participants With Abnormal Findings for Clinical Chemistry Parameters Through 96 Weeks
timeFrame: Up to 96 weeks
measure: Number of Participants With Abnormal Findings for Fasting Lipids Through 96 Weeks
timeFrame: Up to 96 weeks
measure: Number of Participants With Abnormal Findings for Urinalysis Parameters Through 96 Weeks
timeFrame: Up to 96 weeks
measure: Number of Participants Undergoing Viral Load Monitoring From Week 48 Through 144 Weeks
timeFrame: Week 48 and up to Week 144
measure: Change From Baseline in Cluster of Differentiation 4+ (CD4+) Cell Count at Week 24
timeFrame: Baseline (Day 1) and Week 24
measure: Change From Baseline in CD4+ Cell Count at Week 48
timeFrame: Baseline (Day 1) and Week 48
measure: Change From Baseline in CD8+ Cell Count at Week 24
timeFrame: Baseline (Day 1) and Week 24
measure: Change From Baseline in CD8+ Cell Count at Week 48
timeFrame: Baseline (Day 1) and Week 48
measure: Change From Baseline in Ratio of CD4+ and CD8+ at Week 24
timeFrame: Baseline (Day 1) and Week 24
measure: Change From Baseline in Ratio of CD4+ and CD8+ at Week 48
timeFrame: Baseline (Day 1) and Week 48
measure: Number of Participants With Disease Progression From Week 24 Through Week 48
timeFrame: Week 24 and up to Week 48
measure: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) From Week 24 Through Week 48
timeFrame: Week 24 and up to Week 48
measure: Number of Participants With Severity of Adverse Events From Week 24 Through Week 48
timeFrame: Week 24 and up to Week 48
measure: Number of Participants With Abnormal Findings for Hematology Parameters From Week 24 Through Week 48
timeFrame: Week 24 and up to Week 48
measure: Number of Participants With Abnormal Findings for Clinical Chemistry Parameters From Week 24 Through Week 48
timeFrame: Week 24 and up to Week 48
measure: Number of Participants With Abnormal Findings for Fasting Lipids From Week 24 Through Week 48
timeFrame: Week 24 and up to Week 48
measure: Number of Participants With Abnormal Findings for Urinalysis Parameters From Week 24 Through Week 48
timeFrame: Week 24 and up to Week 48
measure: Number of Participants Who Discontinued Treatment Due to Adverse Events From Week 24 Through Week 48
timeFrame: Week 24 and up to Week 48
measure: Maximum Observed Plasma Concentration (Cmax) Following Dosing With DTG and 3TC
timeFrame: Pre-dose, 0.5, 1.0, 1.5, 2, 3, 4, 6, 10, and 24 hours post-dose at Week 1
measure: Time of Maximum Observed Plasma Concentration (Tmax) Following Dosing With DTG and 3TC
timeFrame: Pre-dose, 0.5, 1.0, 1.5, 2, 3, 4, 6, 10, and 24 hours post-dose at Week 1
measure: Area Under the Plasma Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC[0-t]) Following Dosing With DTG and 3TC
timeFrame: Pre-dose, 0.5, 1.0, 1.5, 2, 3, 4, 6, 10, and 24 hours post-dose at Week 1
measure: Area Under the Curve (AUC) Over the Dosing Interval (AUC[0-tau]) Following Dosing With DTG and 3TC
timeFrame: Pre-dose, 0.5, 1.0, 1.5, 2, 3, 4, 6, 10, and 24 hours post-dose at Week 1
measure: Apparent Terminal Half-life (t1/2) Following Dosing With DTG and 3TC
timeFrame: Pre-dose, 0.5, 1.0, 1.5, 2, 3, 4, 6, 10, and 24 hours post-dose at Week 1
measure: Observed Pre-dose Concentration Following Dosing With DTG and 3TC
timeFrame: Pre-dose at Week 1
measure: Observed Plasma Concentration at 24 Hours Following Dosing With DTG and 3TC
timeFrame: 24 hours post-dose at Week 1
measure: Number of Participants With Observed Genotypic Resistance to DTG and 3TC
timeFrame: Up to 144 weeks
measure: Number of Participants With Observed Phenotypic Resistance to DTG and 3TC
timeFrame: Up to 144 weeks
Other outcomes:
Locations:
city: Kericho
country: Kenya
facility: GSK Investigational Site
city: Kisumu
country: Kenya
facility: GSK Investigational Site
city: Durban
country: South Africa
facility: GSK Investigational Site
city: Soweto
country: South Africa
facility: GSK Investigational Site
city: Tygerberg
country: South Africa
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Chiang Mai
country: Thailand
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: