Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
GSK1349572 · 17 trials · 7 indications
The percentage of participants with Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) \<50 c/mL at Week 48 was assessed using the Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) "snapshot" algorithm. This algorithm treated all participants without HIV-1 RNA at Week 48 as nonresponders, as well as participants who switched their concomitant ART prior to Week 48 as follows: background ART substitutions non-permitted per protocol (one background ART substitution was permitted for safety or tolerability); background ART substitutions permitted per protocol unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure was determined by the last available HIV-1 RNA assessment while the participant was on-treatment in the randomized phase of the study.
Percentage of participants with plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) with \<50 c/mL was assessed using the Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) snapshot algorithm. The algorithm treats all participants without HIV-1 RNA data as non-responders, as well as participants who switch their concomitant Antiretroviral Therapy (ART) prior to Week 48 as follows: background ART substitutions not permitted per study; background ART substitutions permitted per study unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure will be determined by the last available HIV-1 RNA assessment while the subject was on-treatment. Intent-to-Treat Exposed (ITT-E) Population comprised all randomized participants who received at least one dose of study medication.
Plasma samples were collected for quantitative HIV-1 RNA analysis at Week 16. The analysis was performed using the time to loss of virological response (TLOVR) dataset. In the TLOVR dataset, participant responses at a specified threshold of HIV-1 RNA (\<50 copies/mL) are determined by using the Food and Drug Administration's TLOVR algorithm. Using the TLOVR algorithm, participants are considered to have failed on therapy if they never achieved confirmed RNA levels below the threshold, if they had confirmed rebound of RNA above the threshold, if they made a non-permitted change in background regimen, or if they permanently discontinued investigational product for any reason. Data are reported per the Week 16 report. In later cuts of the data, the Week 16 values may have changed (because of the nature of the TLOVR algorithm).ITT-E Population included all randomized participants who received at least one dose of study medication
Change from Baseline in Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) was calculated as the Day 11 value minus the Baseline value. Blood samples for the measurement of HIV-1 RNA levels were obtained throughout the treatment period (Day 1 to Day 11).
AUC is defined as the area under the GSK1349572 concentration-time curve as a measure of drug exposure. AUC(0-inf) is defined as the area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time. AUC(0-24) is defined as the area under the concentration-time curve from time zero (pre-dose) to24 hours. Blood samples for pharmacokinetic (PK) analysis of GSK1349572 were obtained on Day 1at pre-dose (within 15 minutes prior to dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post GSK1349572 dose administration.
Cmax is defined as the maximum observed plasma concentration, and C24 is defined as the concentration at 24 hours post dose. Blood samples for PK analysis of GSK1349572 were obtained on Day 1at pre-dose (within 15 minutes prior to dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post GSK1349572 dose administration. From the plasma concentration-time curve, Cmax was determined by standard non-compartmental analysis using WinNonlin Pro 4.1 or higher.
tmax is defined as the time to the maximum obsevered plasma concentration. Absorption lag time is defined as the time taken for a drug to appear in the systemic circulation following administration. tlag was estimated based on PK sampling times of 0 (pre-dose), 0.5, 1, 1.5, 2 3, 4, 6, 8, 12, and 24 hours post-dose. Blood samples for PK analysis of GSK1349572 were obtained on Day 1at pre-dose (within 15 minutes prior to dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post GSK1349572 dose administration. From the plasma concentration-time curve, tmax was determined by standard non-compartmental analysis using WinNonlin Pro 4.1 or higher.
The terminal half-life (t1/2) of GSK1349572 is defined as the time required for the plasma concentration of GSK1349572 to reach half of its original concentration. Blood samples for PK analysis of GSK1349572 were obtained on Day 1at pre-dose (within 15 minutes prior to dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post GSK1349572 dose administration.
The CL/F is defined as the apparent total clearance of the drug from plasma after oral administration. Blood samples for PK analysis of GSK1349572 were obtained on Day 1at pre-dose (within 15 minutes prior to dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post GSK1349572 dose administration.
AUC is defined as the area under the GSK1349572 concentration-time curve as a measure of drug exposure. AUC(0-tau) is defined as the area under the concentration-time curve over the dosing interval. Blood samples for PK analysis of GSK1349572 were obtained on Day 10at pre-dose (within 15 minutes prior to dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post GSK1349572 dose administration.
C0 is defined as the pre-dose concentration. Ctau is defined as the concentration at the end of the dosing interval. Cmin is defined as the minimum observed concentration during one dosing interval. Cmax is defined as the maximum obsevered plasma concentration. Blood samples for PK analysis of GSK1349572 were obtained on Day 10 at pre-dose (within 15 minutes prior to dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post GSK1349572 dose administration.
tmax is defined as the time to the maximum obsevered plasma concentration. Blood samples for PK analysis of GSK1349572 were obtained on Day 10 at pre-dose (within 15 minutes prior to dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post GSK1349572 dose administration. From the plasma concentration-time curve, tmax was determined by standard non-compartmental analysis using WinNonlin Pro 4.1 or higher.
The terminal half-life (t1/2) of GSK1349572 is defined as the time required for the plasma concentration of GSK1349572 to reach half of its original concentration. Blood samples for PK analysis of GSK1349572 were obtained on Day 10 at pre-dose (within 15 minutes prior to dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post GSK1349572 dose administration.
The CL/F is defined as the apparent total clearance of the drug from plasma after oral administration. Blood samples for PK analysis of GSK1349572 were obtained on Day 10 at pre-dose (within 15 minutes prior to dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post GSK1349572 dose administration.
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.
Concomitant medications received during the study period are presented by generic term. Only those concomitant medications that were received by at least two participants are presented. "Multiple ingredient" is the term used in the statistical package for items that contain more than one active ingredient.
Blood pressure measurement included systolic blood pressure (SBP) and diastolic BP (DBP). Change in the mean blood pressure from Baseline was calculated as the post-Baseline value minus the Baseline value. Data are presented for change from Baseline at Day 1 (2 hours post dose \[hrs\]), Day 4 (1 hr pre-dose), Day 7 (1 hr pre-dose), and Day 10 (1 hr pre-dose and 2 hrs post dose).
Heart rate is the measure of heart beats per minute (bpm). Change in the mean heart rate from Baseline was calculated as the post-Baseline value minus the Baseline value. Data are presented for change from Baseline at Day 1 (2 hours post dose \[hrs\]), Day 4 (1 hr pre-dose), Day 7 (1 hr pre-dose), and Day 10 (1 hr pre-dose and 2 hrs post dose).
A 12-lead electrocardiogram (ECG) was performed by qualified personnel at the site after the participant had rested for at least 5 minutes in a semi-recumbent or supine position. If a QTc measurement of \>=500 milliseconds (msec) was noted on a scheduled or unscheduled ECG, two additional ECGs were to be obtained within 5 minutes to confirm the abnormality. The number of participants with abnormal clinically significant (CS) and not clinically significant (NCS) ECG findings are presented here. The site determined if an ECG finding is significant or not. ECGs were obtained at Screening, Day 1 (pre-dose \[twice\] and then 1.0, 1.5, and 2.0 hours \[hrs\] post dose), Day 4 (pre-dose), Day 7 (pre-dose), Day 10 (pre-dose and then 1.0, 1.5, and 2.0 hrs post dose), Day 11 (prior to the 24 hr PK sample \[pre lab\]), and Follow-up.
Clinical laboratory toxicities were graded according to the National Institutes of Allergy and Infectious Diseases (NIAID), Division of Acquired Immunodeficiency Syndrome (DAIDS). Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented only for Grade 3 and Grade 4 laboratory abnormalities. Clinical laboratory abnormalities included: increased glucose, lipase, decreased platelets, and triglycerides.
Plasma GSK1349572 PK parameters: AUC(0-24), Cmax, and C24, and dose-normalized AUC(0-24), Cmax, and C24 following single dose administration of 100mg and 50mg.
Plasma GSK1349572 PK parameters: AUC(0-24), Cmax, and C24, and dose-normalized AUC(0-24), Cmax, and C24 following single dose administration of 100mg and 50mg.
Plasma GSK1349572 PK parameters: AUC(0-24), Cmax, and C24, and dose-normalized AUC(0-24), Cmax, and C24 following single dose administration of 100mg and 50mg.
Plasma GSK1349572 steady-state AUC(0-tau), Cmax, C0, Ctau, and Cmin following administration of GSK1349572 50mg q24h for 5 days and following co-administration with EFV 600mg q24h for 14 days.
Plasma GSK1349572 steady-state AUC(0-tau), Cmax, C0, Ctau, and Cmin following administration of GSK1349572 50mg q24h for 5 days and following co-administration with EFV 600mg q24h for 14 days.
Plasma GSK1349572 steady-state AUC(0-tau), Cmax, C0, Ctau, and Cmin following administration of GSK1349572 50mg q24h for 5 days and following co-administration with EFV 600mg q24h for 14 days.
Plasma GSK1349572 steady-state AUC(0-tau), Cmax, C0, Ctau, and Cmin following administration of GSK1349572 50mg q24h for 5 days and following co-administration with EFV 600mg q24h for 14 days.
Plasma GSK1349572 steady-state AUC(0-tau), Cmax, C0, Ctau, and Cmin following administration of GSK1349572 50mg q24h for 5 days and following co-administration with EFV 600mg q24h for 14 days.
| Arm | Type | Description |
|---|---|---|
| GSK1349572 + Raltegravir Placebo | EXPERIMENTAL | Subjects will receive GSK1349572 50mg once daily plus raltegravir placebo twice daily. |
| Raltegravir + GSK1349572 Placebo | ACTIVE_COMPARATOR | Subjects will receive raltegravir 400mg twice daily plus GSK1349572 placebo once daily. |
| GSK1349572 (N=~394) | EXPERIMENTAL | GSK1349572 50mg once daily + raltegravir placebo twice daily + NRTI background therapy once daily |
| raltegravir (N=~394) | ACTIVE_COMPARATOR | raltegravir 400mg twice daily + GSK1349572 placebo once daily + NRTI background therapy once daily |
| 10 mg GSK1349572 | EXPERIMENTAL | subjects will receive GSK1349572 10mg once daily blinded to dose |
| 25mg GSK1349572 | EXPERIMENTAL | subjects will receive GSK1349572 25mg once daily blinded to dose |
| 50mg GSK1349572 | EXPERIMENTAL | subjects will receive GSK1349572 50mg once daily blinded to dose |
| efavirenz control | OTHER | efavirenz will serve as the internal control arm |
| Treatment A | EXPERIMENTAL | GSK1349572 2 mg or placebo every 24 hours for 10 days. Screening visit up to 30 days prior to first dose and follow-up for 11 days after last dose. |
| Treatment B | EXPERIMENTAL | GSK1349572 10 mg or placebo every 24 hours for 10 days. Screening visit up to 30 days prior to first dose and follow-up for 11 days after last dose. |
| Treatment C | EXPERIMENTAL | GSK1349572 50 mg or placebo every 24 hours for 10 days. Screening visit up to 30 days prior to first dose and follow-up for 11 days after last dose. |
| Arm 1 | EXPERIMENTAL | Subjects will have a screening visit within 30 days prior to the first dose of study drug, three treatment periods, and a follow-up visit 7-14 days after the last dose of study drug. Subjects enrolled in Arm 1 will receive GSK1349572 50 mg once daily for 7 days, GSK1348572 50 mg twice daily for 7 days, and GSK1349572 50 mg twice daily in combination with rifampin 600 mg once daily for 14 days. |
| Arm 2 | EXPERIMENTAL | Subjects will have a screening visit within 30 days prior to the first dose of study drug, two treatment periods, and a follow-up visit 7-14 days after the last dose of study drug. Subjects in Arm 2 will receive GSK1349572 50 mg once daily for 7 days and GSK1349572 50 mg once daily in combination with rifabutin 300 mg once daily for 14 days. |
| Single Arm | EXPERIMENTAL | All subjects will receive a 50 mg single dose of GSK1349572 |
| Part 1 Cohort 1 | EXPERIMENTAL | 8 subjects with moderate hepatic impairment defined by a Child-Pugh score of 7 to 9 will receive a single oral dose of GSK1349572 50 mg in the morning followed by 72 hour serial PK sampling. There will be a screening visit within 30 days prior to the dose of study drug and a follow-up visit within 7-10 days after the study drug. |
| Part 1 Cohort 2 | EXPERIMENTAL | 8 healthy subjects matched by gender, age and BMI to the subjects in Cohort 1 will receive a single oral dose of GSK1349572 50 mg in the morning followed by 72 hour serial PK sampling. There will be a screening visit within 30 days prior to the dose of study drug and a follow-up visit within 7-10 days after the study drug. |
| Part 2 Cohort 3 | EXPERIMENTAL | 8 subjects with mild hepatic impairment defined by a Child-Pugh score of 5 to 6 will receive a single oral dose of GSK1349572 50 mg in the morning followed by 72 hour serial PK sampling. There will be a screening visit within 30 days prior to the dose of study drug and a follow-up visit within 7-10 days after the study drug. This cohort will only be done if the AUC from Cohort 1 is greater than or equal to 2 times the AUC from Cohort 2. |
| Part 2 Cohort 4 | EXPERIMENTAL | 8 healthy subjects matched by gender, age and BMI to the subjects in Cohort 3 will receive a single oral dose of GSK1349572 50 mg in the morning followed by 72 hour serial PK sampling. There will be a screening visit within 30 days prior to the dose of study drug and a follow-up visit within 7-10 days after the study drug. This cohort will only be done if the AUC from Cohort 1 is greater than or equal to 2 times the AUC from Cohort 2. |
| Part A | EXPERIMENTAL | Approximately 12 subjects will be enrolled. In the first treatment period, all subjects will receive GSK1349572 50 mg every 24 hours for 5 days. In Period 2, subjects will receive GSK1349572 50 mg every 24 hours in combination with fosamprenavir 700 mg plus ritonavir 100 mg every 12 hours for 10 days. Day 1 of Period 2 will be the day after Day 5 of Period 1. Subjects will have a screening visit within 30 days prior to the first dose of study drug, two treatment periods, and a follow-up visit 7-14 days after the last dose of study drug. |
| Part B | EXPERIMENTAL | Approximately 15 subjects will be enrolled and receive three single doses of GSK1349572 approximately one week apart. One will be the current tablet formulation containing micronized drug substance and 2 will be new tablet versions, one containing unmicronized drug substance and one containing an intermediate particle size drug substance. Subjects will have a screening visit within 30 days prior to the first dose of study drug, three treatment periods, and a follow-up visit 7-14 days after the last dose of study drug. |
| Cohort 1 | EXPERIMENTAL | Subjects will receive a single dose of GSK1349572 100 mg in Period 1 followed by a washout of at least 6 days. Subjects will then receive GSK1349572 50 mg once a day for 5 days in Period 2. Period 3 will begin immediately after Period 2. In Period 3 subjects will receive GSK1349572 50 mg once a day in the morning and Efavirenz 600 mg once a day at bedtime for 14 days. There will be a screening visit up to 30 days before Period 1 and a follow up visit 7-14 days after the end of Period 3. |
| ARM 3 | EXPERIMENTAL | ARM 3: GSK1349572 50mg QD and TPV/RTV 500/200mg BID (Treatment C). |
| Sequence 1 | EXPERIMENTAL | - |
| Sequence 2 | EXPERIMENTAL | - |
| GSK1349572 | OTHER | GSK1349572 |
| Name | Type | Description |
|---|---|---|
| GSK1349572 | DRUG | 50mg once daily |
| Raltegravir | DRUG | 400mg twice daily |
| GSK1349572 Placebo | DRUG | Inactive placebo tablet once daily |
| Raltegravir Placebo | DRUG | Inactive placebo tablet twice daily |
| GSK1349572 (dolutegravir) | DRUG | GSK1349572 50 mg taken once daily with or without food |
| ABC/3TC | OTHER | Abacavir/Lamivudine background therapy once daily |
| TDF/FTC | OTHER | Tenofovir/emtricitabine background therapy once daily |
| efavirenz | DRUG | approved therapy for HIV-1 infection, used as an internal study control |
| Placebo | DRUG | Placebo is a tablet with no drug in it. |
| Rifampin | DRUG | Rifampin is approved by the FDA for the treatment of tuberculosis. |
| Rifabutin | DRUG | Rifabutin is approved by the FDA for the treatment of tuberculosis. |
| Iohexol Injection | DRUG | Iohexol is an FDA approved radiologic contrast medium |
| Para-aminohippurate infusion | DRUG | Para-aminohippurate is an agent to measure effective renal plasma flow. |
| Fosamprenavir | DRUG | Fosamprenavir is a drug in the protease inhibitor class that is approved by the FDA for the treatment of HIV infection. |
| Ritonavir | DRUG | Ritonavir is a drug in the protease inhibitor class that is approved by the FDA for the treatment of HIV infection. |
| GSK1349572 250 mg | DRUG | This is an experimental HIV medication in the integrase inhibitor class. |
| Placebo Suspension | DRUG | Placebo is a liquid with no drug in it. |
| Moxifloxacin 400 mg | DRUG | This is an FDA approved antibiotic in the fluoroquinolone class. |
| GSK1349572 and tenofovir | DRUG | - |
Inclusion Criteria: * Antiretroviral therapy (ART)-experienced, Human Immunodeficiency Virus (HIV) -1 infected adults at least 18 years of age. * Women capable of becoming pregnant must use appropriate contraception during the study (as defined by the protocol). * HIV-1 infection as documented by H...
GSK1349572 is an investigational small molecule being developed for the treatment of Human Immunodeficiency Virus (HIV) infection, including HIV-1. It has been studied in healthy volunteers and in patients with HIV, including those with tuberculosis or herpesviridae co-infections.
GSK1349572 is being developed by GSK plc, which trades under the ticker GSK. The company has conducted clinical trials of this drug in the United States and multiple other countries.
GSK1349572 has been studied in Phase 1 and Phase 3 clinical trials. The Phase 3 trial compared GSK1349572 50mg once daily to raltegravir 400mg twice daily in patients with HIV-1 infection.
GSK1349572 has been studied in several completed trials, including NCT01068925, a drug interaction study with tipranavir/ritonavir in healthy volunteers, and NCT01227824, a Phase 3 trial comparing it to raltegravir. Other trials include NCT01231542 and NCT01332565.
Yes, GSK1349572 is also known as dolutegravir, sometimes abbreviated as DTG. One clinical trial, NCT01332565, explicitly refers to GSK1349572 as dolutegravir in its title.