Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication DELSTRIGO ® is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg: with no prior antiretroviral treatment history, OR to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions… FDA label
Also known as MK-1439, DOR
Doravirine · 12 trials · 8 indications
The non-inferiority will be assessed in terms of virologic efficacy at week 48 under allocated treatment using the FDA snapshot algorithm (window period of 42-54 weeks), and measured by the proportion of subjects achieving a rate of HIV 1 RNA \<50 copies/mL, in HIV-1 infected, treatment-naive subjects with pre-treatment viral load (HIV-1 RNA) ≥ 1,000 copies/mL. The rate of HIV 1 RNA will be measured by RT-PCR.
The percentage of participants in each arm achieving HIV-1 RNA levels \<50 copies/mL was determined. Plasma HIV-1 RNA levels were quantified with the Abbott RealTime HIV-1 Assay. Data were handled according to the US Food and Drug Administration (FDA) "snapshot" approach and all missing data were considered treatment failures, regardless of the reason.
The percentage of participants in each arm with HIV-1 RNA levels \<50 copies/mL at Week 48 was determined. Plasma HIV-1 RNA levels were quantified with the Abbott RealTime HIV-1 Assay. Data were handled according to the US Food and Drug Administration (FDA) "snapshot" approach in which all missing data are considered treatment failures, regardless of the reason.
The percentage of participants in each arm experiencing ≥1 pre-specified Tier-1 neuropsychiatric AEs was determined. The list of Tier-1 neuropsychiatric AE categories included "dizziness", "sleep disorders and disturbances", and "altered sensorium" (including disturbance in attention).
The percentage of participants in each arm achieving HIV-1 RNA levels \<50 copies/mL at Week 48 was determined. Plasma HIV-1 RNA levels were quantified with the Abbott RealTime HIV-1 Assay. Data were handled according to the US Food and Drug Administration (FDA) "snapshot" approach and all missing data were considered treatment failures, regardless of the reason.
Per protocol, intensive pharmacokinetic (PK) sampling includes multiple blood samples collected up to 24 hours postdose at a single visit to determine AUC0-24hr.
Per protocol, intensive PK sampling includes multiple blood samples collected up to 24 hours postdose at a single visit to determine Cmax.
Per protocol, intensive PK sampling includes multiple blood samples collected up to 24 hours postdose at a single visit to determine C24.
Per protocol, intensive PK sampling includes multiple blood samples collected up to 24 hours postdose at a single visit to determine Tmax.
Per protocol, intensive PK sampling includes multiple blood samples collected up to 12 hours postdose at a single visit to determine AUC0-12hr.
Per protocol, intensive PK sampling includes multiple blood samples collected up to 12 hours postdose at a single visit to determine Cmax.
Per protocol, intensive PK sampling includes multiple blood samples collected up to 12 hours postdose at a single visit to determine C12.
Per protocol, intensive PK sampling includes multiple blood samples collected up to 12 hours postdose at a single visit to determine Tmax.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study interventions.
Grade 3 or 4 AEs are "severe symptoms that cause inability to perform usual social and functional activities with intervention or hospitalization indicated" (Grade 3), or "potentially life-threatening events" (Grade 4).
The percentage of participants with events of death at Week 24 will be reported.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study interventions.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, that is considered to be related to the study interventions.
A questionnaire was used to solicit for CNS toxicity based on the following 10 events: dizziness; depression/low mood; insomnia/sleeplessness; anxiety/nervousness; confusion; impaired concentration/attention; headache; somnolence/daytime sleepiness; aggressive mood/behavior; and abnormal dreams. Participants were asked to rate the intensity for each of the 10 events as none (Grade 0), mild (Grade 1), moderate (Grade 2), or severe (Grade 3). Mild = symptom is noticeable but does not interfere with normal activities; moderate = symptom has some impact on normal activities; severe = symptom prevents conduct of normal activities. Percentage of participants with at least one CNS toxicity of Grade 2 or higher were recorded, based on the last observation carried forward (LOCF) approach.
The percentage of participants achieving HIV-1 ribonucleic acid (RNA) \<50 copies/mL in plasma at Week 48 was calculated. The Abbott RealTime HIV-1 Assay, which has a lower limit of reliable quantification (LoQ) of 40 copies/mL, was used to measure the HIV-1 RNA level in plasma samples obtained at Week 48 visit.
The percentage of participants experiencing ≥1 AE up to Week 48 was calculated. An AE was defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy could be determined.
The percentage of participants who discontinued from study medication due to an adverse event was calculated. An AE was defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy could be determined.
The percentage of participants experiencing ≥1 AE up to Week 96 was calculated. An AE was defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy could be determined.
The percentage of participants who discontinued from study medication due to an adverse event was calculated. An AE was defined as any unfavorable and unintended sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy could be determined.
Assessment of the percentage of participants receiving doravirine at all doses (25 mg, 50 mg, 100 mg, or 200 mg), compared with participants receiving efavirenz 600 mg, who had at least 1 AE over 24 weeks of treatment. An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product.The percentage of participants in any treatment group with at least 1 AE was primarily assessed for Weeks 0-24.
Assessment of the percentage of participants receiving doravirine at all doses (25 mg, 50 mg, 100 mg, or 200 mg), compared with participants receiving efavirenz 600 mg, who discontinued therapy due to an AE over 24 weeks of treatment. An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product.The percentage of participants in any treatment group who discontinued therapy due to an AE was primarily assessed for Weeks 0-24.
Assessment of the percentage of participants receiving doravirine at 100 mg, compared with participants receiving efavirenz 600 mg, who had at least 1 AE over 24 weeks of treatment. An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product.The percentage of participants in any treatment group with at least 1 AE was assessed for Weeks 0-24.
Assessment of the percentage of participants receiving doravirine at 100 mg, compared with participants receiving efavirenz 600 mg, who had CNS events over 8 weeks of treatment. CNS events were pooled and evaluated as pre-specified by the protocol (depression, nightmare, confusional state, suicidal ideation, nervous system disorder, psychotic disorder, abnormal dreams, suicide attempt, acute psychosis, delirium, depressed level of consciousness, hallucination, hallucination auditory, hallucination visual, completed suicide, suicidal behavior, major depression, depressed mood, depressive symptom, insomnia, disturbance in attention, somnolence, dizziness, or concentration impaired). The percentage of participants in either treatment group with CNS events was assessed over Weeks 0-8.
Assessment of the percentage of participants receiving doravirine at 100 mg, compared with participants receiving efavirenz 600 mg, who had CNS events over 24 weeks of treatment. CNS events were pooled and evaluated as pre-specified by the protocol (depression, nightmare, confusional state, suicidal ideation, nervous system disorder, psychotic disorder, abnormal dreams, suicide attempt, acute psychosis, delirium, depressed level of consciousness, hallucination, hallucination auditory, hallucination visual, completed suicide, suicidal behavior, major depression, depressed mood, depressive symptom, insomnia, disturbance in attention, somnolence, dizziness, or concentration impaired). The percentage of participants in either treatment group with CNS events was assessed over Weeks 0-24.
Assessment of the virologic response to doravirine at all studied doses (25 mg, 50 mg, 100 mg, and 200 mg), compared to efavirenz, each in combination with TRUVADA, as measured by the percentage of participants with plasma HIV-1 RNA \<40 copies/mL at Week 24. HIV RNA levels were determined using the Abbott RealTime HIV-1 Assay, which has a limit of reliable quantification of 40 copies/mL. The percentage of participants in any treatment group with a virologic response was assessed at Week 24. The Non-Completer = Failure (NC=F) approach, in which participants who prematurely discontinued assigned treatment for any reason and were considered as failures thereafter, was used as the primary approach to handle missing data this analysis of efficacy.This primary outcome was analyzed for HIV-1 RNA \<40 copies/mL in Part I.
Assessment of the virologic response to doravirine at 100 mg, compared to efavirenz, each in combination with TRUVADA, as measured by the percentage of participants with HIV-1 RNA \<40 copies/mL at Week 24. HIV RNA levels were determined using the Abbott RealTime HIV-1 Assay, which has a limit of reliable quantification of 40 copies/mL. The percentage of participants in any treatment group with a virologic response was assessed at Week 24. The NC=F approach was used as the primary approach to handle missing data this analysis of efficacy. This primary outcome was analyzed for HIV-1 RNA \<40 copies/mL in Part I \& Part II combined.
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method.
The AUC0-24 of the R- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by liquid chromatographic-tandem mass spectrometric (LC-MS/MS) detection. The lower limit of quantification (LLoQ) was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
The C24 of the R- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
The Cmax of the R- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
The Tmax of the R- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
The AUC0-24 of the S- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
The C24 of the S- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
The Cmax of the S- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
The Tmax of the S- methadone enantiomer was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
The AUC0-24 of total methadone was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
The C24 of total methadone was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
The Cmax of total methadone was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
The Tmax of total methadone was determined on Day 1 (methadone alone) and on Day 6 (methadone + doravirine). Plasma samples collected for methadone assay were analyzed for R- and S-methadone concentrations by Pharma Medica Research Inc. (Ontario, Canada). The analytical method used liquid-liquid extraction for analyte isolation followed by LC-MS/MS detection. The LLoQ was 0.0250 ng/mL for each enantiomer. The analytical range was 0.0250 - 15.0 ng/mL.
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method
Blood was collected for the determination of plasma doravirine using a liquid chromatographic tandem mass spectrometric method
The change from baseline to Day 7 in plasma HIV RNA viral load was determined for each arm. Results are expressed as change in HIV RNA log10 copies/mL after 7 daily doses of doravirine or placebo. It was hypothesized that at least 1 dose of doravirine would be superior to placebo as documented by the upper bound of the 90% confidence interval \<-1. Plasma HIV RNA levels were determined using the Abbott RealTime HIV assay which has a linear range from 40 to 10 million copies/mL.
| Arm | Type | Description |
|---|---|---|
| Doravirine arm | EXPERIMENTAL | Doravirine (100 mg) + tenofovir DF (300 mg) + lamivudine (300mg) administered daily |
| Dolutegravir arm | ACTIVE_COMPARATOR | Dolutegravir (50 mg) + tenofovir DF 300 mg + XTC (300 mg if lamivudine or 200 mg if emtricitabine) administered daily |
| Immediate Switch to Doravirine, Tenofovir, Lamivudine | EXPERIMENTAL | Participants receiving continuous antiretroviral therapy with a ritonavir- or cobicistat-boosted protease inhibitor (atazanavir, darunavir, or lopinavir) or cobicistat-boosted elvitegravir or a non nucleoside reverse transcriptase inhibitor (NNRTI) (specifically, efavirenz, nevirapine, or rilpivirine) in combination with 2 NRTIs for \>=6 months with undetectable HIV-1 RNA will switch on Day 1 to doravirine, tenofovir, lamivudine single tablet by mouth once daily for 48 weeks in the Base Study and, optionally, for up to an additional 6 years in the Study Extensions |
| Delayed Switch to Doravirine, Tenofovir, Lamivudine | ACTIVE_COMPARATOR | Participants receiving continuous antiretroviral therapy with a ritonavir- or cobicistat-boosted protease inhibitor (atazanavir, darunavir, or lopinavir) or cobicistat-boosted elvitegravir or a NNRTI (specifically, efavirenz, nevirapine, or rilpivirine) in combination with 2 NRTIs for \>=6 months with undetectable HIV-1 RNA will continue on this therapy until Week 24, at which time they will switch to doravirine, tenofovir, lamivudine single tablet by mouth once daily for 24 weeks in the Base Study and, optionally, for up to an additional 6 years in the Study Extensions |
| Doravirine, Tenofovir, Lamivudine | EXPERIMENTAL | Treatment-naive HIV-infected participants will receive doravirine, tenofovir, lamivudine, a single-tablet FDC containing doravirine 100 mg + lamivudine 300 mg + tenofovir disoproxil fumarate 300 mg, q.d. by mouth for 96 weeks. Participants will also take 1 placebo tablet matched to ATRIPLA™ q.d. by mouth for 96 weeks in order to maintain blinding. |
| ATRIPLA™ | ACTIVE_COMPARATOR | Treatment-naive HIV-infected participants will receive ATRIPLA™, a single-tablet FDC containing efavirenz 600 mg + emtricitabine 200 mg + tenofovir disoproxil fumarate 300 mg (equivalent to 245 mg tenofovir disoproxil), q.d. by mouth for 96 weeks. Participants will also take 1 placebo tablet matched to doravirine, tenofovir, lamivudine q.d. by mouth for 96 weeks in order to maintain blinding. |
| Doravirine 100 mg | EXPERIMENTAL | Double-blind Doravirine 100 mg administered orally (p.o.) once daily (q.d.) + investigator selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants may continue in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o., q.d. for an additional 96 weeks. Eligible participants may continue to receive the Doravirine regimen in Study Extension 2 until Doravirine becomes locally available, or for an additional 96 weeks, whichever comes first. Eligible participants may continue to receive the Doravirine regimen in Study Extension 3 until Doravirine becomes locally available, or for an additional 96 weeks, whichever comes first. |
| Darunavir 800 mg and Ritonavir 100 mg | ACTIVE_COMPARATOR | Double-blind Darunavir 800 mg and Ritonavir 100 mg administered p.o. q.d. + investigator selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for 96 weeks. Eligible participants may continue in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants may continue to receive the Doravirine regimen in Study Extension 2 until Doravirine becomes locally available, or for an additional 96 weeks, whichever comes first. Eligible participants may continue to receive the Doravirine regimen in Study Extension 3 until Doravirine becomes locally available, or for an additional 96 weeks, whichever comes first. |
| Doravirine as a single entity plus 2 NRTIs or Doravirine as a FDC with 3TC and TDF | EXPERIMENTAL | Participants receive doravirine (DOR) at 7.2 mg to 100 mg, based on weight, PLUS 2 nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTIs), based on local label, for 96 weeks, OR a fixed-dose combination (FDC) of doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF), based on weight, for 96 weeks. |
| Deferred Switch to Doravirine, Tenofovir, Lamivudine | EXPERIMENTAL | Participants will continue on their ongoing ATRIPLA™ regimen orally, once daily for 12 weeks, followed by open-label doravirine, tenofovir, lamivudine orally, once daily for 24 weeks. Participants who meet eligibility criteria can enter study extension 1 to receive open-label doravirine, tenofovir, lamivudine for an additional 96 weeks. Participants who meet eligibility criteria can enter study extension 2 to receive open-label doravirine, tenofovir, lamivudine, with a maximum total duration of treatment of 228 weeks. Participants who meet eligibility criteria can enter study extension 3 to receive open-label doravirine, tenofovir, lamivudine, with a maximum total duration of treatment of 324 weeks. |
| DOR/3TC/TDF | EXPERIMENTAL | Treatment-naïve HIV-1 infected participants with NNRTI transmitted resistance-associated mutations were treated with open-label MK-1439A (DOR/3TC/TDF 100mg/300mg/300mg) as a FDC tablet taken once daily by mouth for 96 weeks in the Base Study. In addition, eligible participants continued to receive the same MK-1439A regimen from Week 96 to Week 192 during the Extension Study. |
| Doravirine 25 mg | EXPERIMENTAL | Doravirine 25 mg + TRUVADA® Participants in this arm will receive doravirine 25 mg in Part I and the selected doravirine dose (either 25 mg, 50 mg, 100 mg, or 200 mg) in Part II. These participants also receive placebo that matches efavirenz. |
| Doravirine 50 mg | EXPERIMENTAL | Doravirine 50 mg + TRUVADA® Participants in this arm will receive doravirine 50 mg in Part I and the selected doravirine dose (either 25 mg, 50 mg, 100 mg, or 200 mg) in Part II. These participants also receive placebo that matches efavirenz. |
| Doravirine 200 mg | EXPERIMENTAL | Doravirine 200 mg + TRUVADA® Participants in this arm will receive doravirine 200 mg in Part I and the selected doravirine dose (either 25 mg, 50 mg, 100 mg, or 200 mg) in Part II. These participants also receive placebo that matches efavirenz. |
| Efavirenz | ACTIVE_COMPARATOR | Efavirenz + TRUVADA® Participants in this arm will receive efavirenz in Part I and in Part II. These participants also receive placebo that matches doravirine. |
| Severe Renal Impairment | EXPERIMENTAL | Participants with severe renal impairment receive a single oral dose of 100 mg doravirine |
| Healthy Matched Control | EXPERIMENTAL | Healthy participants matched for age and weight receive a single oral dose of 100 mg doravirine |
| Maintenance Methadone and MK-1439 | EXPERIMENTAL | Participants maintained on a stable methadone regimen (20 to 200 mg once daily) for ≥14 days prior to Day 1 will continue to receive methadone maintenance once per day on Days 1 to 7. From Day 2 to 6, participants will also receive doravirine 100 mg once daily. |
| Part 1: Moderate Hepatic Insufficiency | EXPERIMENTAL | Participants with moderate hepatic insufficiency receive a single oral dose of 100 mg doravirine on Day 1 of Part 1. All participants in this arm were to have moderate hepatic insufficiency based on the Child-Pugh scale. |
| Part 1: Healthy Matched Control | EXPERIMENTAL | Healthy participants matched for age and weight receive a single oral dose of 100 mg doravirine on Day 1 of Part 1. |
| Part 2: Mild Hepatic Insufficiency | EXPERIMENTAL | Participants with mild hepatic insufficiency receive a single oral dose of 100 mg doravirine on Day 1 of Part 1. All participants in this arm were to have mild hepatic insufficiency based on the Child-Pugh scale. This arm was to be enrolled and investigated only if a clinically meaningful increase in exposure of doravirine was observed in participants with moderate hepatic insufficiency in Part 1. |
| Panel A: Doravirine 25 mg or Placebo | EXPERIMENTAL | Participants will receive oral doses of doravirine 25 mg or placebo once daily for 7 days. |
| Panel B: Doravirine 200 mg or Placebo | EXPERIMENTAL | Panel B (doravirine 200 mg or placebo once daily for 7 days) will initiate upon satisfactory review of safety and tolerability from Panel A, and all safety, tolerability and pharmacokinetic data from the study MK-1439-001. |
| Panel C: Doravirine or Placebo | EXPERIMENTAL | Panel C is optional. If conducted, the dose will be confirmed after review of data from prior panels. |
| Name | Type | Description |
|---|---|---|
| Doravirine + tenofovir DF + lamivudine | DRUG | Oral administration |
| Dolutegravir + tenofovir DF + lamivudine or emtricitabine | DRUG | Oral administration |
| Doravirine, Tenofovir, Lamivudine | DRUG | Single tablet containing MK-1439 (doravirine) 100 mg, lamivudine 300 mg, and tenofovir disoproxil fumarate 300 mg |
| Baseline regimen of ritonavir- or cobicistat-boosted protease inhibitor | DRUG | Baseline regimen of antiretroviral therapy with a ritonavir- or cobicistat-boosted protease inhibitor (atazanavir, darunavir, or lopinavir) administered according to the product circular |
| Baseline regimen of cobicistat-boosted elvitegravir | DRUG | Baseline regimen of antiretroviral therapy with cobicistat-boosted elvitegravir administered according to the product circular |
| Baseline regimen of a non-nucleoside reverse transcriptase inhibitor | DRUG | Baseline regimen of antiretroviral therapy with a NNRTI (efavirenz, nevirapine, or rilpivirine) administered according to the product circular |
| Baseline regimen of two nucleoside reverse transcriptase inhibitors | DRUG | Baseline regimen of antiretroviral therapy with two NRTIs administered according to the product circular |
| ATRIPLA™ | DRUG | One ATRIPLA™ tablet taken q.d. by mouth |
| Placebo | DRUG | Placebo tablets matched to ATRIPLA® or Doravirine, Tenofovir, Lamivudine. |
| Doravirine | DRUG | Doravirine 100 mg tablet administered p.o. q.d. |
| Darunavir | DRUG | Darunavir 800 mg tablet administered p.o. q.d. |
| Ritonavir | DRUG | Ritonavir 100 mg tablet administered p.o. q.d. |
| TRUVADA™ or EPZICOM™/KIVEXA™ | DRUG | The investigator selects either TRUVADA™, a tablet containing 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate p.o. q.d. or EPZICOM™/KIVEXA™, a tablet containing 600 mg abacavir sulfate and 300 mg lamivudine, p.o. q.d. |
| 2 NRTIs | DRUG | Administered orally |
| DOR/3TC/TDF | DRUG | Administered orally |
| Doravirine, Tenofovir, Lamivudine - Blinded | DRUG | A single tablet FDC containing doravirine 100 mg, lamivudine (3TC) 300 mg and tenofovir disoproxil fumarate (TDF) 300 mg administered orally, once daily for 12 weeks during the Blinded period |
| Doravirine, Tenofovir, Lamivudine - Open-Label | DRUG | A single-tablet FDC containing doravirine 100 mg, 3TC 300 mg and TDF 300 mg administered orally, once daily for either 12 or 24 weeks during the Open-Label Period; also an additional 96 weeks during the Open-Label extension period 1; a maximum total duration of treatment of 228 weeks during the Open-Label extension period 2; and a maximum total duration of treatment of 324 weeks during the Open-Label extension period 3. |
| ATRIPLA^TM | DRUG | A single tablet FDC containing efavirenz (EFV) 600 mg, emtricitabine (FTC) 200 mg, and TDF 300 mg administered orally, once daily for 12 weeks during the Blinded period |
| Placebo to ATRIPLA™ | DRUG | A single placebo to ATRIPLA™ tablet administered orally, once daily for 12 weeks during the Blinded period |
| Placebo to Doravirine, Tenofovir, Lamivudine | DRUG | A single placebo to doravirine, tenofovir, lamivudine tablet administered orally, once daily for 12 weeks during the Blinded period |
| Doravirine/lamivudine/tenofovir disoproxil fumarate | DRUG | FDC tablet containing MK-1439 (doravirine) 100 mg / lamivudine 300 mg / tenofovir disoproxil fumarate 300 mg taken by mouth. |
| Efavirenz | DRUG | Efavirenz 600 mg tablet orally at bedtime taken without food on an empty stomach for 96 weeks |
| TRUVADA® | DRUG | Open-label TRUVADA® (fixed combination 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate) tablet taken orally with food in the morning for 96 weeks |
| Placebo for Doravirine | DRUG | Placebo tablets matching doravirine |
| Placebo for Efavirenz | DRUG | Placebo tablets matching efavirenz |
| Methadone | DRUG | Methadone 20 to 200 mg (10 mg/mL if oral solution concentrate) oral tablet once per day. |
Inclusion Criteria: * Be at least 18 years of age on the day of signing the informed consent. * Be HIV-1 positive as determined according to national testing strategies * Have a plasma HIV-1 RNA ≥1000 copies/mL within 30 days prior to the randomization, * Have HIV treatment indication based on phys...
Doravirine is a small molecule antiviral medicine developed by Merck & Company, Inc. (MRK) for the treatment of HIV infections, including HIV-1 infection and human immunodeficiency virus infection. It is studied both as a single agent and in combination regimens, and it has also been evaluated in people with renal impairment.
Doravirine is used to treat HIV-1 infection and human immunodeficiency virus infection. It is being studied in treatment-naive adults living with HIV-1 and in children aged 4 weeks to under 12 years weighing less than 45 kg. It has also been assessed in virologically suppressed patients switching from another regimen.
Doravirine targets HIV-1. It is a small molecule directed at the virus itself rather than at a human protein, which is consistent with its development as an antiretroviral agent for HIV-1 infection and human immunodeficiency virus infection.
Doravirine is developed by Merck & Company, Inc., which trades under the ticker MRK. Merck is the sponsor of the clinical program, including the pediatric study MK-1439-066 and the switching study MK-1439A-028.
Doravirine is investigational and remains in clinical development. Its program spans Phase 1, Phase 2, and Phase 3 studies, and the overall development stage recorded for the asset is Phase 2. It is not described as approved, and the Phase 3 DORAvirine versus dolutegravir study NCT06203132 is currently recruiting.
Doravirine has been studied in five trials. NCT06203132 is a recruiting Phase 3 study comparing doravirine-based and dolutegravir-based antiretroviral regimens in treatment-naive adults with HIV-1. NCT04375800 is a recruiting Phase 2 pediatric study. NCT02715700 and NCT02652260 are completed Phase 1 and Phase 2 studies.