Effects of Switching From ATRIPLA™ (Efavirenz, Tenofovir, Emtricitabine) to MK-1439A (Doravirine, Tenofovir, Lamivudine) in Virologically-Suppressed Participants (MK-1439A-028)

Phase 2

Completed

Conditions: HIV-1
Central Nervous System

Interventions: Drug: Doravirine, Tenofovir, Lamivudine - Blinded
Drug: ATRIPLA^TM
Drug: Doravirine, Tenofovir, Lamivudine - Open-Label
Drug: Placebo to ATRIPLA™
Drug: Placebo to Doravirine, Tenofovir, Lamivudine

Registration Number: NCT02652260

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: This study aims to evaluate a switch from fixed dose combination (FDC) treatment with ATRIPLA\^TM for 12 weeks prior to screening to FDC treatment with Doravirine, Tenofovir, Lamivudine (MK-1439A) in virologically-suppressed, human immunodeficiency virus type 1 (HIV-1)-infected participants. The primary hypothesis is that switching from ATRIPLA\^TM to Doravirine, Tenofovir, Lamivudine results in a lower proportion of participants with at least one CNS toxicity of at least Grade 2 intensity at Week 12 than continuation of ATRIPLA\^TM treatment.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 86

Inclusion Criteria

is taking ATRIPLA™, generic versions of ATRIPLA™, or the components of ATRIPLA™ (EFV,TDF plus emtricitabine),
has documentation of HIV-1 ribonucleic acid (RNA) < 50 copies/mL during the 12 weeks prior to screening while on ATRIPLA™.
has plasma HIV-1 RNA levels below the limits of quantification (BLoQ) at the screening visit.
if genotyped prior to starting initial antiretroviral regimen, must have no known resistance to any of the study agents
has at least one EFV-associated CNS toxicities of Grade 2 or worse intensity both at the time of screening and at Study Day 1
is highly unlikely to become pregnant or to impregnate a partner
To be eligible for study extension 1, participants from Immediate Switch Group (ISG) must have completed Study Week 24, and benefited from study participation; participants from Deferred Switch Group (DSG) must have completed Study Week 36, and benefited from study participation as determined by the investigator
To be eligible for study extension 2, participants from ISG must have completed Study Week 120, and benefited from study participation; participants from DSG must have completed Study Week 132, and benefited from study participation as determined by the investigator

Exclusion Criteria

is a user of recreational or illicit drugs or has had a recent history of drug or alcohol abuse or dependence.
has ongoing Grade 4 CNS toxicity during screening period that requires a prompt change in ART
has been treated for a viral infection other than HIV-1, such as hepatitis B, with an agent that is active against HIV-1 including, but not limited to, adefovir, emtricitabine, entecavir, lamivudine or tenofovir.
has documented or known resistance to study drugs including doravirine, lamivudine, and/or tenofovir
has participated in, or anticipates participating in a study with an investigational compound/device within 30 days prior to signing informed consent
has used systemic immunosuppressive therapy or immune modulators or anticipates using them within 30 days prior to this study
requires or anticipates requiring any of the prohibited medications
has significant hypersensitivity or other contraindication to any of the components of the study drugs
has a current (active) diagnosis of acute hepatitis due to any cause.
has evidence of decompensated liver disease manifested by the presence of or a history of ascites, esophageal or gastric variceal bleeding, hepatic encephalopathy or other signs or symptoms of advanced liver diseases, or has liver cirrhosis and a Child-Pugh Class C score or Pugh-Turcotte (CPT) score > 9.
is pregnant, breastfeeding, or expecting to conceive.
female is expecting to donate eggs (at any time during the study) or male is expecting to donate sperm (at any time during the study).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Immediate Switch to Doravirine, Tenofovir, Lamivudine	Placebo to ATRIPLA™	Participants on a baseline regimen of ATRIPLA™ for at least 12 weeks prior to screening will be switched to blinded doravirine, tenofovir, lamivudine orally, once daily for 12 weeks, followed by open-label doravirine, tenofovir, lamivudine orally, once daily for an additional 12 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 216 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 312 weeks.
Deferred Switch to Doravirine, Tenofovir, Lamivudine	ATRIPLA^TM	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.
Deferred Switch to Doravirine, Tenofovir, Lamivudine	Placebo to Doravirine, Tenofovir, Lamivudine	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.
Immediate Switch to Doravirine, Tenofovir, Lamivudine	Doravirine, Tenofovir, Lamivudine - Blinded	Participants on a baseline regimen of ATRIPLA™ for at least 12 weeks prior to screening will be switched to blinded doravirine, tenofovir, lamivudine orally, once daily for 12 weeks, followed by open-label doravirine, tenofovir, lamivudine orally, once daily for an additional 12 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 216 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 312 weeks.
Immediate Switch to Doravirine, Tenofovir, Lamivudine	Doravirine, Tenofovir, Lamivudine - Open-Label	Participants on a baseline regimen of ATRIPLA™ for at least 12 weeks prior to screening will be switched to blinded doravirine, tenofovir, lamivudine orally, once daily for 12 weeks, followed by open-label doravirine, tenofovir, lamivudine orally, once daily for an additional 12 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 216 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 312 weeks.
Deferred Switch to Doravirine, Tenofovir, Lamivudine	Doravirine, Tenofovir, Lamivudine - Open-Label	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.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With at Least One Central Nervous System (CNS) Toxicity of at Least Grade 2 Intensity at Week 12	Week 12	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With at Least One CNS Toxicity of at Least Grade 2 Intensity at Week 4	Week 4	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.
Change From Baseline in CNS Toxicity Score at Week 4	Baseline and Week 4	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. The CNS toxicity score was calculated by summing across all 10 CNS toxicities and converting the sum to a percentage of the maximum possible sum of intensities (10 x 3 = 30). A positive change from baseline score indicates worsening symptoms. A negative change from baseline score indicates improvement in symptoms.
Change From Baseline in CNS Toxicity Score at Week 12	Baseline and Week 12	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. The CNS toxicity score was calculated by summing across all 10 CNS toxicities and converting the sum to a percentage of the maximum possible sum of intensities (10 x 3 = 30). A positive change from baseline score indicates worsening symptoms. A negative change from baseline score indicates improvement in symptoms.
Percentage of Participants With at Least One CNS Toxicity of at Least Grade 2 Intensity at Time of Switch, and at 24 Weeks Post-switch for the Combined Treatment Groups	Baseline (time of switch) and 24 weeks post-switch	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. For the Immediate Switch Group (ISG) time of switch was study Day 1, and week 24 post-switch was week 24. For the Delayed Switch Group (DSG) time of switch was study week 12, and week 24 post-switch was week 36.
CNS Toxicity Scores at Time of Switch, and at 24 Weeks Post-switch for the Combined Treatment Groups	Baseline (time of switch) and 24 weeks post-switch	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). The CNS toxicity score was calculated by summing across all 10 CNS toxicities and converting the sum to a percentage of the maximum possible sum of intensities (10 x 3 = 30). A higher CNS score indicates worse symptoms. A positive change in CNS score indicates worsening symptoms. A negative change indicates improvement in symptoms. For the ISG time of switch was study Day 1, and week 24 post-switch was week 24. For the DSG time of switch was study week 12, and week 24 post-switch was week 36.
Change From Baseline in Fasting Lipids at Week 12	Baseline (study Day 1) and study week 12	Blood was collected under fasting conditions on Day 1 and on week 12 in order to determine the concentration of the following lipids: low-density lipoprotein (LDL) cholesterol; Non high-density lipoprotein (HDL) cholesterol; cholesterol; HDL cholesterol; and triglyceride.
Change in Fasting Lipids Between Time of Switch and Week 24 Post-switch for the Combined Treatment Groups	Baseline (time of switch) and 24 weeks post-switch	Blood was collected under fasting conditions at time of switch and 24 weeks post-switch in order to determine the change from baseline of the following lipids: low-density lipoprotein (LDL) cholesterol; Non high-density lipoprotein (HDL) cholesterol; cholesterol; HDL cholesterol; and triglyceride. For the ISG time of switch was study Day 1, and week 24 post-switch was week 24. For the DSG time of switch was study week 12, and week 24 post-switch was week 36.
Percentage of Participants With HIV-1 RNA <50 and <40 Copies/ml at Week 24 Post-switch for the Combined Treatment Groups	24 weeks post-switch	Blood was collected under fasting conditions at 24 weeks post-switch in order to determine the HIV-1 RNA. For the ISG week 24 post-switch was week 24. For the DSG week 24 post-switch was week 36.
Change From Time of Switch to Week 24 Post Switch in CD4 T-cell Count for the Combined Treatment Groups	Baseline (time of switch) and 24 weeks post-switch	Blood was collected at time of switch and at 24 weeks post-switch in order to determine the CD4 T-cell count. For the ISG time of switch was study Day 1, and week 24 post-switch was week 24. For the DSG time of switch was study week 12, and week 24 post-switch was week 36.
Number of Participants With One or More Adverse Events (AEs) Through Study Week 12	Up to Week 12	An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol - specified procedure, whether or not considered related to the medicinal product or protocol - specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Number of Participants With One or More Drug-related AEs Through Study Week 12	Up to Week 12	An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol - specified procedure, whether or not considered related to the medicinal product or protocol - specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. A drug-related AE was determined by the investigator to be related to the drug.
Number of Participants With One or More Serious Adverse Events (SAEs) Through Study Week 12	Up to Week 12	A serious adverse event (SAE) is any AE occurring at any dose or during any use of Sponsor's product that results in any of the following: death; is life threatening; results in persistent or significant disability/incapacity; results in or prolongs an existing hospitalization; is a congenital anomaly/birth defect; is another important medical event; is a cancer; is associated with an overdose.
Number of Participants With One or More Drug-related SAEs Through Study Week 12	Up to Week 12	A serious adverse event (SAE) is any AE occurring at any dose or during any use of Sponsor's product that results in any of the following: death; is life threatening; results in persistent or significant disability/incapacity; results in or prolongs an existing hospitalization; is a congenital anomaly/birth defect; is another important medical event; is a cancer; is associated with an overdose. A drug-related SAE was determined by the investigator to be related to the drug.
Number of Participants Who Discontinued Treatment Due to an AE Through Study Week 12	Up to Week 12	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol - specified procedure, whether or not considered related to the medicinal product or protocol - specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Number of Participants With One or More AEs for the Combined Treatment Groups 24 Weeks After the Switch	24 weeks post-switch	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol - specified procedure, whether or not considered related to the medicinal product or protocol - specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. For the ISG 24 week post-switch was week 24; for the DSG week 24 post-switch was week 36.
Number of Participants With One or More Drug-related AEs for the Combined Treatment Groups 24 Weeks After the Switch	24 weeks post-switch	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol - specified procedure, whether or not considered related to the medicinal product or protocol - specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. A drug-related AE was determined by the investigator to be related to the drug. For the ISG 24 week post-switch was week 24; for the DSG week 24 post-switch was week 36.
Number of Participants With One or More SAEs for the Combined Treatment Groups 24 Weeks After the Switch	24 weeks post-switch	A serious adverse event (SAE) is any AE occurring at any dose or during any use of Sponsor's product that results in any of the following: death; is life threatening; results in persistent or significant disability/incapacity; results in or prolongs an existing hospitalization; is a congenital anomaly/birth defect; is another important medical event; is a cancer; is associated with an overdose. For the ISG 24 week post-switch was week 24; for the DSG week 24 post-switch was week 36.
Number of Participants With One or More Drug-related SAEs for the Combined Treatment Groups 24 Weeks After the Switch	24 weeks post-switch	A serious adverse event (SAE) is any AE occurring at any dose or during any use of Sponsor's product that results in any of the following: death; is life threatening; results in persistent or significant disability/incapacity; results in or prolongs an existing hospitalization; is a congenital anomaly/birth defect; is another important medical event; is a cancer; is associated with an overdose. A drug-related SAE was determined by the investigator to be related to the drug. For the ISG 24 week post-switch was week 24; for the DSG week 24 post-switch was week 36.
Number of Participants Who Discontinued Treatment Due to an AE for the Combined Treatment Groups 24 Weeks After the Switch	24 weeks post-switch	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol - specified procedure, whether or not considered related to the medicinal product or protocol - specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. For the ISG 24 week post-switch was week 24; for the DSG week 24 post-switch was week 36.