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

Study Overview
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Brief Summary
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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.

Official Title
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Phase IIb, Double-Blinded, Multicenter, Randomized Study to Assess the Effect on Central Nervous System (CNS) Toxicity of Switching From ATRIPLA™ (Efavirenz, Tenofovir, Emtricitabine) to MK-1439A (Doravirine, Tenofovir, Lamivudine) in Virologically-Suppressed Subjects.

Conditions
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HIV-1, Central Nervous System

Intervention / Treatment
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* Drug: Doravirine, Tenofovir, Lamivudine - Blinded
* Drug: Doravirine, Tenofovir, Lamivudine - Open-Label
* Drug: ATRIPLA^TM
* Drug: Placebo to ATRIPLA™
* Drug: Placebo to Doravirine, Tenofovir, Lamivudine


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Immediate Switch to Doravirine, Tenofovir, Lamivudine<br>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. | Drug: Doravirine, Tenofovir, Lamivudine - Blinded<br>* 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<br>* Other names: MK-1439A;Drug: Doravirine, Tenofovir, Lamivudine - Open-Label<br>* 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.<br>* Other names: MK-1439A;Drug: Placebo to ATRIPLA™<br>* A single placebo to ATRIPLA™ tablet administered orally, once daily for 12 weeks during the Blinded period<br>|
| Experimental: Deferred Switch to Doravirine, Tenofovir, Lamivudine<br>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. | Drug: Doravirine, Tenofovir, Lamivudine - Open-Label<br>* 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.<br>* Other names: MK-1439A;Drug: ATRIPLA^TM<br>* 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<br>Drug: Placebo to Doravirine, Tenofovir, Lamivudine<br>* A single placebo to doravirine, tenofovir, lamivudine tablet administered orally, once daily for 12 weeks during the Blinded period<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With at Least One Central Nervous System (CNS) Toxicity of at Least Grade 2 Intensity at 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. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With at Least One CNS Toxicity of at Least Grade 2 Intensity at 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. | Week 4 | 
| Change From Baseline in CNS Toxicity Score at 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. | Baseline and Week 4 | 
| Change From Baseline in CNS Toxicity Score at 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. | Baseline and Week 12 | 
| 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 | 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. | Baseline (time of switch) and 24 weeks post-switch | 
| CNS Toxicity Scores at Time of Switch, and at 24 Weeks Post-switch for the Combined Treatment Groups | 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. | Baseline (time of switch) and 24 weeks post-switch | 
| Change From Baseline in Fasting Lipids at 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. | Baseline (study Day 1) and study week 12 | 
| Change in Fasting Lipids Between Time of Switch and Week 24 Post-switch for the Combined Treatment Groups | 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. | Baseline (time of switch) and 24 weeks post-switch | 
| Percentage of Participants With HIV-1 RNA <50 and <40 Copies/ml at Week 24 Post-switch for the Combined Treatment Groups | 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. | 24 weeks post-switch | 
| Change From Time of Switch to Week 24 Post Switch in CD4 T-cell Count for the Combined Treatment Groups | 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. | Baseline (time of switch) and 24 weeks post-switch | 
| Number of Participants With One or More Adverse Events (AEs) Through Study 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. | Up to Week 12 | 
| Number of Participants With One or More Drug-related AEs Through Study 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. | Up to Week 12 | 
| Number of Participants With One or More Serious Adverse Events (SAEs) Through Study 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. | Up to Week 12 | 
| Number of Participants With One or More Drug-related SAEs Through Study 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. | Up to Week 12 | 
| Number of Participants Who Discontinued Treatment Due to an AE Through Study 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. | Up to Week 12 | 
| Number of Participants With One or More AEs for the Combined Treatment Groups 24 Weeks After the 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. | 24 weeks post-switch | 
| Number of Participants With One or More Drug-related AEs for the Combined Treatment Groups 24 Weeks After the 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. | 24 weeks post-switch | 
| Number of Participants With One or More SAEs for the Combined Treatment Groups 24 Weeks After the 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. | 24 weeks post-switch | 
| Number of Participants With One or More Drug-related SAEs for the Combined Treatment Groups 24 Weeks After the 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. | 24 weeks post-switch | 
| Number of Participants Who Discontinued Treatment Due to an AE for the Combined Treatment Groups 24 Weeks After the 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. | 24 weeks post-switch |