Evaluating the Pharmacokinetics, Safety, and Tolerability of Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (MK-1439A) in HIV-1-Infected Children and Adolescents

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the pharmacokinetics, safety, and tolerability of doravirine (also called MK-1439 or DOR) and doravirine/lamivudine/tenofovir disoproxil fumarate (also called MK-1439A or DOR/3TC/TDF) in HIV-1-infected children and adolescents.

Detailed Description
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This study evaluated the pharmacokinetics (PK), safety, and tolerability of DOR and DOR/3TC/TDF in HIV-1-infected children and adolescents. This study was conducted in two cohorts: Cohort 1 and Cohort 2. At study entry (Day 0), participants in Cohort 1 received a single dose of DOR added to their current HIV regimens. (The antiretroviral drugs in their current HIV regimens were not be provided by the study.) Participants in Cohort 1 underwent intensive PK evaluations, and had an additional study visit at Week 2. The study team in consultation with a Study Monitoring Committee evaluated data from Cohort 1 before enrolling participants in Cohort 2. Participants in Cohort 2 received DOR/3TC/TDF once daily from Day 0 through Week 96. They had study visits at Weeks 1, 2, 4, 8, 12, 16, 24, 36, 48, 64, 80, and 96. Study visits included physical examinations, PK evaluations, and blood and urine collection.

Official Title
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Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (MK-1439A) in HIV-1-Infected Children and Adolescents

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Doravirine (DOR)
* Drug: Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF)
* Drug: Antiretroviral (ARV) medications


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Weight greater than or equal 35 kg at entry If not of legal age to provide independent informed consent: Parent or guardian was willing and able to provide written informed consent for study participation; in addition, when applicable per local Institutional Review Board / Ethics Committee (IRB/EC) policies and procedures, potential participant was willing and able to provide written informed assent for study participation. If of legal age to provide independent informed consent as determined by site Standard Operating Procedures (SOPs) and consistent with site IRB/EC policies and procedures: Potential participant was willing and able to provide written informed consent for study participation Confirmed HIV-1-infection based on documented testing of two samples collected at different time points. More information on this criterion can be found in the protocol. Antiretroviral therapy (ART) exposure, virologic suppression, and resistance requirements, as follows: Cohort 1 ART exposure requirements, based on individual or parent/guardian's report and, if available, confirmed by medical records: At entry, receiving combination ART with raltegravir (RAL) or dolutegravir (DTG) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs); AND At entry, had not received non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitor (PIs), or cobicistat within the previous 30 days; AND Virologic suppression, as documented in medical records and as defined by: One or more HIV RNA polymerase chain reaction (PCR) result below the level of quantification (BLLQ) within 15 months prior to enrollment, AND If any HIV RNA PCR tests had been done within 3 months prior to enrollment, all results were below the level of quantification, AND HIV RNA PCR result less than 40 copies/mL at screening, performed as per the protocol. Cohort 2 ART-naive ART exposure requirements, based on individual or parent/guardian's report and, if available, confirmed by medical records: At entry, received no antiretrovirals (ARVs) for treatment of HIV infection including investigational agents (prior receipt of ARVs for prevention of perinatal transmission was permitted); AND Screening genotypic resistance test results indicated susceptibility to doravirine (DOR), tenofovir disoproxil fumarate (TDF), and lamivudine (3TC) (see the protocol for more information; result must be available prior to enrollment), performed as per the protocol; AND If available, as documented in medical records, any prior genotypic resistance test result indicated susceptibility to DOR, TDF, and 3TC (see the protocol for more information). Note: For individuals that were re-screened, the genotypic resistance test did not need to be repeated. Cohort 2 ART-experienced ART exposure requirements, based on individual or parent/guardian's report and, if available, confirmed by medical records: No previous history of change in ARVs due to clinical or virologic failure, in the opinion of the site investigator or designee; AND Virologic suppression, as documented in medical record and as defined by: One or more HIV RNA PCR result BLLQ within 15 months prior to enrollment, AND If any HIV RNA PCR tests had been done within 3 months prior to enrollment, all results were below the level of quantification, AND HIV RNA PCR result less than 40 copies/mL at screening (see the protocol for more information); AND If available, as documented in medical records, any prior genotypic resistance test result indicated susceptibility to DOR, TDF, and 3TC (see the protocol for more information). Note: This group of ARV-experienced, virologically suppressed participants were only enrolled once there was data from the adult switch studies indicating virologic efficacy and safety (see the protocol for more information). Sites were informed via a Clarification Memorandum when ART-experienced participants could be enrolled. A single, unconfirmed HIV-1 RNA result greater than or equal to the level of quantification but less than 500 copies/mL, between 3 and 15 months, prior to enrollment was not exclusionary as long as the other criteria for documentation of virologic suppression were met. Grade 2 or lower hemoglobin, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase, and lipase on specimens obtained at screening For Cohort 2 only, grade 2 or lower creatinine, proteinuria, and glycosuria on specimens obtained at screening Estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m^2, on specimens obtained at screening, based on the Schwartz equation. More information on this criterion can be found in the protocol. For females who had reached menarche or who were engaging in sexual activity (self-reported), negative pregnancy test at entry For females engaging in sexual activity that could lead to pregnancy (self-reported), agreed to use two effective, medically accepted birth control methods while on study and for two weeks after permanently discontinuing study drug For males engaging in sexual activity that could lead to pregnancy (self-reported), agreed to use condoms while on study and for two weeks after permanently discontinuing study drug Able and willing to swallow available formulation(s) (tablet or, as available, oral granules). Exclusion Criteria: • 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. Note: Individuals with chronic hepatitis B who had grade 2 or lower ALT and AST and had no significant impairment of hepatic synthetic function (significant impairment of hepatic synthetic function was defined as a serum albumin less than 2.8 mg/dL or an international normalized ratio (INR) greater than 1.7 in the absence of another explanation for the abnormal laboratory value) were eligible. • For Cohort 2 only, detectable hepatitis C virus (HCV) by RNA PCR or current or planned treatment with direct antiviral agent for HCV. Note: HCV antibody positivity but undetectable by HCV RNA PCR results were permitted. Presence of any active AIDS-defining opportunistic infection History of malignancy (ever), with the exception of localized malignancies such as squamous cell or basal cell carcinoma of the skin Clinical evidence of pancreatitis, as determined by the clinician (at entry) Use of nafcillin, dicloxacillin, or any of the prohibited medications, within 30 days prior to study entry (see the protocol for a complete list of prohibited medications) For females, currently breastfeeding an infant at entry Enrolled in another clinical trial of an investigational agent, device, or vaccine Unlikely to adhere to the study procedures or keep appointments, in the opinion of the site investigator or designee Used, or anticipates using, chronic systemic immunosuppressive agents or systemic interferon (e.g., for treatment of HCV infection) within 30 days prior to study entry. Note: Systemic corticosteroids (e.g., prednisone or equivalent up to 2 mg/kg/day) for replacement therapy or short courses (less than or equal to 30 days) were permitted. See the protocol for a complete list of prohibited medications. Diagnosed with current active tuberculosis and/or was currently being treated with a rifampicin-containing regimen Individual had any other condition, that in the opinion of the site investigator or designee, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving study objectives

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: DOR<br>Participants received a single dose of DOR at study entry (Day 0). | Drug: Doravirine (DOR)<br>* 100 mg of DOR administered orally<br>* Other names: MK-1439;Drug: Antiretroviral (ARV) medications<br>* Participants in Cohort 1 received a combination of dolutegravir (DTG) or raltegravir (RAL) plus two nucleoside reverse transcriptase inhibitors (NRTIs). The ARV drugs were prescribed by participants' own health care providers and were not provided by the study.<br>* Other names: ARVs;|
| Experimental: Cohort 2: DOR/3TC/TDF<br>Participants received DOR/3TC/TDF from Day 0 through Week 96. | Drug: Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF)<br>* DOR/3TC/TDF administered orally as a fixed-dose combination (as a tablet, 100 mg/300 mg/300 mg) once daily<br>* Other names: MK-1439A;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) Parameter: Single-dose Area-under-the-curve (AUC0-∞) of Doravirine (DOR) (Cohort 1) | Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin version 6.3, Pharsight Corp., Mountain View, CA). Area under the curve (AUC) was determined using non-compartmental analyses and estimated by the linear up/log down trapezoidal rule, from time zero to infinity. Steady state AUC0-24 is equivalent to single dose AUC0-∞. | Measured during the entry (day 0) visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12, 24, 48 and 72 hours post-dose. | 
| PK Parameter: Single-dose Maximum Concentration (Cmax) of DOR (Cohort 1) | Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). | Measured during the entry (day 0) visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12, 24, 48 and 72 hours post-dose. | 
| PK Parameter: Single-dose 24 Hour-concentration (C24hr) of DOR (Cohort 1) | Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). | Measured during the entry (day 0) visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12, 24, 48 and 72 hours post-dose. | 
| Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug | Percentage and Clopper-Pearson 95% Confidence Interval (CI) of participants with Grade 3 or higher AEs judged by the medical clinic as related to the study drug. AEs were graded based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017 (see References). | Cohort 1: Measured from Day 0 through Week 2; Cohort 2: Measured from Day 0 through Week 24. | 
| Percentage of Participants With Serious Adverse Events (SAEs) Assessed as Related to Study Drug | Percentage and Clopper-Pearson 95% CI of participants with SAEs judged by the medical clinic as related to the study drug. SAEs were reported according to Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual) (see references). | Cohort 1: Measured from Day 0 through Week 2; Cohort 2: Measured from Day 0 through Week 24. | 
| Percentage of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events Assessed as Related to Study Drug | Percentage and Clopper-Pearson 95% CI of participants with permanent discontinuation of study drug due to AEs judged by the medical clinic as related to the study drug. | Cohort 1: Measured from Day 0 through Week 2; Cohort 2: Measured from Day 0 through Week 24. | 
| Percentage of Participants With Grade 5 Adverse Events (Death) Regardless of Relationship to Study Drug | Percentage and Clopper-Pearson 95% CI of participants with Grade 5 AEs (death) regardless of relationship to study drug. | Cohort 1: Measured from Day 0 through Week 2; Cohort 2: Measured from Day 0 through Week 24. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK Parameter: AUC0-24hr of DOR (Cohort 2) | Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Area under the curve (AUC) was determined using non-compartmental analyses and estimated by the linear up/log down trapezoidal rule, from time zero to 24 hours. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2. | Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 2, 4, 12 and 24 hours post-dose. | 
| PK Parameter: AUC0-24hr of 3TC (Cohort 2) | Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Area under the curve (AUC) was determined using non-compartmental analyses and estimated by the linear up/log down trapezoidal rule, from time zero to 24 hours. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2. | Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12 and 24 hours post-dose. | 
| PK Parameter: AUC0-24hr of Tenofovir (Cohort 2) | Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Area under the curve (AUC) was determined using non-compartmental analyses and estimated by the linear up/log down trapezoidal rule, from time zero to 24 hours. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2. | Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12 and 24 hours post-dose. | 
| PK Parameter: Cmax of DOR (Cohort 2) | Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Cmax was projected from individual plasma concentration-time profiles using the non-parametric superposition function in WinNonLin v6.3. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2. | Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 2, 4, 12 and 24 hours post-dose. | 
| PK Parameter: Cmax of 3TC (Cohort 2) | Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Cmax was projected from individual plasma concentration-time profiles using the non-parametric superposition function in WinNonLin v6.3. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2. | Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12 and 24 hours post-dose. | 
| PK Parameter: Cmax of Tenofovir (Cohort 2) | Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Cmax was projected from individual plasma concentration-time profiles using the non-parametric superposition function in WinNonLin v6.3. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2. | Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12 and 24 hours post-dose. | 
| PK Parameter: C24hr of DOR (Cohort 2) | Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). C24hr was projected from individual plasma concentration-time profiles using the non-parametric superposition function in WinNonLin v6.3. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2. | Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 2, 4, 12 and 24 hours post-dose. | 
| PK Parameter: C24hr of 3TC (Cohort 2) | Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). C24hr was projected from individual plasma concentration-time profiles using the non-parametric superposition function in WinNonLin v6.3. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2. | Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12 and 24 hours post-dose. | 
| PK Parameter: C24hr of Tenofovir (Cohort 2) | Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). C24hr was projected from individual plasma concentration-time profiles using the non-parametric superposition function in WinNonLin v6.3. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2. | Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12 and 24 hours post-dose. | 
| Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 24 (Cohort 2) | Virologic responses were assessed at week 24 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA >200 copies/mL; otherwise participants with missing values were excluded. | Measured at week 24. | 
| Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 48 (Cohort 2) | Virologic responses were assessed at week 48 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA >200 copies/mL; otherwise participants with missing values were excluded. | Measured at week 48. | 
| Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 96 (Cohort 2) | Virologic responses were assessed at week 96 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA >200 copies/mL; otherwise participants with missing values were excluded. | Measured at week 96. | 
| Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 24 (Cohort 2) | Virologic responses were assessed at week 24 as percentage of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA >50 copies/mL. Otherwise participants with missing values were excluded. | Measured at week 24. | 
| Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 48 (Cohort 2) | Virologic responses were assessed at week 48 as percentage of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA >50 copies/mL. Otherwise participants with missing values were excluded. | Measured at week 48. | 
| Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 96 (Cohort 2) | Virologic responses were assessed at week 96 as percentage of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA >50 copies/mL. Otherwise participants with missing values were excluded. | Measured at week 96. | 
| Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 24 (Cohort 2) | Virologic responses were assessed at week 24 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA >40 copies/mL; Otherwise participants with missing values were excluded. | Measured at week 24. | 
| Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 48 (Cohort 2) | Virologic responses were assessed at week 48 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA >40 copies/mL; Otherwise participants with missing values were excluded. | Measured at week 48. | 
| Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 96 (Cohort 2) | Virologic responses were assessed at week 96 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA >40 copies/mL; Otherwise participants with missing values were excluded. | Measured at week 96. | 
| Summary of log10 Drop From Baseline to Week 24 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2) | The differences between log10 HIV RNA at Week 24 minus at Day 0 are summarized. | Measured at Day 0 and week 24. | 
| Summary of log10 Drop From Baseline to Week 48 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2) | The differences between log10 HIV RNA at Week 48 minus at Day 0 are summarized. | Measured at Day 0 and week 48. | 
| Summary of log10 Drop From Baseline to Week 96 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2) | The differences between log10 HIV RNA at Week 96 minus at Day 0 are summarized. | Measured at Day 0 and week 96. | 
| Summary of Changes in CD4 Count From Baseline to Week 24 (Cohort 2) | The mean difference is calculated as CD4 count at Week 24 minus CD4 count at Day 0 with associated 95% Clopper-Pearson CI. | Measured at Day 0 and week 24. | 
| Summary of Changes in CD4 Count From Baseline to Week 48 (Cohort 2) | The mean differences is calculated as CD4 count at Week 48 minus CD4 count at Day 0 with associated 95% Clopper-Pearson CI. | Measured at Day 0 and week 48. | 
| Summary of Changes in CD4 Count From Baseline to Week 96 (Cohort 2) | The mean difference is calculated as CD4 count at Week 96 minus CD4 count at Day 0 with associated 95% Clopper-Pearson CI. | Measured at Day 0 and week 96. | 
| Summary of Changes in CD4% From Baseline to Week 24 (Cohort 2) | The mean difference is calculated as CD4% at Week 24 minus CD4% at Day 0 with associated 95% Clopper-Pearson CI. | Measured at Day 0 and week 24. | 
| Summary of Changes in CD4% From Baseline to Week 48 (Cohort 2) | The mean difference is calculated as CD4% at Week 48 minus CD4% at Day 0 with associated 95% Clopper-Pearson CI. | Measured at Day 0 and week 48. | 
| Summary of Changes in CD4% From Baseline to Week 96 (Cohort 2) | The mean difference is calculated as CD4% at Week 96 minus CD4% at the Day 0 with associated 95% Clopper-Pearson CI. | Measured at Day 0 and week 96. | 
| Percentage of Participants With Grade 3 or Higher Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study | Percentage and Clopper-Pearson 95% CI of participants with Grade 3 or higher AEs judged by the medical clinic as related to the study drug. AEs were graded based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017 (DAIDS) AE Grading table corrected version 2.1 (see References). | Measured from Day 0 through Week 96. | 
| Percentage of Participants With Serious Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study | Percentage and Clopper-Pearson 95% CI of participants with SAEs judged by the medical clinic as related to the study drug. SAEs were reported according to version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual) (see references). | Measured from Day 0 through Week 96. | 
| Percentage of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study | Percentage and Clopper-Pearson 95% CI of participants with permanent discontinuation of study drug due to AEs judged by the medical clinic as related to the study drug. | Measured from Day 0 through Week 96. | 
| Percentage of Participants With Grade 5 Adverse Events (Death) Regardless of Relationship to Study Drug (Cohort 2) Through End of Study | Percentage and Clopper-Pearson 95% CI of participants with Grade 5 adverse events (death). | Measured from Day 0 through Week 96. |