Evaluation of the Safety and Efficacy of Reformulated Raltegravir (MK-0518) 1200 mg Once Daily in Combination With TRUVADA™ in Human Immunodeficiency Virus (HIV)-1 Infected, Treatment-Naive Participants (MK-0518-292)

Study Overview
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Brief Summary
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To evaluate the safety and efficacy of reformulated raltegravir (MK-0518) 1200 mg once daily in combination with TRUVADA™ versus raltegravir 400 mg twice daily in combination with TRUVADA™ in HIV-1 infected, treatment-naive participants. The primary hypothesis being tested is that reformulated raltegravir 1200 mg once-daily is non-inferior to raltegravir 400 mg twice-daily, each in combination therapy with TRUVADA™, as assessed by the proportion of participants achieving HIV-1 ribonucleic acid (RNA) <40 copies/mL at Week 48.

Official Title
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A Phase III Multicenter, Double-Blind, Randomized, Active Comparator-Controlled Clinical Trial to Evaluate the Safety and Efficacy of Reformulated Raltegravir 1200 mg Once Daily Versus Raltegravir 400 mg Twice Daily, Each in Combination With TRUVADA™, in Treatment-Naïve HIV-1 Infected Subjects

Conditions
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HIV Infection

Intervention / Treatment
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* Drug: Reformulated Raltegravir
* Drug: Raltegravir
* Drug: TRUVADA™
* Drug: Placebo to Reformulated Raltegravir
* Drug: Placebo to Raltegravir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 positive Naïve to antiretroviral therapy including investigational antiretroviral agents Not of reproductive potential or, if of reproductive potential agrees to 1) true abstinence, or 2) use of an acceptable method of birth control during the study Exclusion Criteria: Use of recreational or illicit drugs or has recent history of drug or alcohol abuse or dependence 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, tenofovir, entecavir, emtricitabine, or lamivudine Has documented or known resistance to raltegravir, emtricitabine, and/or tenofovir before the first dose of study drug Has participated in a study with an investigational compound or device within 30 days or anticipates participating in such a study during this study Has used systemic immunosuppressive therapy or immune modulators within 30 days or is anticipated to need them during the study (short courses of corticosteroids are allowed) Requires or is anticipated to require any of the following prohibited medications while in the study: phenobarbital, phenytoin, rifampin, rifabutin, or calcium, magnesium and aluminum containing antacids, such as TUMS™, Maalox™ and Milk of Magnesia™ Has significant hypersensitivity or other contraindication to any of the components of the study drugs Has current, active diagnosis of acute hepatitis due to any cause Is pregnant, breastfeeding, or expecting to conceive during the study Female participant expecting to donate eggs or male participant expecting to donate sperm during the study Is or has a family member (spouse or children) who is investigational staff or sponsor staff directly involved in this trial

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Reformulated Raltegravir<br>Reformulated raltegravir 1200 mg (2x 600 mg tablets) orally once daily plus placebo to raltegravir 1 tablet orally twice daily plus TRUVADA™ orally once daily for 96 weeks | Drug: Reformulated Raltegravir<br>* Reformulated raltegravir 1200 mg (2x 600 mg tablets) orally once daily<br>Drug: TRUVADA™<br>* Emtricitabine / tenofovir disoproxil fumarate 200 / 300 mg tablet administered once-daily with food (open-label)<br>Drug: Placebo to Raltegravir<br>* Placebo to raltegravir 1 tablet orally twice daily<br>|
| Active Comparator: Raltegravir<br>Raltegravir 400 mg tablet orally twice daily plus placebo to reformulated raltegravir 2 tablets orally once daily plus TRUVADA™ orally once daily for 96 weeks | Drug: Raltegravir<br>* Raltegravir 400 mg tablet orally twice daily<br>Drug: TRUVADA™<br>* Emtricitabine / tenofovir disoproxil fumarate 200 / 300 mg tablet administered once-daily with food (open-label)<br>Drug: Placebo to Reformulated Raltegravir<br>* Placebo to reformulated raltegravir 2 tablets orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving <40 Copies/mL Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Week 48 | From blood samples collected at week 48, HIV-1 RNA levels were determined by the Abbott RealTime HIV-1 Assay, which has a limit of reliable quantification (LoQ) of 40 copies/mL. The NC=F approach as defined by FDA snapshot approach was used as the primary approach to analysis where all missing data were treated as failures regardless of the reason. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving <40 Copies/mL Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Week 96 | From blood samples collected at week 96, HIV-1 RNA levels were determined by the Abbott RealTime HIV-1 Assay, which has a limit of reliable quantification (LoQ) of 40 copies/mL. The NC=F approach as defined by FDA snapshot approach was used as the primary approach to analysis where all missing data were treated as failures regardless of the reason. | Week 96 | 
| Change From Baseline in Cluster of Differentiation 4 (CD4) Cell Count at Week 48 | CD4 cells were counted from blood collected at baseline and week 48, and the change from baseline determined from week 48 minus baseline values. | Baseline and Week 48 | 
| Change From Baseline in CD4 Cell Count at Week 96 | CD4 cells were counted from blood collected at baseline and week 96, and the change from baseline determined from week 96 minus baseline values. | Baseline and Week 96 | 
| Percentage of Participants With an Adverse Event (AE) at Week 48 | An adverse event (AE) is defined as 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 unfavourable and unintended sign (including an abnormal laboratory finding), 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 48 | 
| Percentage of Participants With an AE After 96 Weeks of Treatment | An AE is defined as 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 unfavourable and unintended sign (including an abnormal laboratory finding), 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 98 (96 weeks of treatment + 2 weeks of follow up) | 
| Percentage of Participants With a Drug-Related AE at Week 48 | An AE is defined as 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 unfavourable and unintended sign (including an abnormal laboratory finding), 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. An investigator who is a qualified physician evaluated whether or not an AE was drug-related. | Up to Week 48 | 
| Percentage of Participants With a Drug-Related AE After 96 Weeks of Treatment | An AE is defined as 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 unfavourable and unintended sign (including an abnormal laboratory finding), 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. An investigator who is a qualified physician evaluated whether or not an AE was drug-related. | Up to Week 98 (96 weeks of treatment + 2 weeks of follow up) | 
| Percentage of Participants With a Serious Adverse Event (SAE) at Week 48 | A serious adverse event (SAE) is any AE occurring at any dose or during any use of Sponsor's product that does the following: results in death; is life threatening; results in persistent or significant disability/incapacity; results in or prolongs an existing inpatient hospitalization; is a congenital anomaly/birth defect; is a cancer; is associated with an overdose; is another important medical event. | Up to Week 48 | 
| Percentage of Participants With a SAE After 96 Weeks of Treatment | A SAE is any AE occurring at any dose or during any use of Sponsor's product that does the following: results in death; is life threatening; results in persistent or significant disability/incapacity; results in or prolongs an existing inpatient hospitalization; is a congenital anomaly/birth defect; is a cancer; is associated with an overdose; is another important medical event. | Up to Week 98 (96 weeks of treatment + 2 weeks of follow up) | 
| Percentage of Participants With a Serious and Drug-Related AE at Week 48 | A SAE is any AE occurring at any dose or during any use of Sponsor's product that does the following: results in death; is life threatening; results in persistent or significant disability/incapacity; results in or prolongs an existing inpatient hospitalization; is a congenital anomaly/birth defect; is a cancer; is associated with an overdose; is another important medical event. An investigator who is a qualified physician evaluated whether or not a SAE is drug-related. | Up to Week 48 | 
| Percentage of Participants With a Serious and Drug-Related AE After 96 Weeks of Treatment | A SAE is any AE occurring at any dose or during any use of Sponsor's product that does the following: results in death; is life threatening; results in persistent or significant disability/incapacity; results in or prolongs an existing inpatient hospitalization; is a congenital anomaly/birth defect; is a cancer; is associated with an overdose; is another important medical event. An investigator who is a qualified physician evaluated whether or not a SAE is drug-related. | Up to Week 98 (96 weeks of treatment + 2 weeks of follow up) | 
| Percentage of Participants Who Discontinued From Drug Therapy Due to an AE at Week 48 | An AE is defined as 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 unfavourable and unintended sign (including an abnormal laboratory finding), 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 48 | 
| Percentage of Participants Who Discontinued From Drug Therapy Due to an AE up to Week 96 | An AE is defined as 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 unfavourable and unintended sign (including an abnormal laboratory finding), 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 96 |