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) (onceMRK)

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
HIV Infection	Drug: Reformulated Raltegravir; Drug: Raltegravir; Drug: TRUVADA™; Drug: Placebo to Reformulated Raltegravir; Drug: Placebo to Raltegravir	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	802 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	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
Actual Study Start Date :	May 23, 2014
Actual Primary Completion Date :	December 21, 2015
Actual Study Completion Date :	December 19, 2016

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Reformulated Raltegravir; 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; Reformulated raltegravir 1200 mg (2x 600 mg tablets) orally once daily; Drug: TRUVADA™; Emtricitabine / tenofovir disoproxil fumarate 200 / 300 mg tablet administered once-daily with food (open-label); Drug: Placebo to Raltegravir; Placebo to raltegravir 1 tablet orally twice daily
Active Comparator: Raltegravir; 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; Raltegravir 400 mg tablet orally twice daily; Drug: TRUVADA™; Emtricitabine / tenofovir disoproxil fumarate 200 / 300 mg tablet administered once-daily with food (open-label); Drug: Placebo to Reformulated Raltegravir; Placebo to reformulated raltegravir 2 tablets orally once daily

Outcome Measures

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Primary Outcome Measures :

1. Percentage of Participants Achieving <40 Copies/mL Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Week 48 [ Time Frame: 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.

Secondary Outcome Measures :

1. Percentage of Participants Achieving <40 Copies/mL Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Week 96 [ Time Frame: 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.
2. Change From Baseline in Cluster of Differentiation 4 (CD4) Cell Count at Week 48 [ Time Frame: Baseline and 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.
3. Change From Baseline in CD4 Cell Count at Week 96 [ Time Frame: Baseline and 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.
4. Percentage of Participants With an Adverse Event (AE) at Week 48 [ Time Frame: Up to 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.
5. Percentage of Participants With an AE After 96 Weeks of Treatment [ Time Frame: Up to Week 98 (96 weeks of treatment + 2 weeks of follow up) ]
   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.
6. Percentage of Participants With a Drug-Related AE at Week 48 [ Time Frame: Up to 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.
7. Percentage of Participants With a Drug-Related AE After 96 Weeks of Treatment [ Time Frame: Up to Week 98 (96 weeks of treatment + 2 weeks of follow up) ]
   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.
8. Percentage of Participants With a Serious Adverse Event (SAE) at Week 48 [ Time Frame: Up to 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.
9. Percentage of Participants With a SAE After 96 Weeks of Treatment [ Time Frame: Up to Week 98 (96 weeks of treatment + 2 weeks of follow up) ]
   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.
10. Percentage of Participants With a Serious and Drug-Related AE at Week 48 [ Time Frame: Up to 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.
11. Percentage of Participants With a Serious and Drug-Related AE After 96 Weeks of Treatment [ Time Frame: Up to Week 98 (96 weeks of treatment + 2 weeks of follow up) ]
    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.
12. Percentage of Participants Who Discontinued From Drug Therapy Due to an AE at Week 48 [ Time Frame: Up to 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
13. Percentage of Participants Who Discontinued From Drug Therapy Due to an AE up to Week 96 [ Time Frame: 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

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Investigators

Study Director:	Medical Director	Merck Sharp & Dohme Corp.

More Information

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Publications of Results:

Cahn P, Kaplan R, Sax PE, Squires K, Molina JM, Avihingsanon A, Ratanasuwan W, Rojas E, Rassool M, Bloch M, Vandekerckhove L, Ruane P, Yazdanpanah Y, Katlama C, Xu X, Rodgers A, East L, Wenning L, Rawlins S, Homony B, Sklar P, Nguyen BY, Leavitt R, Teppler H; ONCEMRK Study Group. Raltegravir 1200 mg once daily versus raltegravir 400 mg twice daily, with tenofovir disoproxil fumarate and emtricitabine, for previously untreated HIV-1 infection: a randomised, double-blind, parallel-group, phase 3, non-inferiority trial. Lancet HIV. 2017 Nov;4(11):e486-e494. doi: 10.1016/S2352-3018(17)30128-5. Epub 2017 Sep 11.

Responsible Party:	Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:	NCT02131233 History of Changes
Other Study ID Numbers:	0518-292; 2013-001939-47 ( EudraCT Number )
First Posted:	May 6, 2014
Results First Posted:	October 31, 2016
Last Update Posted:	August 22, 2018
Last Verified:	July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
Plan Description:	https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
URL:	http://engagezone.msd.com/ds_documentation.php

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Additional relevant MeSH terms:

HIV Infections; Acquired Immunodeficiency Syndrome; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; Raltegravir Potassium	Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors