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)

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02131233

Acronym

onceMRK

Enrollment

802

Registered

2014-05-06

Start date

2014-05-23

Completion date

2016-12-19

Last updated

2019-01-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

HIV Infection

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.

Interventions

DRUGReformulated Raltegravir

Reformulated raltegravir 1200 mg (2x 600 mg tablets) orally once daily

DRUGRaltegravir

Raltegravir 400 mg tablet orally twice daily

DRUGTRUVADA™

Emtricitabine / tenofovir disoproxil fumarate 200 / 300 mg tablet administered once-daily with food (open-label)

DRUGPlacebo to Reformulated Raltegravir

Placebo to reformulated raltegravir 2 tablets orally once daily

DRUGPlacebo to Raltegravir

Placebo to raltegravir 1 tablet orally twice daily

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants Achieving <40 Copies/mL Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Week 48	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

Measure	Time frame	Description
Change From Baseline in Cluster of Differentiation 4 (CD4) Cell Count at Week 48	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.
Change From Baseline in CD4 Cell Count at Week 96	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.
Percentage of Participants With an Adverse Event (AE) at Week 48	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.
Percentage of Participants With an AE After 96 Weeks of Treatment	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.
Percentage of Participants With a Drug-Related AE at Week 48	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.
Percentage of Participants With a Drug-Related AE After 96 Weeks of Treatment	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.
Percentage of Participants Achieving <40 Copies/mL Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Week 96	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.
Percentage of Participants With a SAE After 96 Weeks of Treatment	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.
Percentage of Participants With a Serious and Drug-Related AE at Week 48	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.
Percentage of Participants With a Serious and Drug-Related AE After 96 Weeks of Treatment	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.
Percentage of Participants Who Discontinued From Drug Therapy Due to an AE at Week 48	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
Percentage of Participants Who Discontinued From Drug Therapy Due to an AE up to Week 96	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
Percentage of Participants With a Serious Adverse Event (SAE) at Week 48	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.

Participant flow

Pre-assignment details

These results stop at Week 96.

Participants by arm

Arm	Count
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	531
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	266
Total	797

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	7	6
Overall Study	Death	0	1
Overall Study	Lack of Efficacy	6	3
Overall Study	Lost to Follow-up	14	13
Overall Study	Non-Compliance With Study Drug	8	5
Overall Study	Not Treated	2	3
Overall Study	Physician Decision	7	0
Overall Study	Pregnancy	4	0
Overall Study	Withdrawal by Subject	18	11

Baseline characteristics

Characteristic	Raltegravir	Total	Reformulated Raltegravir
Age, Continuous	36.9 Years STANDARD_DEVIATION 11	35.9 Years STANDARD_DEVIATION 10.5	35.4 Years STANDARD_DEVIATION 10.3
Sex: Female, Male Female	32 Participants	123 Participants	91 Participants
Sex: Female, Male Male	234 Participants	674 Participants	440 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	375 / 531	184 / 266
serious Total, serious adverse events	51 / 531	42 / 266

Outcome results

Primary

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.

Time frame: Week 48

Population: All randomized participants who received at least one dose of study treatment

Arm	Measure	Value (NUMBER)
Reformulated Raltegravir	Percentage of Participants Achieving <40 Copies/mL Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Week 48	88.9 Percentage of participants
Raltegravir	Percentage of Participants Achieving <40 Copies/mL Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Week 48	88.3 Percentage of participants

Comparison: The 95% Confidence Interval (CI) for the treatment differences in percent response were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (screening HIV-1 RNA \<=100,000 copies/mL or HIV-1 RNA \>100,000 copies/mL)95% CI: [-4.204, 5.223]

Secondary

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.

Time frame: Baseline and Week 96

Population: All randomized participants who received at least one dose of study treatment and have baseline data. The Observed Failure (OF) approach to handling missing values assumed baseline-carry-forward for all failures, and excluded other missing values.

Arm	Measure	Value (MEAN)
Reformulated Raltegravir	Change From Baseline in CD4 Cell Count at Week 96	261.6 cells/mm^3
Raltegravir	Change From Baseline in CD4 Cell Count at Week 96	262.2 cells/mm^3

Comparison: The 95% CI for mean difference in CD4 change was based on t-distribution.95% CI: [-32.8, 31.6]

Secondary

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.

Time frame: Baseline and Week 48

Arm	Measure	Value (MEAN)
Reformulated Raltegravir	Change From Baseline in Cluster of Differentiation 4 (CD4) Cell Count at Week 48	232.0 cells/mm^3
Raltegravir	Change From Baseline in Cluster of Differentiation 4 (CD4) Cell Count at Week 48	234.1 cells/mm^3

Comparison: The 95% CI for mean difference in CD4 change was based on t-distribution.95% CI: [-30.9, 26.7]

Secondary

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.

Time frame: Week 96

Population: All randomized participants who received at least one dose of study treatment

Arm	Measure	Value (NUMBER)
Reformulated Raltegravir	Percentage of Participants Achieving <40 Copies/mL Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Week 96	81.5 Percentage of participants
Raltegravir	Percentage of Participants Achieving <40 Copies/mL Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Week 96	80.1 Percentage of participants

Secondary

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

Time frame: Up to Week 48