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Comparative Trial Of Maraviroc Versus Emtricitabine/Tenofovir Both With Darunavir/Ritonavir In Antiretroviral-Naive Patients Infected With CCR5 Tropic HIV 1 (MODERN)

This study has been terminated.
(See termination reason in detailed description.)
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT01345630
First received: April 27, 2011
Last updated: December 11, 2015
Last verified: December 2015
  Purpose
The purpose of this study is to assess whether maraviroc administered once daily is non-inferior to emtricitabine/tenofovir also administered once daily each in combination with darunavir/ritonavir in the treatment of antiretroviral-naive patients as evaluated at Week 48 of treatment.

Condition Intervention Phase
HIV-1
Drug: Maraviroc
Drug: Emtricitabine/tenofovir
Drug: darunavir/ritonavir 800/100 mg
Drug: placebo for emtricitabine/tenofovir
Drug: placebo for maraviroc
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Double‑Blind, Comparative Trial Of Maraviroc + Darunavir/Ritonavir Versus Emtricitabine/Tenofovir + Darunavir/Ritonavir For The Treatment Of Antiretroviral‑Naive Hiv‑Infected Patients With Ccr5‑Tropic Hiv‑1

Resource links provided by NLM:


Further study details as provided by ViiV Healthcare:

Primary Outcome Measures:
  • Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL. [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    The proportion of participants who achieved HIV-1 RNA <50 copies/mL at week 48 was assessed according to Food and Drug Administration's (FDA's) Missing, Switch, Discontinuation'=Failure (MSDF) Snapshot algorithm. The algorithm used the plasma HIV-1 RNA in the Week 48 visit window, followed the "virology-first principle" and considers a participant who has a missing plasma HIV-1 RNA, or switches to prohibited ARV regimen or discontinues from the study or study drug for any reason, or dies, as a failure.


Secondary Outcome Measures:
  • Frequency of Adverse Events (AE). [ Time Frame: Week 96 ] [ Designated as safety issue: Yes ]
    Number of participants with treatment-emergent non serious AEs

  • Number of Participants With Grade 3 or 4 AEs [ Time Frame: Week 96 ] [ Designated as safety issue: Yes ]
    Number of participants with grade 3 or 4 AEs are presented here.

  • Number of Participants Who Discontinued Due to AEs [ Time Frame: Week 96 ] [ Designated as safety issue: Yes ]
    Number of participants who discontinued due to AEs are reported here. Three participants (two from the MVC+DRV/r arm and one from the FTC/TDF+DRV/r arm) were not considered as discontinued due to AE because other reasons for discontinuation were prioritized for these participants.

  • Number of Treatment-related AEs [ Time Frame: Week 96 ] [ Designated as safety issue: Yes ]
    Number of treatment-related AEs are presented here.

  • Number of Participants With Treatment-emergent Serious Adverse Events [ Time Frame: Week 96 ] [ Designated as safety issue: Yes ]
    Total number of participants with treatment-emergent serious adverse events are reported

  • Number of Participants With Abnormal Laboratory Values [ Time Frame: Week 96 ] [ Designated as safety issue: Yes ]
    Number of participants with laboratory abnormalities are reported

  • Severity of Abnormal Laboratory Values [ Time Frame: Week 96 ] [ Designated as safety issue: Yes ]
    Number of participants who had clinically significant laboratory abnormalities of Grade 3 and Grade 4 according to DAIDS. Abnormality incidence of highest grade was reported for a labcode for each individual participant.

  • The Relationship Between the Proportion of Participants With Plasma HIV-1 RNA <50 Copies/mL at the Week 48 and the Screening Tropism Test (Genotype Test or ESTA). [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    The relationship of the proportion of participants achieving HIV-1 RNA <50 copies/mL at Week 48 with the screening tropism test for the MVC containing regimen was analyzed. Virologic response for a participant at Week 48 was derived using the FDA's Snapshot MSDF algorithm. Difference in proportions of patients with plasma HIV-1 RNA <50 copies/mL at week 48 between the maraviroc and the emtricitabine/tenofovir treatment arms, with two-sided 95% confidence interval, among patients who are R5 by genotype (including some who were originally randomized to ESTA and are R5 by genotype upon retesting), were calculated via the Maximum Likelihood method. The estimate was adjusted for the screening plasma HIV RNA level (<100,000 vs. ≥100,000) copies/mL via the Mantel Haenszel (MH) method.

  • Virologic Outcomes at Week 48 Using Protocol-Defined Treatment Failure (PDTF). [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    Per the protocol participants who meet the following criteria were regarded as PDTFs requiring a confirmatory plasma HIV-1 RNA determination: • Decrease in plasma HIV-1 RNA <1 log10 from baseline after Week 4 unless plasma HIV-1 RNA is <50 copies/mL, or • Plasma HIV-1 RNA >1.0 log10 above the nadir value after Week 4 where the nadir is the lowest plasma HIV-1 RNA concentration, or • Plasma HIV-1 RNA ≥50 copies/mL at any time after Week 24, or • Plasma HIV-1 RNA ≥50 copies/mL after suppression to <50 copies/mL on two consecutive visits, or • Decrease in plasma HIV-1 RNA ≤2 log10 from baseline on or after Week 12 unless plasma HIV-1 RNA is <400 copies/mL. Decrease in plasma HIV-1 RNA ≤2 log10 from baseline on or after Week 12 unless plasma HIV-1 RNA is <50 copies/mL (before August 30 2012) or <400 copies/mL (after August 30 2012).

  • Tropism Change Between Screening or Baseline and PDTF [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    For participants meeting the PDTF criteria, tropism was assessed using the original randomized and alternate assays (ie, both genotype testing and ESTA). Data reported here corresponds to the timepoint at or after PDTF.

  • Number of Participants With Viral Resistance to Maraviroc (Maraviroc Treated Participants Only) in Participants Meeting PDTF Criteria. [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    For participants meeting the PDTF criteria, viral resistance to maraviroc for maraviroc treated participants was assessed in patients with R5 virus at failure. The resistance level is calculated by reference to a laboratory strain of virus that is analyzed in parallel with the clinical isolate to identify 50% inhibitory concentrations (IC50). The maximal percent inhibition is the percent inhibition that is achieved in a titration of the drug at high concentrations when the addition of more drug does not result in increased inhibition. Maximal percent inhibition is obtained in the same way as the titration for IC50, but the key measure is of the plateau height of percent inhibition, where increased concentration of maraviroc does not result in additional inhibition. This is consistent with the virus developing some ability to use maraviroc-bound CCR5 for entry. A significant change in IC50 is not required for this mechanism.

  • Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    For participants meeting the PDTF criteria, viral resistance (both genotypic and phenotypic) to NRTI, NNRTI, and PI's were assessed at Baseline and on-treatment. The assessment was performed using the overall (i.e. net) susceptibility score provided using the PhenoSense GT assay. The number of participants with successful assessments were 15/17 for the MVC+DRV/r arm and 3/3 for the FTC/TDF+DRV/r arm.

  • Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 4 (CD4, Cell/mm^3) [ Time Frame: Baseline, Week 48 ] [ Designated as safety issue: No ]
    The differences in the magnitude of changes in CD4+ at Baseline and at Week 48 for maraviroc versus emtricitabine/tenofovir were compared.

  • Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD4 (%) [ Time Frame: Baseline, Week 48 ] [ Designated as safety issue: No ]
    The differences in the magnitude of changes in CD4+ from Baseline through Week 48 for maraviroc versus emtricitabine/tenofovir were compared.

  • Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 8 (CD8, Cell/mm^3) [ Time Frame: Baseline, Week 48 ] [ Designated as safety issue: No ]
    The differences in the magnitude of changes in CD8+ cell counts from baseline through Week 48 for maraviroc versus emtricitabine/tenofovir were compared.

  • Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD8 (%) [ Time Frame: Baseline, Week 48 ] [ Designated as safety issue: No ]
    The differences in the magnitude of changes in CD8+ cell counts from Baseline through Week 48 for maraviroc versus emtricitabine/tenofovir were compared.

  • Absolute Change in CD4+/CD8+ Ratio From Baseline to Week 48 [ Time Frame: Baseline, Week 48 ] [ Designated as safety issue: No ]
    The differences in the magnitude of changes in CD4+/CD8+ ratio from Baseline through Weeks 48 for maraviroc versus emtricitabine/tenofovir were compared.

  • Changes in Peripheral Fat Distribution Using Dual Energy X-ray Absorptiometry [DEXA] Scan From Baseline and at Week 48. [ Time Frame: Week 48 ] [ Designated as safety issue: Yes ]
    A sub-study was conducted in which the participants underwent whole-body DEXA scans to evaluate peripheral fat tissue estimates for left and right arms and legs and truncal fat mass and truncal lean mass. Truncal abdominal fat were estimated from the DEXA scan field set on the torso. The effects on estimates of fat mass and lean mass were addressed by providing LSMs of change from baseline.

  • Changes in Trunk to Limb Fat Distribution Using DEXA Scan From Baseline and at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: Yes ]
    A sub-study was conducted in which the participants underwent whole-body DEXA scans to evaluate peripheral fat tissue estimates for left and right arms and legs and truncal fat mass and truncal lean mass. Truncal abdominal fat were estimated from the DEXA scan field set on the torso. The effects on estimates of fat mass and lean mass were addressed by providing LSMs of change from baseline.

  • Changes in Bone Mineral Density (Using DEXA Scan and Serum Markers) From Baseline and at Week 48 - Total Hip BMD [ Time Frame: Week 48 ] [ Designated as safety issue: Yes ]
    Bone mineral density was evaluated by DEXA scan in a subset of participants who consented to these evaluations. The effects on BMD were addressed by providing LSMs of change from baseline bone mineral density of the lumbar spine (L1-L4), left total hip and femoral neck as measured by the DEXA scan.

  • Changes in Bone Mineral Density (Using DEXA Scan and Serum Markers) From Baseline and at Week 48 - Femoral Neck BMD [ Time Frame: Week 48 ] [ Designated as safety issue: Yes ]
    Bone mineral density was evaluated by DEXA scan in a subset of participants who consented to these evaluations. The effects on BMD were addressed by providing LSMs of change from Baseline bone mineral density femoral neck as measured by the DEXA scan.

  • Changes in Bone Mineral Density (Using DEXA Scan and Serum Markers) From Baseline and at Week 48 - AP Lumbar Spine (L1 - L4) BMD [ Time Frame: Week 48 ] [ Designated as safety issue: Yes ]
    Bone mineral density was evaluated by DEXA scan in a subset of participants who consented to these evaluations. The effects on BMD were addressed by providing LSMs of change from baseline bone mineral density of the lumbar spine (L1-L4) as measured by the DEXA scan.

  • Change in Bone Turnover Markers From Baseline and at Week 48 - Blood Osteocalcin [ Time Frame: Week 48 ] [ Designated as safety issue: Yes ]
    Bone turnover marker, osteocalcin, was collected in the subset of participants participating in the DEXA scan sub-study.

  • Change in Bone Turnover Markers From Baseline and at Week 48 - Type 1 Collagen Peptide (CTX-1) [ Time Frame: Week 48 ] [ Designated as safety issue: Yes ]
    Bone turnover marker, C-telopeptide of type 1 collagen (CTx), was collected in the subset of participants participating in the DEXA scan sub-study.


Enrollment: 813
Study Start Date: September 2011
Study Completion Date: January 2014
Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Maraviroc
Maraviroc 150 mg once daily plus darunavir/ritonavir 800/100 mg once daily plus placebo for emtricitabine/tenofovir once daily.
Drug: Maraviroc
Maraviroc tablet 150 mg once daily for 96 weeks.
Other Name: Selzentry, Celsentri
Drug: darunavir/ritonavir 800/100 mg
darunavir/ritonavir 800/100 mg
Drug: placebo for maraviroc
placebo for maraviroc
Other Name: Selzentry, Celsentri
Active Comparator: Emtricitabine/tenofovir
Emtricitabine/tenofovir 200/300 mg once daily plus darunavir/ritonavir 800/100 mg once daily plus placebo for maraviroc once daily.
Drug: Emtricitabine/tenofovir
Emtricitabine/tenofovir tablet 200/300 mg once daily for 96 weeks.
Other Name: Truvada
Drug: placebo for emtricitabine/tenofovir
placebo for emtricitabine/tenofovir
Other Name: Truvada

Detailed Description:
The study was terminated on October 8, 2013 following a preliminary review of the Week 48 primary efficacy data by the study's external independent Data Monitoring Committee (DMC). The DMC assessed the data as demonstrating significant differences between the treatment arms in virologic responses and failures. The DMC recommended and the Sponsor concurred that the study be terminated because of the inferior efficacy of the Maraviroc arm as compared to the comparator arm (Emtricitabine/Tenofovir).
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Plasma HIV-1 RNA equal to or greater than 1,000 copies/mL measured at the Screening Visit.
  • CD4 count equal to or greater than 100 cells/mm3 at Screening.
  • Have only R5 HIV 1 at Screening as verified by a randomized tropism assay.

Exclusion Criteria:

  • Prior treatment with any other HIV antiretroviral therapy for more than 14 days at any time.
  • Any evidence of genotypic/phenotypic resistance to darunavir, tenofovir, and emtricitabine.
  • CXCR4 using virus detected using randomized tropism determination or repeated failure to obtain an interpretable tropism result.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01345630

  Show 177 Study Locations
Sponsors and Collaborators
ViiV Healthcare
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT01345630     History of Changes
Other Study ID Numbers: A4001095  2010-021785-30 
Study First Received: April 27, 2011
Results First Received: August 14, 2014
Last Updated: December 11, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by ViiV Healthcare:
Double-blind
comparative
trial
maraviroc
versus
emtricitabine/tenofovir
both with darunavir/ritonavir
antiretroviral-naive
Ccr5 tropic
Hiv 1
patients.

Additional relevant MeSH terms:
Ritonavir
Darunavir
Tenofovir
Maraviroc
Emtricitabine
Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
CCR5 Receptor Antagonists

ClinicalTrials.gov processed this record on September 27, 2016