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A prospective, randomized, open-label pilot study to assess virologic suppression and immunologic recovery associated with a two-drug antiretroviral regimen of Raltegravir and the protease inhibitor lopinavir/ritonavir (LPV/r) and a three drug regimen with Raltegravir and two nRTIs (emtricitabine/tenofovir) in HIV-1 infected treatment-naïve subjects.
Immunology Substudy added to determine the kinetics of recovery of CD4 T cells and subpopulations (regulatory T cell [T regs], TH-17 and TH1) after treatment initiation with Raltegravir based regimens and their relationship with functional CD8 T cells and if Raltegravir containing therapies leads to decreases in markers of gut microbial translocation and of cellular and soluble markers of immune activation.
A009 is a prospective, randomized, open-label pilot study to assess virologic suppression and immune recovery rates associated with a two-drug potent antiretroviral regimen of raltegravir and the protease inhibitor lopinavir/ritonavir and a three-drug regimen with raltegravir and two nRTIs (emtricitabine/tenofovir) in treatment-naïve subjects.
HIV-1-infected subjects who are antiretroviral drug-naïve and have plasma HIV-1 RNA levels ≥5000 copies/ml obtained within 30 days prior to study entry will be randomized 1:1 to Raltegravir 400 mg BID + LPV 400 mg/RTV 100 mg BID (Arm A) or Raltegravir 400 mg BID + FTC 200 mg/TDF 300 mg QD (Arm B).
Subjects will have measurements of HIV-1 RNA and CD4+ and CD8+ T-cell counts at pre-entry and entry. The average of these measurements will be used to establish their baseline values. Following entry, subjects will have plasma HIV-1 RNA samples drawn at days 2, 4, 8 and at weeks 2, 4, 8, 16, 24, 32, 40 and 48 and at virologic failure. CD38 expression on CD4+/CD8+ cells and CD38/HLA-DR activation antigen on CD4+ and CD8+ cells and subsets T-cell percentage will be done at entry, day 8 and weeks 4, 8, 24 and at virologic failure by advanced flow cytometry.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Raltegravir & Lopinavir/ritonavir | Active Comparator | Raltegravir 400 mg tablet and Lopinavir/ritonavir capsule by mouth, every 12 hours for 48 weeks |
|
| Raltegravir & emtricitabine/tenofovir | Active Comparator | Raltegravir 400 mg tablet bu mouth, every 12 hours for 48 weeks and tenofovir/embritcitabine 200 mg/100 mg table by mouth, once daily for 48 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Raltegravir & Lopinavir/ritonavir | Drug | Two drug regimen of an integrase inhibitor and ritonavir boosted protease inhibitor |
|
| Measure | Description | Time Frame |
|---|---|---|
| Time to Confirmed Virologic Failure | time to confirmed viologic failure at 24 weeks (up to 48 weeks) | weeks |
| Time to Virologic Failure | time to virologic failure at week 24 (up to 48 weeks) | week 24 (up to 48 weeks) |
| Measure | Description | Time Frame |
|---|---|---|
| Study Medication Toxicity-related Discontinuation . | grade 3 and grade 4 symptoms and laboratory study treatment limiting toxicity | 48 weeks |
| Weeks to HIV-1 RNA <200 Copies/ml | time to viral suppression noted as week on study treatment to attain HIV-1 RNA < 200 copies/ml |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Margaret A Fischl, M.D. | University of Miami AIDS Clinical Research Unit | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Miami AIDS Clinical Research Unit | Miami | Florida | 33136 | United States |
Participants with acute or recent HIV-1 infection, major resistance-associated mutation on any genotype performed at any time prior to study entry, serious illness requiring systemic treatment and/or hospitalization within 7 days of study entry, HBsAg positivity, acute hepatitis of any etiology, clinically significant liver disease were excluded
Patients were randomly assigned to receive one of two regimens Raltegravir (Isentress, Merck & Company) 400 mg twice daily with either Lopinavir/ritonavir (Kaletra, Abbott Laboratories) 200 mg/100 mg twice daily or with emtricitabine/tenofovir (Truvada, Gilead Sciences) 200 mg/100 mg twice daily.
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| ID | Title | Description |
|---|---|---|
| FG000 | Raltegravir & Lopinavir/Ritonavir | Raltegravir 400 mg tablet and Lopinavir/ritonavir 400 mg/100 mg capsules every 12 hours for 48 weeks Raltegravir and Lopinavir/ritonavir: 400 mg BID for 48 weeks 400mg/100 mg BID for 48 weeks |
| FG001 | Raltegravir & Emtricitabine/Tenofovir | Raltegravir 400 mg tablet every 12 hours & emtricitabine 200mg/tenofovir 300 mg tab once daily for 48 weeks Raltegravir, emtricitabine, tenofovir: 400 mg BID for 48 weeks 200 mg QD for 48 weeks 300 mg QD for 48 |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Raltegravir & Lopinavir/Ritonavir | Raltegravir 400 mg tablet every 12 hours for 48 & Lopinavir/ritonavir 400 mg/100 mg capsules every 12 hours for 48 weeks Raltegravir and Lopinavir/ritonavir: 400 mg BID for 48 weeks 400mg/100 mg BID for 48 weeks |
| BG001 | Raltegravir & Emtricitabine/Tenofovir |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Time to Confirmed Virologic Failure | time to confirmed viologic failure at 24 weeks (up to 48 weeks) | descriptive | Posted | Median | 95% Confidence Interval | weeks | weeks |
|
1 year
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Raltegravir & Lopinavir/Ritonavir | Raltegravir 400 mg tablet and Lopinavir/ritonavir 400 mg/100 mg capsules every 12 hours for 48 weeks Raltegravir and Lopinavir/ritonavir: 400 mg BID for 48 weeks 400mg/100 mg BID for 48 weeks |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Total bilirubin | Hepatobiliary disorders | Serious | Systematic Assessment | grade 3 or greater elevation in total bilirubin |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| nausea and vomiting | Gastrointestinal disorders | Serious | Systematic Assessment |
Pilot study with 44 subjects and generalization f results is limited by the small sample size.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Director AIDS Clinical Research Unit | University of Miami School of Medicine | 305-243-3838 | mfischl@med.miami.edu |
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| ID | Term |
|---|---|
| D015658 | HIV Infections |
| D000163 | Acquired Immunodeficiency Syndrome |
| ID | Term |
|---|---|
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D015229 | Sexually Transmitted Diseases, Viral |
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| ID | Term |
|---|---|
| D000068898 | Raltegravir Potassium |
| D061466 | Lopinavir |
| D019438 | Ritonavir |
| C558899 | lopinavir-ritonavir drug combination |
| D000068679 | Emtricitabine |
| D000068698 | Tenofovir |
| D000069480 | Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination |
| ID | Term |
|---|---|
| D011760 | Pyrrolidinones |
| D011759 | Pyrrolidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| Raltegravir and emtricitabine/tenofovir | Drug | Three drug regimen of an integrase inhibitor and a fixed dose combination of a non-nucleoside/nucleotide inhibitors |
|
|
| from date of treatment start to first week documented viral suppression |
| Change From Baseline CD4+ and CD8+ Cell Counts | mean change in CD4+ and CD8+ T-lymphocytes counts from baseline (defined as the average of pre-entry and entry values) at weeks 16 and 24 in the two treatment arms | Baseline, Weeks 16 and 24 |
| Study Medication Tolerability | study treatment tolerability as measured by number of subjects receiving study treatment who either discontinued or changed any component of study treatment | date started study treatment to first week documented change study treatment up to week 48 |
Raltegravir 400 mg tablet every 12 hours for 48 weeks & emtricitabine 200mg/ tenofovir 300 mg tab once daily for 48 weeks Raltegravir, emtricitabine, tenofovir: 400 mg BID for 48 weeks 200 mg QD for 48 weeks 300 mg QD for 48 |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
|
| Secondary | Study Medication Toxicity-related Discontinuation . | grade 3 and grade 4 symptoms and laboratory study treatment limiting toxicity | Posted | Number | participants | 48 weeks |
|
|
|
| Secondary | Weeks to HIV-1 RNA <200 Copies/ml | time to viral suppression noted as week on study treatment to attain HIV-1 RNA < 200 copies/ml | Posted | Median | 95% Confidence Interval | week to viral supresssion | from date of treatment start to first week documented viral suppression |
|
|
|
| Secondary | Change From Baseline CD4+ and CD8+ Cell Counts | mean change in CD4+ and CD8+ T-lymphocytes counts from baseline (defined as the average of pre-entry and entry values) at weeks 16 and 24 in the two treatment arms | Change from baseline compared between arms using repeated measures analysis of covariance. Linear mixed models used to accomplish these analyses. | Posted | Mean | Standard Error | cells/mm3 | Baseline, Weeks 16 and 24 |
|
|
|
| Secondary | Study Medication Tolerability | study treatment tolerability as measured by number of subjects receiving study treatment who either discontinued or changed any component of study treatment | Posted | Number | participants | date started study treatment to first week documented change study treatment up to week 48 |
|
|
|
| Primary | Time to Virologic Failure | time to virologic failure at week 24 (up to 48 weeks) | Posted | Median | Standard Deviation | weeks | week 24 (up to 48 weeks) |
|
|
|
| 4 |
| 21 |
| 1 |
| 21 |
| EG001 | Raltegravir & Emtricitabine/Tenofovir | Raltegravir 400 mg tablet every 12 hours & emtricitabine 200mg/tenofovir 300 mg tab once daily for 48 weeks Raltegravir, emtricitabine, tenofovir: 400 mg BID for 48 weeks 200 mg QD for 48 weeks 300 mg QD for 48 | 0 | 23 | 0 | 23 |
|
| trigylcerides | Endocrine disorders | Serious | Systematic Assessment | grade 3 or greater elevation in fasting blood triglycerides |
|
| diarrhea | Gastrointestinal disorders | Serious | Systematic Assessment |
|
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| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
| D012897 | Slow Virus Diseases |
| D011744 |
| Pyrimidinones |
| D011743 | Pyrimidines |
| D013844 | Thiazoles |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D001393 | Azoles |
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D063065 | Organophosphonates |
| D009943 | Organophosphorus Compounds |
| D000225 | Adenine |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D004338 | Drug Combinations |
| D004364 | Pharmaceutical Preparations |