HIV Infections
Conditions
Brief summary
The objective of this study is to compare the efficacy and safety of Tipranavir/ritonavir (TPV/r, 500mg/200mg twice daily) to the safety and efficacy of Darunavir/ritonavir (DRV/r 600 mg /100 mg twice daily) in combination with investigator selected optimised background regimens in patients who are three-class (Nucleoside reverse transcriptase inhibitors (NRTI), Nonnucleoside reverse transcriptase inhibitors (NNRTI), and Protease inhibitor (PI)) treatment-experienced (a minimum of 3-months duration for each class) with resistance to more than one PI on the screening virtual phenotype resistance testing.
Interventions
Sponsors
Study design
Eligibility
Inclusion criteria
1. Signed informed consent prior to trial participation. 2. HIV-1 infected male or female \>18 years of age. 3. Three-class (NRTI, NNRTI, and PI) treatment-experienced patients (a minimum of 3-months duration for each class or documented class hypersensitivity/intolerance) with resistance (minimal or reduced response) to more than one PI on the screening virtual phenotype resistance testing. In the case of NNRTIs, NNRTI resistance in the absence of exposure is equivalent to being NNRTI treatment experienced. 4. Patient's optimized background regimen must contain one of the following ARV options: * A minimum of two genotypically active nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) reported as maximal response or sensitive on the screening virtual phenotype report. * A minimum of one genotypically active NRTI reported as maximal response or sensitive on the screening virtual phenotype report plus Enfuvirtide if not used previously. * A minimum of one genotypically active NRTI reported as maximal response or sensitive on the screening virtual phenotype report plus an integrase inhibitor if not used previously and if available through an expanded access program and allowed by local regulatory authorities. * A minimum of one genotypically active NRTI reported as maximal response or sensitive on the screening virtual phenotype report plus the CCR5 chemokine receptor antagonist Maraviroc if available through an expanded access program, not used previously and allowed by local regulatory authorities. * Zero or one genotypically active NRTI reported as maximal response or sensitive on the screening virtual phenotype report plus two of the following drugs, Enfuvirtide, an integrase inhibitor and Maraviroc if available, not used previously and allowed by local regulatory authorities. * Two genotypically partially active NRTIs (provided that they are not part of the current failing regimen) reported as reduced response on the screening virtual phenotype report plus one of the following drugs, Enfuvirtide, an integrase inhibitor or Maraviroc if available, not used previously and allowed by local regulatory authorities. 5. Patient has been on their current (failing) PI-containing regimen for at least 8 weeks prior to randomization. 6. Patient has on-going viral replication (defined as an HIV-1 viral load of ≥ 500 copies/mL) and a successful virtual phenotype obtained at screening. 7. Any baseline CD4 cell count will be allowed. 8. Karnofsky performance score of ≥ 70. 9. Acceptable screening laboratory values that indicate adequate baseline organ function. Laboratory values are considered acceptable if the following apply: * ALT ≤2.5 x ULN and AST ≤2.5 x ULN (≤DAIDS Grade 1, Appendix 10.1). * Any DAIDS grade cholesterol, triglycerides, GGT, CPK or LDH is acceptable. * All other laboratory test values must be ≤DAIDS Grade 2. 10. Willingness to initiate CD4+ cell count-guided chemoprophylaxis to prevent opportunistic infections. 11. Willingness to abstain from ingesting substances which may alter plasma study drug levels by interaction with the cytochrome P450 system during the study. Inclusion Criteria: 1. Previous use of Tipranavir (TPV) or Darunavir (DRV). 2. Full genotypic resistance (reported as minimal response) to Tipranavir (TPV) or Darunavir (DRV) on screening virtual phenotype: 3. Female patient of child-bearing potential who: has a positive serum pregnancy test at screening, is breast feeding, is planning to become pregnant, is not willing to use double-barrier methods (simultaneous use of two different methods such as diaphragm with spermicidal substance and condom) of contraception or requires ethinyl estradiol administration. Barrier methods of contraception include diaphragm with spermicidal substance, condom for females, cervical caps and condoms. 4. History of Progressive Multifocal Leukoencephalopathy (PML), Visceral Kaposi's Sarcoma (KS), and/or any malignancy. 5. Any AIDS defining illness that is unresolved, symptomatic or not stable on treatment for at least 12 weeks at screening visit. 6. Use of immunomodulatory drugs (such as interferon, cyclosporin, hydroxyurea and interleukin 2) within 30 days prior to randomization. 7. Current use of systemic cytotoxic chemotherapy. 8. All contraindications listed in the product monographs of Aptivus, Prezista and Norvir.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Time to Virologic Failure Through 48 Weeks of Treatment, Using Viral Load (VL) < 50 Copies/Millilitre (mL) as the Response Criterion. | 48 weeks of treatment |
Secondary
| Measure | Time frame |
|---|---|
| Intent-To-Treat Analysis of Virologic Response at Week 48, Using VL < 50 Copies/mL as the Response Criterion Where Patients Are Followed Until Week 48 for VL Regardless of Whether or Not They Remain on Study Drug. | 48 weeks of treatment |
| Time to Virologic Failure Through 48 Weeks of Treatment, Using VL < 400 Copies/mL as the Response Criterion. | 48 weeks of treatment |
| Response up to 48 Weeks Using VL < 50 Copies/mL Using Censored | up to 48 weeks |
| Response up to 48 Weeks Using VL < 50 Copies/mL Using NCF | up to 48 weeks |
| Response up to 48 Weeks Using VL < 50 Copies/mL Using Intent-to-treat | up to 48 weeks |
| Response up to 48 Weeks Using VL < 400 Copies/mL Using Censored | up to 48 weeks |
| Response up to 48 Weeks Using VL < 400 Copies/mL Using NCF | up to 48 weeks |
| Response up to 48 Weeks Using VL < 400 Copies/mL Using Intent-to-treat | up to 48 weeks |
| Response up to 48 Weeks Using at Least a 1 log10 Reduction in Viral Load From Baseline Using Censored | up to 48 weeks |
| Response up to 48 Weeks Using at Least a 1 log10 Reduction in Viral Load From Baseline Using NCF | up to 48 weeks |
| Treatment Response at Week 48, Using VL < 50 Copies/mL as the Response Criterion and the FDA Definition for Handling Drug Discontinuations ((NCF) Non-Completers=Failure). | 48 weeks of treatment |
| Daily Average in CD4+ Cell Count Change From Baseline at up to Week 8 | up to week 8 |
| Daily Average in CD4+ Cell Count Change From Baseline up to Week 24 | up to week 24 |
| Daily Average in CD4+ Cell Count Change From Baseline up to Week 48 | up to week 48 |
| Daily Average in Viral Load Change From Baseline up to Week 8 | up to week 8 |
| Daily Average in Viral Load Change From Baseline up to Week 24 | up to week 24 |
| Daily Average in Viral Load Change From Baseline up to Week 48 | up to week 48 |
| Change From Baseline in CD4+ Cell Count up to Week 48 | up to week 48 |
| Change From Baseline in log10 Viral Load up to Week 48 | up to week 48 |
| Occurrence of New AIDS Progression Events or Death | through 48 weeks of treatment |
| Response up to 48 Weeks Using at Least a 1 log10 Reduction in Viral Load From Baseline Using Intent-to-treat | up to 48 weeks |
Countries
Belgium, Canada, France, Germany, Greece, Italy, Portugal, Puerto Rico, Spain, Thailand, The Bahamas, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tipranavir 500 mg/Ritonavir 200 mg Tipranavir (TPV) 250 mg soft gelatin capsules Ritonavir (RTV) 100 mg soft gelatin capsules dose: 500 mg TPV/200 mg RTV, twice daily mode of admin.: Oral | 19 |
| Darunavir 600 mg/Ritonavir 100 mg Prezista® (DRV) 300 mg tablets Ritonavir (RTV) 100 mg soft gelatin capsules dose: 600 mg DRV/100 mg RTV, twice daily mode of admin.: Oral | 20 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Early termination of the trial | 16 | 18 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Tipranavir 500 mg/Ritonavir 200 mg | Darunavir 600 mg/Ritonavir 100 mg | Total |
|---|---|---|---|
| Age, Continuous | 44.3 Years STANDARD_DEVIATION 6.1 | 43.1 Years STANDARD_DEVIATION 6.2 | 43.6 Years STANDARD_DEVIATION 6.1 |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 15 Participants | 17 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 19 | 7 / 20 |
| serious Total, serious adverse events | 0 / 19 | 2 / 20 |
Outcome results
Time to Virologic Failure Through 48 Weeks of Treatment, Using Viral Load (VL) < 50 Copies/Millilitre (mL) as the Response Criterion.
Time frame: 48 weeks of treatment
Change From Baseline in CD4+ Cell Count up to Week 48
Time frame: up to week 48
Change From Baseline in log10 Viral Load up to Week 48
Time frame: up to week 48
Daily Average in CD4+ Cell Count Change From Baseline at up to Week 8
Time frame: up to week 8
Daily Average in CD4+ Cell Count Change From Baseline up to Week 24
Time frame: up to week 24
Daily Average in CD4+ Cell Count Change From Baseline up to Week 48
Time frame: up to week 48
Daily Average in Viral Load Change From Baseline up to Week 24
Time frame: up to week 24
Daily Average in Viral Load Change From Baseline up to Week 48
Time frame: up to week 48
Daily Average in Viral Load Change From Baseline up to Week 8
Time frame: up to week 8
Intent-To-Treat Analysis of Virologic Response at Week 48, Using VL < 50 Copies/mL as the Response Criterion Where Patients Are Followed Until Week 48 for VL Regardless of Whether or Not They Remain on Study Drug.
Time frame: 48 weeks of treatment
Occurrence of New AIDS Progression Events or Death
Time frame: through 48 weeks of treatment
Response up to 48 Weeks Using at Least a 1 log10 Reduction in Viral Load From Baseline Using Censored
Time frame: up to 48 weeks
Response up to 48 Weeks Using at Least a 1 log10 Reduction in Viral Load From Baseline Using Intent-to-treat
Time frame: up to 48 weeks
Response up to 48 Weeks Using at Least a 1 log10 Reduction in Viral Load From Baseline Using NCF
Time frame: up to 48 weeks
Response up to 48 Weeks Using VL < 400 Copies/mL Using Censored
Time frame: up to 48 weeks
Response up to 48 Weeks Using VL < 400 Copies/mL Using Intent-to-treat
Time frame: up to 48 weeks
Response up to 48 Weeks Using VL < 400 Copies/mL Using NCF
Time frame: up to 48 weeks
Response up to 48 Weeks Using VL < 50 Copies/mL Using Censored
Time frame: up to 48 weeks
Response up to 48 Weeks Using VL < 50 Copies/mL Using Intent-to-treat
Time frame: up to 48 weeks
Response up to 48 Weeks Using VL < 50 Copies/mL Using NCF
Time frame: up to 48 weeks
Time to Virologic Failure Through 48 Weeks of Treatment, Using VL < 400 Copies/mL as the Response Criterion.
Time frame: 48 weeks of treatment
Treatment Response at Week 48, Using VL < 50 Copies/mL as the Response Criterion and the FDA Definition for Handling Drug Discontinuations ((NCF) Non-Completers=Failure).
Time frame: 48 weeks of treatment