E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020161 |
E.1.2 | Term | HIV infection |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to assess the efficacy of UK-453,061 when used in combination with darunavir/ritonavir and an optimized NRTI for the treatment of subjects with prior NNRTI use and documented evidence of NNRTI resistance associated mutations (RAMs). Efficacy will be measured by the percentage of subjects with HIV-1 RNA level <50 copies/mL at 24 weeks. |
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E.2.2 | Secondary objectives of the trial |
• To assess efficacy as measured by percentage of subjects with HIV-1 RNA level <50 copies/mL at 48 and 96 weeks. • To assess efficacy as measured by percentage of subjects with HIV-1 RNA level <400 copies/mL. • To assess efficacy as measured by change from baseline in log10 transformed HIV-1 RNA levels. • To assess the pharmacokinetics (PK) and pharmacokinetic/pharmacodynamic (PK/PD) relationship of UK-453,061. • To assess safety and tolerability of UK-453,061. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the trial: 1. Evidence of a signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study. 2. Male or female at least 18 years of age available for a follow-up period of at least 96 weeks. 3. HIV-1 RNA viral load of ≥500copies/mL measured by the Roche Amplicor® HIV-1 Monitor test (version 1.5) at the screening visit. 4. Virologically failed a single NNRTI-based regimen with documented evidence of NNRTI resistance mutations at screening or on historical genotype. Subjects may have PI experience/resistance. 5. Negative urine pregnancy test at the Day 1 visit, prior to receiving the first dose of study medication, for Women of Child Bearing Potential (WOCBP). NOTE: WOCBP includes any female who has experienced menarche and who has not undergone successful surgical sterilization or is not post-menopausal (ie, no menstrual periods for at least 2 years). Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products (intrauterine devices; barrier methods: eg, condom or diaphragm with spermicide) to prevent pregnancy, who are practicing abstinence, or who have a partner that is sterile (eg, vasectomy), should be considered to be of child bearing potential. 6. Effective barrier contraception for WOCBP and males. In addition, WOCBP must use another acceptable method of contraception for the duration of the study and for 28 days after leaving the study. Acceptable contraception includes, but is not limited to oral, implanted or injectable hormone therapy and intrauterine devices. 7. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. |
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E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the trial: 1. Suspected or documented active, untreated HIV-1 related opportunistic infection (OI) or other condition requiring acute therapy at the time of randomization. Subjects on a stable (>30 days) secondary OI prophylaxis regimen or chronic treatment are eligible for the study, as are subjects on a primary OI prophylaxis regimen of any duration, except Trimethoprim-sulfamethoxazole. Subjects on primary, secondary prophylaxis and therapy with Trimethoprim-sulfamethoxazole must be on therapy >60 days. 2. On therapy for Hepatitis B. 3. Acute Hepatitis B and/or C within 30 days of randomization. 4. Hepatitis C, on therapy with interferon and/or ribavirin for <60 days. 5. Treatment for an active OI, or unexplained temperature >38.5 °C, for 7 consecutive days within 30 days prior to randomization. 6. Lack of prior use of a NNRTI, even if the current or historical HIV-1 genotype exhibits resistance to NNRTIs. 7. Previous use of darunavir or etravirine. 8. Inability to use an active NRTI based on resistance testing and treatment history. 9. Total bilirubin ≥1.5 times the upper limit of normal (unless the elevation is attributed to unconjugated hyperbilirubinemia secondary to current use of atazanavir and other etiologies have been eliminated). 10. AST and/or ALT >3 times the upper limit of normal. 11. Cardiac events (MI, bypass surgery, angioplasty) within 6 months of randomization. 12. Cirrhosis of the liver. 13. Absolute neutrophil count ≤750 cells/mm3. 14. Platelet count ≤50,000 cells/mm3. 15. Hemoglobin ≤7 g/dL. 16. Concomitant therapy with other investigational agents within 30 days prior to enrollment into the study. 17. Participation in other investigational studies within 30 days prior to study start and/or during study participation. 18. Contraindicated medications being taken at the time of randomization that must be continued during the study period, including immunomodulators for the treatment of HIV-1 infection (interferon for the ongoing treatment of hepatitis C infection is permitted, if the subject has been on it for >60 days see exclusion 4). Subjects diagnosed with hepatitis C may be treated for hepatitis C during the study if deemed necessary by the subject’s physician. 19. Presence of resistance associated with etravirine, or UK-453,061 as listed below: •The presence of 3 or greater NNRTI-associated resistance mutations; •>10-fold change in the UK-453,061 IC50 compared to that of the reference virus on phenotypic testing; •Phenotypic resistance to etravirine, as defined by >2.9 fold change based on Monogram PhenoSense™ assay; •Potential UK-453,061 associated mutations: K101E, V108I, E138K, Y188L, G190E/Q, F227C/L, L234I when present either: •In combination with other NNRTI resistance associated mutations (including those indicated above as potential UK-453,061 resistance associated mutations); or •As a single mutation with an associated >10-fold change in IC50. •The presence of the potential UK-453,061 resistance associated double mutation L100I+K103N, regardless of the fold change in IC50. 20. Presence of the following NRTI associated mutations; T69 insertion, Q151 complex. 21. Evidence of either genotypic or phenotypic resistance to darunavir/ritonavir as determined by the Monogram Bioscience PhenoSense GTTM assay. Note: It is incumbent upon the investigator to be thoroughly familiar with the prescribing information for all drugs used in the study, to review the genotype/phenotype results and to assess the risk for QTc prolongation. |
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E.5 End points |
E.5.1 | Primary end point(s) |
● The percentage of subjects with HIV-1 RNA <50 copies/mL at 24 weeks. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
The optimized NRTI, darunavir/ritonavir & etravirine are open label. UK-453,061 doses are blinded. |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |