| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HIV-1 treatment in combination with other agents |
| Trattamento dell'HIV-1 in combinazione con altri agenti |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10020161 |
| E.1.2 | Term | HIV infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 confirm the hypothesis that UK-427,857 added to Optimized Background Therapy (OBT) provides an additional reduction in plasma HIV-1 RNA compared to OBT alone, as measured by the difference between each of the two UK-427,857 regimens versus the placebo regimen in the mean changes from baseline in plasma HIV-1 RNA at Week 48. An interim analysis will be performed at Week 24. |
| Definire se UK-427,857 somministrato in combinazione con una terapia standard ottomizzata (OBT), produca un ulteriore diminuzione nel livello della carica virale, in confronto alla sola terapia con OBT. La valutazione sara` effettuata, per ognuno dei due dosaggi di UK-427,857 contro placebo, sulle variazioni medie della carica virale alla settimana 48 di trattamento rispetto al basale. E prevista un analisi ad interim alla settimana 24.La sicurezza sara` determinata valutando:-Segni vitali-Test dilab ( in particolare Test di gravidanza, epatite, ematologia, biochimica,enzimi epatici, metabolismo dei grassi, analisi delle urine)-Registrazione di qualsiasi evento avverso e trattamenti concomitanti. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives include assessments of safety and tolerability of UK-427,857 when added to OBT versus OBT alone. |
| -Confr.la % di sogg con livelli di HIV-1 RNA inferiori a 400 copie/mL,per ognuna delle 2 dosi di UK-427,857 alla sett 24 e 48 di tratt verso placebo-Confr.la % di sogg con livelli di HIV-1 RNA inferiori a 50 copie/mL per ognuna delle 2 dosi di UK-427,857 alla sett 24 e 48 di tratt verso placebo-Confr.la % di sogg che raggiungono almeno una riduz di 0.5 log10 in copie di HIV-1 RNA per ognuna delle 2 dosi di UK-427,857 verso placebo alla sett 24 e 48 di tratt rispetto al basale.- Confr.la % di sogg che raggiungono almeno una riduz di 1 log10 nei livelli di HIV-1 RNA per ognuna delle 2 dosi di UK-427,857 alla sett 24 e 48 di tratt rispetto al basale,verso placebo.-Det.il tempo per il raggiungim di perdita di risp virologica per ognuna delle 2 dosi di UK-427,857 durante le 48 sett di tratt verso placebo.-Confr.il cambiamento nella conta delle cellule CD4 e CD8 dal basale alle sett 24,48 di tratt per ognuna delle 2 dosi di UK-427,857 verso placebo.-etc |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. Provide a signed and dated written informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the trial. 2. Men or women at least 16 years of age (or minimum age as determined by local regulatory authorities or as legal requirements dictate) available for a follow-up period of at least 48 weeks. 3. HIV-1 RNA viral load of ≥5,000 copies/mL measured by Roche Amplicor HIV-1 Monitor (version 1.5) at the screening visit. 4. Stable pre-study antiretroviral regimen, or on no antiretroviral agents, for at least 4 weeks. 5. Documented genotypic (http://iasusa.org/resistance_mutations/index.html as determined by the Monogram Bioscience (formerly Virologic) GeneSeq HIV drug resistance assay) or phenotypic (fold change of patient’s virus ≥ cutoff value based on Monogram Bioscience PhenoSense HIV drug resistance assay) resistance to 3 of the 4 antiretroviral drug classes [Nucleoside or nucleotide reverse transcriptase inhibitors (nRTIs), Non-nucleoside reverse transcriptase inhibitors (NNRTIs), Protease Inhibitors (PIs) or Entry Inhibitors (EIs)] OR Antiretroviral-class experience ≥6 months (sequential or cumulative) with at least three of the following: a. One nucleoside or nucleotide reverse transcriptase inhibitor b. One non-nucleoside reverse transcriptase inhibitor c. Two protease inhibitors (excluding low-dose ritonavir) d. Enfuvirtide 6. Be willing to initiate and remain on randomized treatment without any changes or additions to the OBT regimen, except for toxicity management or upon meeting criteria for treatment failure. 7. A negative urine pregnancy test at the baseline visit, prior to receiving the first dose of study medication, for Women of Child Bearing Potential (WOCBP). NOTE: WOCBP include 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. 8. Effective barrier contraception for WOCBP and males. In addition, WOCBP must use another acceptable method of contraception for the duration of the study. Acceptable contraception includes, but is not limited to, oral, implanted or injectable hormone therapy and intrauterine devices. |
| NA |
|
| E.4 | Principal exclusion criteria |
| 1. Patients requiring treatment with more than 6 antiretroviral agents (excluding low-dose ritonavir). 2. Prior treatment with UK-427,857 or another experimental HIV entry inhibitor for more than 14 days. 3. Active alcohol or substance abuse sufficient, in the Investigator’s judgment, to prevent adherence to study medication and/or follow-up. 4. Lactating women, or planned pregnancy during the trial period. 5. Suspected or documented active, untreated HIV-1 related opportunistic infection (OI) or other condition requiring acute therapy (eg, hepatitis C virus infection) at the time of randomization [patients on a stable (>1 month) secondary OI prophylaxis regimen or chronic treatment (eg, for hepatitis C virus infection) are eligible for the study; patients on a primary OI prophylaxis regimen of any duration are also eligible for the study]. 6. Treatment for an active opportunistic infection, or unexplained temperature >38.5°C for 7 consecutive days, within 30 days prior to randomization. 7. Malignancy requiring parenteral chemotherapy that must be continued for the duration of the trial. 8. Initiating therapy with a potentially myelosuppressive, neurotoxic, hepatotoxic and/or cytotoxic agent within 60 days prior to randomization, or the expected need for such therapy during the study period. NOTE: Timethoprim-sulfamethoxaole may not be initiated 60 days prior to randomization but may be continued if the subject is on stable therapy. The use of isoniazid is prohibited. 9. Documented or suspected acute hepatitis or pancreatitis within 30 days prior to randomization. 10. Renal insufficiency defined as a serum creatinine greater than 3 times the upper limit of normal. 11. Total bilirubin, greater than 2.5 times the upper limit of normal (unless unconjugated hyperbilirubinemia due to atazanavir or indinavir). Changes of one or more grades in total bilirubin between screening and the randomization visit should be reviewed with the Pfizer medical monitor before the initiation of double-blind study medication. 12. AST or ALT greater than 5 times the upper limit of normal. Changes in one or more grades in AST or ALT between screening and the randomization visit should be reviewed with the Pfizer medical monitor before the initiation of double-blind study medication. 13. Cirrhosis of the liver. 14. Absolute neutrophil count ≤750 cells/mm3. 15. Platelet count ≤50,000 cells/mm3. 16. Hemoglobin ≤7 g/dL. 17. Clinically significant malabsorption syndrome (eg, ≥6 loose stools per day for at least 7 consecutive days) within 30 days prior to randomization. 18. Inability to tolerate oral medication. 19. X4-or dual/mixed-tropic virus detected by the PhenoSense™ viral entry assay or repeated assay failure. 20. Concomitant therapy with other investigational agents (other than experimental antiretroviral agents available through pre-approval access programs). 21. Contraindicated medications (eg, immunomodulators for the treatment of HIV-1 infection; interferon for the ongoing treatment of hepatitis C infection is permitted) being taken by the subject at the time of randomization that must be continued during the study period (See Section 5.5). 22. Any safety, behavioral, clinical, or administrative reasons that, in the Investigator’s judgment, would potentially compromise study compliance or the ability to evaluate safety/efficacy. |
| NA |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline to 48 weeks in HIV-1 RNA measured on a logarithmic [base 10] scale. An interim analysis will be performed at Week 24. |
| -Variazione dal basale alla settimana 48 di trattamento dell'RNA di HIV-1 misurata su scala logaritmica di base 10.Alla settimana 24 sara' effettuata un analisi ad interim -% dei pazienti con meno di 50/400 copie di HIV-1 RNA per millilitro di plasma-Tempo di diminuzione della risposta virologica-Variazioni nella conta di CD4 e CD8- Cambiamenti nel genotipo, fenotipo e tropismo negli insuccessi terapeutici- % di pazienti con patologia che definisce l'AIDS |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| - Stesso farmaco ad altro dosaggio |
| - same IMP used at different dosage |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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