| 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 |
| Evaluate the antiviral activity at 24 weeks across 3 doses of RDEA806 (non-nucleoside reverse transcriptase inhibitor [NNRTI]) and the efavirenz regimen (proportion of subjects with human immunodeficiency virus ribonucleic acid (HIV RNA) < 50 copies/mL (intent-to treat [ITT]: non-completer [NC] = failure [F]) |
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| E.2.2 | Secondary objectives of the trial |
•Evaluate the antiviral activity at each study visit across 3 doses of RDEA806 versus the efavirenz regimen
•Evaluate the immunologic changes
•Assess the plasma viral load decay rate of RDEA806
•Compare the time to virological failure through Week 48
•Compare the reduction of plasma log10 HIV-1 RNA from baseline at each study visit for each RDEA806 dose regimen versus the efavirenz regimen
•Compare the Time-Averaged Difference (DAVG) in log10 HIV-1 RNA at Weeks 24 and 48
•Evaluate the changes in viral genotype/phenotype and drug susceptibility •Evaluate the safety and tolerability
•Investigate the pharmacokinetic (PK) profile of RDEA806 and the pharmacokinetic/ pharmacodynamic relationship for RDEA806
•Evaluate: 1) the inter- and intra-patient variation of plasma RDEA806 exposures ; 2) potential trends for time-dependent change in plasma RDEA806 ; and 3) the relationship between plasma AUC and Cmax versus RDEA806 dose level
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| The pharmacokinetic substudy is described in the protocol at selected sites. The objective of the substudy is to obtain concentration-time data at 4 visits of RDEA806 and its major metabolite, M6. The UK site will perform the substudy. |
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| E.3 | Principal inclusion criteria |
- Voluntarily signed the informed consent form for this study
-Documented chronic HIV-1 infection
-HIV-1 plasma viral load at screening visit greater than 5000 HIV-1 RNA copies/ml (assayed by Roche Amplicor HIV-1 Monitor™ v1.5)
-CD4 count > 50 cells/mm3
-Male or female at least 16 years of age (or minimum age as determined by local regulatory authorities)
-A negative urine pregnancy test at the baseline visit prior to receiving the first dose of study drug, for women of childbearing potential. Women of childbearing potential include all females who have not undergone successful surgical sterilization or are not post-menopausal (ie, no menstrual periods for at least 2 years).
-Women of childbearing potential and males must agree to use a non-hormonal double barrier method of birth control (e.g., condom, diaphragm or cap, with a spermicide).
-Antiretroviral treatment naïve (see Exclusion Criteria #6) and agrees not to start antiretroviral therapy prior to enrollment or has only received limited exposure of treatment for 14 days or less and has been off treatment for at least 3 months prior to screening
-Willing and able to meet the protocol requirements
-General medical condition, in the Investigator’s opinion, does not interfere with the assessments and completion of this trial.
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| E.4 | Principal exclusion criteria |
-History or suspicion of alcohol or drug abuse which in the Investigator’s opinion may lead to noncompliance
-Life expectancy of less than 6 months
-HIV-2 co-infections
-Lactating women, or planned pregnancy during the study period
-History of any malignancy within the last 5 years, except for adequately treated basal cell carcinoma, squamous cell skin cancer, or in situ cervical cancer
-Prior use of any antiretroviral agent (NRTI, NNRTI, PI, entry inhibitor or integrase inhibitor) for the treatment of HIV
-Previous therapy with a potentially myelosuppressive, neurotoxic, hepatotoxic and/or cytotoxic agent, or initiation of therapy with such agents within 60 days prior to randomization, or the expected need for such therapy during the study period. Note: Trimethoprim-sulfamethoxazole (Bactrim) cannot be initiated 30 days prior to randomization but can be continued if the subject was on stable therapy.
-Clinically significant malabsorption syndrome, chronic diarrhea (4 to 10 stools/day for 30 days or greater duration), sprue, Whipple’s disease, pancreatic disease, irritable bowel syndrome, Crohn’s disease, ulcerative colitis, or amyloidosis
-Concomitant therapy or required use of astemizole, bepridil, cisapride, midazolam, pimozide, triazolam, voriconazole, St. John's wort (Hypericum perforatum), ergot derivatives, or use of medications prohibited during the study (refer to list of excluded medications, Section 5.9)
-Receipt of any investigational drug within 30 days prior to the trial drug (RDEA806) administration or expected need for such therapy during the study period
-Treatment within 30 days prior to screening with any vaccine or with any immune modulators such as systemic steroids, interleukins, interferons, granulocyte colony-stimulating factor (G-CSF), erythropoietin
-Acute HIV-1 infection (seroconversion illness), currently active acquired immune deficiency syndrome (AIDS)-defining illness (Category C conditions according to the Centers for Disease Control [CDC] Classification System for HIV Infection 1993), suspected or documented active, untreated HIV-1 related opportunistic infection (OI) or acute hepatitis A or acute or chronic hepatitis B or C infection, with the exception of cutaneous Kaposi’s sarcoma not requiring chemotherapy.
-Diagnosis of cirrhosis of the liver.
-Treatment for an active opportunistic infection (OI), or unexplained temperature >38.5°C for 7 consecutive days within 30 days prior to randomization
-Clinically significant laboratory test abnormalities including: serum creatinine > 1.5 x upper limit of normal (ULN) or Creatinine CL < 50, pancreatic amylase or lipase > 1.5 x ULN, alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin 1.5 x ULN, platelet count < 75 x 109 cells/l (75,000/l), or absolute neutrophil count < 0.75 x 109 cells/l (1,000 cells/l)
-Febrile illness within 120 hours prior to initiation of study treatment
-Previously treatment with RDEA806
-History of severe drug allergy or hypersensitivity
-History of cardiac abnormalities including abnormal and clinically relevant ECG changes such as bradycardia (sinus rate < 50 bpm), incomplete left bundle branch block (LBBB), complete LBBB and incomplete right bundle branch block (RBBB) and complete RBBB, second or third degree heart block, intraventricular conduction delay with QRS duration > 120 msec, symptomatic or asymptomatic arrhythmias with the exception of sinus arrhythmia, evidence of ventricular pre-excitation, frequent palpitations or syncopal episodes, heart failure, hypokalemia, family history of sudden death in otherwise healthy individual between the ages of 1 and 30 years.
-Conditions predisposing to QT prolongation including pathological Q-wave (defined as Q-wave >40 msec or depth > 0.4 to 0.5 mV), family history of Long QT Syndrome, any use of concomitant medications that prolong the QT/QTc interval.
-Subjects with a QTcF interval (QT interval corrected for heart rate according to Bazett) > 450 milliseconds (ms) at Screening and at pre-dose on Day 1.
-Evidence of any major resistance-associated mutation to emtricitabine, tenofavir or any NNRTI on any genotype test performed prior to study entry or at the time of screening
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy
Efficacy will be assessed by viral load and immunological (CD4 and CD8 cell count) determinations.
Safety:
Safety will be assessed as adverse and HIV related events, clinical laboratory test results (hematology, chemistry, urinalysis), vital signs, 12-lead electrocardiograms (ECGs), and physical examinations.
Resistance determinations:
HIV-1 resistance in the reverse transcriptase genome will be determined at baseline and upon virologic failure or lack of virologic response. Blood samples will be collected and plasma will be sent to the testing laboratory for HIV-1 genotype analysis. The genotype results will be reported to the Investigator within 21 calendar days of sample receipt. Blood samples will also be obtained at baseline to determine phenotypic susceptibility to RDEA806 and upon confirmed virologic failure or lack of virologic response (HIV RNA > 500 copies/mL) to determine HIV resistance mutations and susceptibility to RDEA806 or efavirenz and to the components of the treatment regimens. |
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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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | Yes |
| 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 |
| Efavirenz is the active comparator and will be given open-label. |
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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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | Information not present in EudraCT |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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