Study to Determine the Antiviral Activity and Safety of Alovudine in Nucleoside-experienced HIV-infected Subjects Experiencing Virologic Failure

Study Overview
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Brief Summary
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The primary objective was to determine the mean change in HIV viral load from baseline to Week 4 compared with placebo after 4 weeks of treatment in highly experienced HIV-infected patients. Secondary objectives were to determine (1) the tolerability, hematologic and hepatic safety of different doses of alovudine and (2) the effect of baseline nucleoside genotypic susceptibility on virologic response after 4 weeks of alovudine administration

Official Title
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Randomised, Double Blind, Placebo-controlled Dose Ranging Trial to Determine the Antiviral Activity and Safety of Alovudine in Nucleoside-experienced HIV-infected Subjects Experiencing Virologic Failure

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Alovudine - low
* Drug: Alovudine - medium
* Drug: Alovudine - high
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent before any trial procedure HIV-1 infected males or females ≥18 years of age Screening genotypic resistance report indicating two or more of the following nucleoside reverse transcriptase inhibitors (NRTI) resistance mutations: 41, 67, 70, 210 and 215 Stable NRTI regimen without stavudine and zidovudine for at least 6 weeks before screening and stable antiretroviral (ARV) background treatment for 3 months before screening HIV-1 viral load ≥1000 copies/mL and <75,000 copies/mL at screening Change in viral load between previous test within 3 months before screening, using local laboratory for routine tests, and screening test was <1.0 log10 copies/mL Acceptable medical history, as assessed by the investigator Current stable ARV medication regimen between screening (Visit 1) and Visit 2 Exclusion Criteria: ARV medication naïve Patients on recent drug holiday, defined as off ARV medications for at least 7 consecutive days within the previous 3 months Female patients of child-bearing potential who : have a positive serum pregnancy test are breast feeding, are planning to become pregnant, or are not willing to use a barrier method of contraception Prior alovudine use Use of investigational medications within 30 days before study entry or during the trial Use of immunomodulatory drugs within 3 months before study entry or during the trial (e.g. interferon, cyclosporine, hydroxyurea, interleukin-2) Current use of rifampin, rifabutine, isoniazid, pyrazinamide, stavudine, zidovudine, ganciclovir, chronic use of hepatotoxic drugs, anti-tumour therapy or probenecid Laboratory values: Neutrophils of Grade 2 or greater abnormality Hemoglobin of Grade 2 or greater abnormality Platelets: Grade 2 or greater abnormality Creatinine of ≥1.25 Upper limit of the normal (ULN) Lipase of Grade 1 or greater abnormality Alanine aminotransaminase (ALT) or Aspartate aminotransaminase (AST) of Grade 2 or greater abnormality Direct bilirubin of Grade 1 or greater abnormality CD4 ≤50 cells/mm3 Hepatitis B (+HBsAg or +HBcAB) or C +Hepatitis C virus (+HCV AB ) co-infection, chronic hepatitis, on-going hepatitis or pancreatitis Any new or active AIDS-defining event within 30 days before study entry Inability to adhere to the requirements of the protocol, including active substance abuse as assessed by the investigator In the opinion of the investigator, likely survival of less than 6 months because of underlying disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alovudine - low<br> | Drug: Alovudine - low<br> <br> Drug: Placebo<br> <br> |
| Experimental: Alovudine - medium<br> | Drug: Alovudine - medium<br> <br> Drug: Placebo<br> <br> |
| Experimental: Alovudine - high<br> | Drug: Alovudine - high<br> <br> |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in HIV viral load measured from plasma samples |  | Up to 4 weeks after drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of virologic responders per treatment arm |  | Up to 4 weeks after drug administration | 
| Proportion of patients experiencing a change of viral load | viral load of ≥1 log10 from baseline to Week 4 | Up to 4 weeks after drug administration | 
| Mean change in CD4+ cell count |  | Up to 4 weeks after drug administration | 
| Percentage of 0.5 virologic responders per treatment arm |  | Up to 4 weeks after drug administration | 
| Percentage of load responders per treatment arm |  | Up to 4 weeks after drug administration | 
| Percentage of 0.7 to 0.9 virologic responders per treatment arm |  | Up to 4 weeks after drug administration | 
| Number of patients with adverse events |  | Up to 4 weeks after drug administration | 
| Number of patients with laboratory test abnormalities and with respect to Division of AIDS (DAIDS) grading |  | Up to 4 weeks after drug administration | 
| Number of patients with serious adverse events |  | Up to 4 weeks after drug administration | 
| Number of patients who discontinued due to adverse event |  | Up to 4 weeks after drug administration | 
| Mean change in CD8+ cell count |  | Up to 4 weeks after drug administration | 
| Number of patients with abnormal changes in laboratory parameters |  | Up to 4 weeks after drug administration |