Safety, Tolerance, Pharmacokinetic and Antiviral Study of Amdoxovir in Combination With Zidovudine in Adults With HIV

NCT00432016 | Completed Phase 1

• 2 other identifiers: RFS-AMDX-203ACA-AI-001-001
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine the short term safety, tolerance, and antiviral effect of zidovudine (AZT) and amdoxovir (AMDX, DAPD) in combination, and whether the dosage for AZT can be reduced, potentially decreasing side effects, while maintaining antiviral effects. Study hypothesis: DADP in combination with AZT is safe and effective, and AZT dosing may be reduced, resulting in lower levels of AZT-monophosphate associated with toxicity and maintaining levels of AZT-triphosphate associated with efficacy.

Conditions

HIV Infections

Keywords

HIV; pharmacokinetics; zidovudine; amdoxovir; DAPD; AMDX; Treatment Naive

Outcome Measures

Primary Outcomes (3)

• Proportion of subjects in each arm with Grade 3 or greater treatment emergent adverse events (AE)

• Plasma Cmax, Cmin, tmax, AUC0→τ, AUC0→∞, t1/2, CL/F of DAPD and AZT in each group at Days 1 and 10

• Intracellular Cmax, Cmin, tmax, AUC0→τ, AUC0→∞, and t1/2 of DXG-TP, -MP and -DP and AZT-TP, -MP, and -DP at Days 1 and 10

Secondary Outcomes (5)

• Change in viral load (plasma HIV-1 RNA) from Baseline through Day 10

• Correlate intracellular DXG-TP and AZT-TP with viral response, as measured by plasma HIV-1 RNA

• Quantitate DXG, AZT, and GAZT in urine with and without DAPD

• Characterize viral rebound (plasma HIV-1 RNA) following drug discontinuation for 48 hr

• Measure CD4+ count changes from Baseline to Day 10

Interventions

zidovudine DRUG

amdoxovir DRUG

pharmacokinetic sampling PROCEDURE

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• HIV-infection
• Antiretroviral therapy naïve, or if experienced, no treatment within 90 days of study screening and plan to remain off therapy for the duration of the screening and study treatment period
• HIV-1 RNA ≥ 5,000 copies/mL within 30 days of study Day 1
• CD4+ count ≥ 200 cells/mm³ within 30 days of study Day 1
• Agree to the use of two forms of adequate contraception for women, one form for men
• Estimated creatinine clearance \> 80 mL/min
• Serum creatinine \< 1.5 g/dL
• Able to give written informed consent prior to study start and adhere to study requirements

You may not qualify if:

• Active alcohol or drug use which in the opinion of the Investigator will likely compromise adherence to the study requirements
• A positive urine test for amphetamines, cocaine, and/or opioids
• Currently has any active AIDS defining illness (Category C condition according to the CDC Classification System for HIV Infection 1993)
• Any active clinically significant disease or findings during screening of medical history or physical examination that in the Investigator's opinion would compromise the outcome of the study
• Receiving oral concomitant antiviral or prophylactic drugs for opportunistic infections within 30 days prior to study entry
• Receiving concomitant treatment with nephrotoxic drugs (e.g., aminoglycosides \[tobramycin, gentamicin, and amikacin\], amphotericin B, vancomycin, cidofovir, foscarnet, cis-platinum, pentamidine), or competitors of renal excretion (e.g., probenecid) within 30 days of study entry
• Visual abnormalities (e.g. cataracts, macular degeneration) other than non-organic decreased visual acuity
• Receiving concomitant treatment with immunosuppressive drugs within 30 days prior to study entry
• Diabetes mellitus Type 1 or 2 which is being treated or not with any anti-diabetes agents
• Current significant gastrointestinal, renal, hepatic, bronchopulmonary, biliary, neurological, cardiovascular, oncologic, allergic, or ophthalmologic diseases including history of cataracts/lens opacities
• The following laboratory values performed within 30 days prior to study Day 1:
• Hemoglobin \< 9.0 g/dL for men; 8.0 g/dL for women
• Platelet count \< 75,000 cells per mL
• Absolute neutrophil count \< 1,000 cells per mL
• AST, ALT, alkaline phosphatase, and amylase \> 3 x ULN

Sponsors & Collaborators

• RFS Pharma, LLC: lead

Study Sites (1)

Hospital Privado Modelo

Buenos Aires, B1602DBG, Argentina

Location

Related Publications (5)

• Barry MG, Khoo SH, Veal GJ, Hoggard PG, Gibbons SE, Wilkins EG, Williams O, Breckenridge AM, Back DJ. The effect of zidovudine dose on the formation of intracellular phosphorylated metabolites. AIDS. 1996 Oct;10(12):1361-7. doi: 10.1097/00002030-199610000-00008.

  PMID: 8902065 BACKGROUND

• Bazmi HZ, Hammond JL, Cavalcanti SC, Chu CK, Schinazi RF, Mellors JW. In vitro selection of mutations in the human immunodeficiency virus type 1 reverse transcriptase that decrease susceptibility to (-)-beta-D-dioxolane-guanosine and suppress resistance to 3'-azido-3'-deoxythymidine. Antimicrob Agents Chemother. 2000 Jul;44(7):1783-8. doi: 10.1128/AAC.44.7.1783-1788.2000.

  PMID: 10858331 BACKGROUND

• Parikh UM, Bacheler L, Koontz D, Mellors JW. The K65R mutation in human immunodeficiency virus type 1 reverse transcriptase exhibits bidirectional phenotypic antagonism with thymidine analog mutations. J Virol. 2006 May;80(10):4971-7. doi: 10.1128/JVI.80.10.4971-4977.2006.

  PMID: 16641288 BACKGROUND

• Thompson MA, Kessler HA, Eron JJ Jr, Jacobson JM, Adda N, Shen G, Zong J, Harris J, Moxham C, Rousseau FS; DAPD-101 Study Group. Short-term safety and pharmacodynamics of amdoxovir in HIV-infected patients. AIDS. 2005 Oct 14;19(15):1607-15. doi: 10.1097/01.aids.0000186822.68606.05.

  PMID: 16184030 BACKGROUND

• Murphy RL, Kivel NM, Zala C, Ochoa C, Tharnish P, Mathew J, Pascual ML, Schinazi RF. Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals. Antivir Ther. 2010;15(2):185-92. doi: 10.3851/IMP1514.

  PMID: 20386073 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

Zidovudine; amdoxovir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Thymidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Dideoxynucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Carlos Zala, MD

  Hospital Privado Modelo

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY

Study Record Dates

• First Submitted: February 5, 2007
• First Posted: February 6, 2007
• Study Start: February 1, 2007
• Study Completion: May 1, 2007
• Last Updated: May 11, 2007

Record last verified: 2007-05

Locations

AR (1)