HIV InfectionsPhase 1/2NCT00432016
Safety, Tolerance, Pharmacokinetic and Antiviral Study of Amdoxovir in Combination With Zidovudine in Adults With HIV
A Phase 1/2 study testing zidovudine, amdoxovir and pharmacokinetic sampling in people with HIV Infections, run by RFS Pharma, LLC at 1 site in Argentina.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- HIV Infections
- What is being tested?
- zidovudine, amdoxovir and pharmacokinetic sampling
- Type of treatment
- Surgery or procedure
- How many people
- 24 participants
- Where
- 1 siteArgentina
- Study dates
- Feb 2007to May 2007
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 22Show fewer
- 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
- Random or fasting glucose > 121 mg/dL
- Serum lipase > 1.5 x ULN
- Urinalysis ≥ 2+ proteinuria and ≥ 2 cellular casts per high powered field (HPF)
- Active acute hepatitis A and/or chronic hepatitis B or C with detectable viremia
- Subjects with clinical or laboratory evidence of significantly decreased hepatic function or decompensation, irrespective of liver enzyme levels (INR > 1.3 or albumin < 30 g/l or bilirubin > 2.5 x ULN)
- Pregnant women
- Breastfeeding women
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Randomized, Placebo-Controlled Study to Evaluate Safety, Tolerance, Pharmacokinetics and Antiviral Activity of Amdoxovir and Zidovudine in Untreated HIV-1 Infected Subjects Currently Untreated
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.
Read the detailed description
By 2008, market data suggest that the most commonly prescribed initial treatment regimen for HIV-1 will consist of Truvada® (FTC and tenofovir disoproxil fumarate (TDF)) and Sustiva® (efavirenz (EFV)). A newly formulated drug called Atripla™ containing all three active ingredient has now been approved by the US FDA. Therefore, second line treatments that are currently in development should provide activity against resultant mutations, primarily M184V/I (17%) and much less commonly K65R (0 to 5%), and ideally prevent or be effective against mutations that may occur during second line therapy.
The goal of our program is to identify an AZT/DAPD co-formulation with reduced resistance development and an improved safety profile for the treatment of HIV infections. DAPD has increased sensitivity to M184V/I strains and is active against thymidine analog mutations (TAMs) that may have occurred during previous antiretroviral regimens. AZT offers anti-K65R activity which is believed to be conferred by the 3'-azido moiety containing pseudo-sugar structure and base components of AZT. Hence, AZT could potentially be incorporated to prevent the emergence of the K65R mutation that could limit the long-term benefit of DAPD.
Since nucleoside reverse transcriptase inhibitors (NRTIs) require intracellular phosphorylation to form their active triphosphates, it is preferable to combine NRTIs with different critical kinases. Thymidine kinase-1 is the critical enzyme for the phosphorylation of AZT to its monophosphates. The enzyme involved in the initial phosphorylation of the active metabolite of DAPD, DXG, is guanosine kinase. Nucleotide competition studies conducted using activated human peripheral blood mononuclear (PBM) cells performed with DAPD and AZT with concentrations between 0.1-10 µM demonstrated no competitive inhibition of DXG-triphosphate formation.
The approved dose for AZT is 300 mg bid, and AZT is available as a 300 mg tablet or 100 mg capsule. A previous study in 10 HIV seropositive individuals comparing cellular AZT-mono, di- and tri-phosphate nucleotides at normal and reduced doses, 100 mg tid versus 300 mg bid, demonstrated a significant decrease in plasma AZT and intracellular AZT-monophosphate (AZT-MP) levels, (AZT-MP is associated with toxicity), without significant changes in AZT-triphosphate (AZT-TP) levels in activated PBM cells or antiviral activity. These findings on the effect of AZT dose on intracellular AZT-TP are supported by computer simulations. Maximal predicted cellular levels of AZT-MP and AZT-TP at steady-state, following 200 mg bid and 300 mg bid dosing in 3,000 simulated individuals demonstrated a high overlap between the AZT-TP histograms (> 85 %), suggesting similar efficacies for the 200 and 300 mg bid doses. The low degree of overlap between the AZT-MP histograms (< 8 %) for the two dose regimens, suggests that there may be fewer toxicities with the 200 mg bid dose, supporting our hypothesis that a zidovudine dose of 200 mg bid could reduce the AZT-MP levels without compromising the AZT-TP levels that would be obtained with a 300 mg bid dose.
This 10 day, proof of principle, pharmacokinetic study will provide important information about reduced AZT dosing to support the development of an AZT/DAPD co-formulation which may prevent the emergence of K65R mutations.
- Conditions
- HIV Infections
- Being tested
- zidovudine, amdoxovir, pharmacokinetic sampling
- Keywords
- HIV, pharmacokinetics, zidovudine, amdoxovir, DAPD, AMDX, Treatment Naive
- Medical subject headings
- HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
zidovudineDrug
amdoxovirDrug
pharmacokinetic samplingProcedure or surgery
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Feb 2007 (estimated)
- Study startFeb 2007
- Study completionMay 2007
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for HIV InfectionsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Double blind
- Enrolment
- 24 participants
Sponsor and investigators
- Lead sponsor
- RFS Pharma, LLC
- Sponsor type
- Industry (pharma, biotech, devices)
- Investigators
- Carlos Zala, MD, Principal investigator, Hospital Privado Modelo
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00432016
- Sponsor's protocol ID
- RFS-AMDX-203
- Other IDs
- ACA-AI-001-001
- Status last verified
- May 2007
- First submitted
- 5 Feb 2007
- Last updated
- 11 May 2007
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 8902065Bazmi 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.
PubMed 10858331Parikh 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.
PubMed 16641288Thompson 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.
PubMed 16184030Murphy 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.
PubMed 20386073
Study at a glance
From the registry record, last updated by the sponsor on 11 May 2007. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized, Placebo-Controlled Study to Evaluate Safety, Tolerance, Pharmacokinetics and Antiviral Activity of Amdoxovir and Zidovudine in Untreated HIV-1 Infected Subjects Currently Untreated
- ClinicalTrials.gov ID
- NCT00432016
- Acronym / sponsor ID
- RFS-AMDX-203
- Conditions
- HIV Infections
- Keywords
- HIV, pharmacokinetics, zidovudine, amdoxovir, DAPD, AMDX, Treatment Naive
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants
- Lead sponsor
- RFS Pharma, LLCIndustry (pharma, biotech, devices)
- Study start
- Feb 2007
- Study completion
- May 2007 (actual)
- First posted
- 6 Feb 2007 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
By 2008, market data suggest that the most commonly prescribed initial treatment regimen for HIV-1 will consist of Truvada® (FTC and tenofovir disoproxil fumarate (TDF)) and Sustiva® (efavirenz (EFV)). A newly formulated drug called Atripla™ containing all three active ingredient has now been approved by the US FDA. Therefore, second line treatments that are currently in development should provide activity against resultant mutations, primarily M184V/I (17%) and much less commonly K65R (0 to 5%), and ideally prevent or be effective against mutations that may occur during second line therapy.
The goal of our program is to identify an AZT/DAPD co-formulation with reduced resistance development and an improved safety profile for the treatment of HIV infections. DAPD has increased sensitivity to M184V/I strains and is active against thymidine analog mutations (TAMs) that may have occurred during previous antiretroviral regimens. AZT offers anti-K65R activity which is believed to be conferred by the 3'-azido moiety containing pseudo-sugar structure and base components of AZT. Hence, AZT could potentially be incorporated to prevent the emergence of the K65R mutation that could limit the long-term benefit of DAPD.
Since nucleoside reverse transcriptase inhibitors (NRTIs) require intracellular phosphorylation to form their active triphosphates, it is preferable to combine NRTIs with different critical kinases. Thymidine kinase-1 is the critical enzyme for the phosphorylation of AZT to its monophosphates. The enzyme involved in the initial phosphorylation of the active metabolite of DAPD, DXG, is guanosine kinase. Nucleotide competition studies conducted using activated human peripheral blood mononuclear (PBM) cells performed with DAPD and AZT with concentrations between 0.1-10 µM demonstrated no competitive inhibition of DXG-triphosphate formation.
The approved dose for AZT is 300 mg bid, and AZT is available as a 300 mg tablet or 100 mg capsule. A previous study in 10 HIV seropositive individuals comparing cellular AZT-mono, di- and tri-phosphate nucleotides at normal and reduced doses, 100 mg tid versus 300 mg bid, demonstrated a significant decrease in plasma AZT and intracellular AZT-monophosphate (AZT-MP) levels, (AZT-MP is associated with toxicity), without significant changes in AZT-triphosphate (AZT-TP) levels in activated PBM cells or antiviral activity. These findings on the effect of AZT dose on intracellular AZT-TP are supported by computer simulations. Maximal predicted cellular levels of AZT-MP and AZT-TP at steady-state, following 200 mg bid and 300 mg bid dosing in 3,000 simulated individuals demonstrated a high overlap between the AZT-TP histograms (> 85 %), suggesting similar efficacies for the 200 and 300 mg bid doses. The low degree of overlap between the AZT-MP histograms (< 8 %) for the two dose regimens, suggests that there may be fewer toxicities with the 200 mg bid dose, supporting our hypothesis that a zidovudine dose of 200 mg bid could reduce the AZT-MP levels without compromising the AZT-TP levels that would be obtained with a 300 mg bid dose.
This 10 day, proof of principle, pharmacokinetic study will provide important information about reduced AZT dosing to support the development of an AZT/DAPD co-formulation which may prevent the emergence of K65R mutations.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Double blind
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (22 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| zidovudine | Drug | – |
| amdoxovir | Drug | – |
| pharmacokinetic sampling | Procedure or surgery | – |
Primary outcome
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
5 secondary outcomes
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 May 2007.
- Background: PubMed 8902065Barry 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.
- Background: PubMed 10858331Bazmi 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.
- Background: PubMed 16641288Parikh 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.
- Background: PubMed 16184030Thompson 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.
- Derived from this study: PubMed 20386073Murphy 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Carlos Zala, MD principal investigator
Hospital Privado Modelo
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing zidovudine, amdoxovir and pharmacokinetic sampling in people with HIV Infections, run by RFS Pharma, LLC at 1 site in Argentina.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 May 2007. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Argentina. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of subjects in each arm with Grade 3 or greater treatment emergent adverse events (AE). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00432016, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 May 2007.