Multicenter Pilot Study To Define The Marker As An Alternate For Tropism Assay

Surrogate Marker For Tropism-A Multi-Center, Open Label, Pilot Study

Status

Terminated

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00496782

Enrollment

Registered

2007-07-04

Start date

2007-07-31

Completion date

2008-10-31

Last updated

2019-01-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

HIV Infections

Keywords

Treatment Experienced

Brief summary

The purpose of this pilot study is to determine whether there is a correlation between viral load reduction (at Day 4, 7 or 14) following a short course (14 days) of Maraviroc added to a failing regimen, and the R5 result of the TrofileTM assay at screening.

Detailed description

The study A4001060 has been discontinued on April 22, 2008. A review of the poor rate of enrollment has projected difficulties in completing the study in a timely manner, despite the best efforts by the sponsor and the sites. Given the difficulties encountered in this pilot study and the need to conduct an even larger confirmatory study, the decision to discontinue the study has therefore been made. It should be noted that safety concerns have not been seen in this study and have not factored into this decision.

Interventions

DRUGmaraviroc

Treatment-experienced subjects on failed therapy, with HIV RNA ≥ 1000 copies/mL, are eligible who will receive a tropism assay at screening (Day -14 to 0). Subjects who are eligible will receive maraviroc added to a failing regimen from Day 1 to 14. On day 15, subjects will discontinue the current treatment regimen and begin a new OBT. Subjects with only R5 HIV will continue receiving maraviroc plus OBT. Subjects with non-R5 virus will discontinue receiving maraviroc but continue to receive the new OBT. Investigator selects OBT based on results of phenotype/genotype testing at baseline. The nominal dose for maraviroc is 300 mg BID. The maraviroc dose should be adjusted based on OBT patient is taking. If OBT includes CYP3A4 inhibitor (with or without inducers) maraviroc dose should be 150 mg BID and if OBT includes CYP3A4 inducer (without inhibitors) maraviroc dose should be 600mg BID. If OBT does not include any CYP3A4 inducers or inhibitors maraviroc dose should be 300 mg BID.

PROCEDURETrofile Assay and HIV RNA quantification assay

Trofile Assay and HIV RNA quantification assay

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

SCREENING

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

16 Years to No maximum

Healthy volunteers

Inclusion criteria

* ≥ 16 years of age (or minimum adult age as determined by local regulatory authorities or as dictated by local law) at the screening visit. * Have an HIV RNA ≥ 1000 copies/mL, at screening. * Subjects receiving another investigational antiretroviral compound through participation in a phase 3 or 4 clinical study are eligible to participate in this trial provided. * That the 2 investigational agents are required to offer the subject a regimen with 2 or 3 active antiretroviral drugs (i.e. one or fewer approved treatment is available to the subject due to prior resistance or intolerance), * Neither protocol prohibits the use of the other antiretroviral agent, AND the dosing of the two agents when used together is known AND a letter from the Pfizer clinical pharmacologists for maraviroc identifies the dose of maraviroc to be used with other investigational agents. * Based on screening genotypic resistance testing results the subject must be able to receive at least 3 active drugs other than maraviroc in the new OBT. This is defined as: * Having three drugs considered susceptible by genotype interpretation (if etravirine will be used, fewer than 3 etravirine resistance mutations will be taken as etravirine susceptibility); or, * Having two drugs considered susceptible by genotype interpretation (if etravirine will be used, fewer than 3 etravirine resistance mutations will be taken as etravirine susceptibility) and be willing to include raltegravir in the OBT not having used raltegravir in the past.

Exclusion criteria

* Potentially life threatening (Grade 4) laboratory abnormality or medical condition. * Severe hepatic impairment (Child-Pugh classification B or C). * End stage renal disease or other disease states requiring dialysis therapy.

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline in Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) With R5 & Non-R5 Tropism Results From the Trofile(tm) Assay	Baseline, Day 4, 7, 14	Spearman's correlation coefficient to assess percentage of participants achieving HIV-1 RNA with tropism

Secondary

Measure	Time frame	Description
Subjects Achieving HIV-1 RNA <400 Copies/mL	Days 4, 7, 14, 28, and Weeks 8, 12, 18, and 24	Number of Subjects Achieving HIV-1 RNA \<400 Copies/mL at each time point
Subjects Achieving HIV-1 RNA <50 Copies/mL	Days 4, 7, 14, 28, and Weeks 8, 12, 18, and 24	Number of Subjects Achieving HIV-1 RNA \<50 Copies/mL at each time point
Subjects With Virologic Failure	Baseline up to Week 24	For this protocol, virologic failure will be confirmed by a repeat viral load test within 2 weeks of first viral load meeting any of the following criteria: 1. Failing to achieve a reduction in HIV-1 RNA \> 0.5 log10 copies/mL from baseline by the second viral load determination (unless the viral load is below level of quantification \[LOQ\]); 2. Experiencing a \> 0.5 log10 increase from nadir in HIV-1 RNA after achieving an HIV-1 RNA reduction from baseline \> 0.5 log10 copies/mL; or 3. Experiencing an HIV-1 RNA \>1000 copies/mL after having achieved an HIV-1 RNA below LOQ.
Time to Virologic Failure	Baseline up to Week 24	For this protocol, virologic failure will be confirmed by a repeat viral load test within 2 weeks of first viral load meeting any of the following criteria: 1. Failing to achieve a reduction in HIV-1 RNA \> 0.5 log10 copies/mL from baseline by the second viral load determination (unless the viral load is below level of quantification \[LOQ\]); 2. Experiencing a \> 0.5 log10 increase from nadir in HIV-1 RNA after achieving an HIV-1 RNA reduction from baseline \> 0.5 log10 copies/mL; or 3. Experiencing an HIV-1 RNA \>1000 copies/mL after having achieved an HIV-1 RNA below LOQ.
Change in Lymphocyte Subset CD4 From Baseline	Day 1 (Baseline), Day 7, 14, 28 and Weeks 24	Calculated average of CD4 at Day 7, 14, 28 and Week 24 minus CD4 at Day 1
Change in Lymphocyte Subset CD8 From Day 1	Day 1(Baseline), Day 7, 14, 28 and Weeks 24	Calculated average of CD8 at Day 7, 14, 28 and Week 24 minus CD8 at Day 1
Change in Detectable Tropism From Baseline	Baseline, Day 15 and Week 24/End of Study/Discontinuation	Number of subjects who switch their tropism status from Baseline to Days 7, 14, and Week 24/End of Study(EOS)/Discontinuation
Change in Detectable Tropism From Screening	Screening (Day -21 to 0), Baseline.	Number of subjects who switch their tropism status from screening to Baseline
Change in Detectable Resistance (Genotype) and Susceptibility (Phenotype) to Drugs in the Regimen From Screening	Screening (Day -21), Baseline (Day 0), Day 14 (after addition of MVC to a failing regimen), Week 24, and time of Virologic Failure.	Change in detectable resistance (genotype) and susceptibility (phenotype) to drugs in the regimen from Screening
Number of Subjects With Susceptibility to Maraviroc	Screening (Day -21 to 0), Day 14, Week 24	Phenotypic susceptibility to maraviroc
Change in Gene Sequence in Gp-160, and the V3 Loop From Screening Visit (Day -21 to 0) to Day 14, Time of Virologic Failure (See Section 6.5.1) and Week 24	Screening (Day -21 to 0), Day 14, time of virologic failure, and Week 24	Change in gene sequence in gp-160, and the V3 loop from Screening visit (Day -21 to 0) to Day 14, time of virologic failure (See Section 6.5.1) and Week 24
Correlation of Mutations in gp160 and the V3 Loop and Decreased Susceptibility to Maraviroc	Screening (Day -21 to 0), Day 14, time of virologic failure, Week 24	—
Change in Lymphocyte Subsets; CD4 and CD8 From Screening.	Screening (Day -14 to 0), Day 1.	Calculated avergae of {CD4 or CD8 at Day 1 - CD4 or CD8 at Screening}

Countries

Canada, United States

Participant flow

Participants by arm

Arm	Count
CCR5-Tropic HIV-1 Subjects treated with maraviroc in addition to the antiviral regimen they were receiving at the time of Screening (which was a failing regimen) for 14 days (including Day 14). On Day 15, subjects who had CC chemokine receptor 5 (CCR5) human immunodeficiency virus (HIV) 1 (based on Trofile™ assay) continued receiving maraviroc in combination with a new optimized background therapy (OBT) selected by the investigator until End of Study; Maraviroc was dosed orally twice daily (BID) with the total dose adjusted according to the OBT drugs.	9
Non-CCR5-Tropic HIV-1 Subjects treated with maraviroc (dosed orally twice daily (BID)) in addition to the antiviral regimen they were receiving at the time of Screening (which was a failing regimen) for 14 days (including Day 14). On Day 15, subjects with non CCR5 HIV 1 or a non reportable Trofile™ assay at Screening had discontinued maraviroc and had a new OBT selected by the investigator until End of Study.	7
Total	16

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Protocol Violation	1	2

Baseline characteristics

Characteristic	CCR5-Tropic HIV-1	Non-CCR5-Tropic HIV-1	Total
Age, Continuous	46.3 years STANDARD_DEVIATION 4.9	41.0 years STANDARD_DEVIATION 4.8	44.0 years STANDARD_DEVIATION 5.4
Sex: Female, Male Female	1 Participants	1 Participants	2 Participants
Sex: Female, Male Male	8 Participants	6 Participants	14 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	9 / 9	4 / 7
serious Total, serious adverse events	4 / 9	0 / 7

Outcome results

Primary

Change From Baseline in Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) With R5 & Non-R5 Tropism Results From the Trofile(tm) Assay

Spearman's correlation coefficient to assess percentage of participants achieving HIV-1 RNA with tropism

Time frame: Baseline, Day 4, 7, 14

Population: Study was canceled: no efficacy data (primary/secondary) was collected per protocol for limited number of patients left in study; only safety data was summarized.

Secondary

Change in Detectable Resistance (Genotype) and Susceptibility (Phenotype) to Drugs in the Regimen From Screening

Change in detectable resistance (genotype) and susceptibility (phenotype) to drugs in the regimen from Screening

Time frame: Screening (Day -21), Baseline (Day 0), Day 14 (after addition of MVC to a failing regimen), Week 24, and time of Virologic Failure.