Clinical trial NCT01009814: Pharmacodynamics, Safety and Pharmacokinetics of BMS-663068, an HIV Attachment Inhibitor, in HIV-1
Official title: Randomized, Open Label, Multiple-Dose Study to Evaluate the Pharmacodynamics, Safety and Pharmacokinetics of BMS-663068 in HIV-1 Infected Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: HIV, HIV attachment inhibitor, attachment inhibitor
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2009-11-09
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Research Hypothesis: Administration of BMS-663068, a prodrug for HIV attachment inhibitor BMS-626529, will result in a mean decrease of at least 1 log10 in HIV RNA at Day 9 following 8 days of therapy in at least one dosing regimen that is safe and well tolerated in Clade B HIV-1 infected subjects.


Eligibility criteria: Inclusion Criteria:

* Clade B HIV-1 infected subjects meeting following criteria at screening:

  * Plasma HIV RNA ≥ 5,000 copies/mL
  * CD4+ lymphocyte ≥ 200 cells/µL
  * Antiretroviral naive or experienced
  * Off all ARV therapy with HIV activity for \> 8 weeks
* BMI of 18 to 35 kg/m2, inclusive.
* Not currently co-infected with HCV or HBV
* Men and women, ≥ 18 years of age

Exclusion Criteria:

* Woman of childbearing potential (WOCBP) unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period up to 12 weeks after the last dose of study drug.
* WOCBP using prohibited contraceptive method including oral, injectable, or implantable hormonal contraceptive agent within 12 weeks of enrollment.
* Women who are pregnant or breastfeeding.
* Women with positive pregnancy test on enrollment or prior to study drug intake.
* Sexually active fertile men not using effective birth control during study and for at least 12 weeks after last dose of study drug if partners are WOCBP.
* Significant acute or chronic medical illness not stable or not controlled with medication or not consistent with HIV infection.
* Current or recent (within 3 months) gastrointestinal disease that, in the opinion of Investigator or Medical Monitor, may impact on drug absorption and/or put subject at risk for GI tract irritation and/or bleeding.
* Acute diarrhea lasting ≥ 1 day, within 3 weeks prior to randomization.
* Major surgery within 4 weeks of study drug intake.
* Gastrointestinal surgery that could impact upon absorption of study drug.
* Donation of blood or plasma to blood bank or in a clinical study (except a Screening visit or follow up visit of less than 50 mL) within 4 weeks of study drug intake.
* Blood transfusion within 4 weeks of study drug intake.
* Inability to tolerate oral medication.
* Inability to be venipunctured and/or tolerate venous access.
* Personal history of clinically relevant cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or additional risk factors for torsades de pointes.
* Personal or family history of long QT syndrome.
* Recent (within 6 months) drug/alcohol abuse
* Any other medical, psychiatric and/or social reason which, in the opinion of the Investigator, would make the candidate inappropriate for participation.
* Evidence of organ dysfunction or clinically significant deviation from normal in physical examination, vital signs, ECG or clinical lab determinations or not consistent with subject's degree of HIV infection.
* Evidence of 2nd or 3rd degree heart block at screening or Day -1
* Positive urine drug screen at Screening or Day -1 without valid prescription (subjects positive for cannabinoids and/or amphetamines will be included).
* Positive blood screen for hepatitis B surface antigen.
* Positive blood screen for hepatitis C antibody and hepatitis C RNA.
* History of significant drug allergy
* Exposure to any investigational drug or placebo within 4 weeks of study drug intake.
* Prescription drugs within 4 weeks prior to study drug intake, unless approved by BMS medical monitor.
* Other drugs, including over-the-counter medications, vitamins and/or herbal preparations, within 1 week prior to study drug intake, unless approved by BMS medical monitor.
* Use of oral, injectable or implantable hormonal contraceptive agent within 12 weeks of study drug intake.
* Use of prescription drugs or OTC drugs that may cause GI tract irritation or bleeding within 2 weeks of study drug intake, unless approved by BMS medical monitor.
* Use of alcohol-containing beverages within 3 days prior to study drug intake.
* Use of grapefruit, grapefruit-containing or Seville orange-containing products within 7 days prior to study drug intake.
* Prisoners or subjects involuntarily incarcerated.
* Subjects compulsorily detained for treatment of either a psychiatric or physical illness.

Primary outcomes:
measure: Mean Logarithm With Base 10 (Log10) Change From Baseline in Human Immunodeficiency Virus (HIV) Ribonucleic Acid (RNA) at Day 9
timeFrame: Baseline and Day 9
Secondary outcomes:
measure: Change From Baseline in Cluster of Differentiation 4 Positive (CD4+) Cell Count and Cluster of Differentiation 8 Positive (CD8+) Cell Count
timeFrame: Baseline (Day 1 pre-dose), Day 8, Day 15 and Day 50
measure: Change From Baseline in Percent CD4+ Cell Count and Percent CD8+ Cell Count
timeFrame: Baseline (Day 1 pre-dose), Day 8, Day 15 and Day 50
measure: Number of Participants With Treatment Emergent Non-serious Adverse Event (Non-SAE) and Serious AE (SAE)
timeFrame: Up to 50 days
measure: Number of Participants With Any Abnormality in Physical Examination
timeFrame: Up to 50 days
measure: Number of Participants With Worst-case Abnormalities in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
timeFrame: Up to 50 days
measure: Number of Participants With Worst-case Abnormalities in Body Temperature, Respiratory Rate [RR], and Heart Rate [HR]
timeFrame: Up to 50 days
measure: Number of Participants With Worst-case Abnormalities in Electrocardiogram (ECG) Parameters
timeFrame: Up to 50 days
measure: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters
timeFrame: Up to 50 days
measure: Maximum Observed Plasma Concentration (Cmax) of BMS-626529 Following Q12H Dosing
timeFrame: Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours
measure: Cmax of BMS-626529 Following QHS Dosing
timeFrame: Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours
measure: Trough Observed Plasma Concentration (Ctrough) of BMS-626529 Following Q12H Dosing
timeFrame: Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours; Days 5,6,7: pre-morning dose
measure: Ctrough of BMS-626529 Following QHS Dosing
timeFrame: Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours; Days 5,6,7: pre-evening dose
measure: Area Under the Concentration-time Curve in One Dosing Interval (AUC [Tau]) of BMS-626529 Following Q12H Dosing
timeFrame: Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours
measure: AUC (Tau) of BMS-626529 Following QHS Dosing
timeFrame: Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours
measure: Area Under the Concentration-time Curve Over a 24-hour Period (AUC [0-24]) of BMS-626529 Following Q12H Dosing
timeFrame: Day 8: pre-morning dose, 1,2,3,4,5,6,8,12, 13,14,15,16,17,18,20 hours
measure: AUC (0-24) of BMS-626529 Following QHS Dosing
timeFrame: Day 8: pre-evening dose, 1,2,3,4,5,6,8 hours
measure: Accumulation Index (AI) of BMS-626529 Following Q12H Dosing
timeFrame: Day 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours
measure: Accumulation Index of BMS-626529 Following QHS Dosing
timeFrame: Day 8: pre-evening dose, 1,2,3,4,5,6,8 hours
measure: Inhibitory Quotient (IQ) of BMS-626529 by Css,Avg and by Lowest Concentration of a Drug During Dosing Interval (Cmin) Following Q12H Dosing
timeFrame: Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours; Day 9: pre-dose, 4,12 hours; Day 10: pre-dose, 12 hours; Day 11: pre-dose; Days 5,6,7: pre-morning dose
measure: Inhibitory Quotient (IQ) of BMS-626529 by Css,Avg and by Lowest Concentration of a Drug During Dosing Interval (Cmin) Following QHS Dosing
timeFrame: Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours; Day 2: pre-evening dose, 12,16 hours; Day 9: pre-dose, 12,16 hours; Day 10: pre-dose, 12 hours; Day 11: pre-dose; Days 5,6,7: pre-evening dose
measure: Inhibitory Quotient of BMS-626529 by Ctrough Following Q12H Dosing
timeFrame: Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours; Day 9: pre-dose, 4,12 hours; Day 10: pre-dose, 12 hours; Day 11: pre-dose; Days 5,6,7: pre-morning dose
measure: Inhibitory Quotient of BMS-626529 by Ctrough Following QHS Dosing
timeFrame: Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours; Days 2: pre-evening dose, 12,16 hours; Day 9: pre-dose, 12,16 hours; Day 10: pre-dose, 12 hours; Day 11: pre-dose; Days 5,6,7: pre-evening dose
measure: Cmax of Ritonavir Following Q12H Dosing
timeFrame: Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours
measure: Cmax of Ritonavir Following QHS Dosing
timeFrame: Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours
measure: Ctrough of Ritonavir Following Q12H Dosing
timeFrame: Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours; Days 5,6,7: pre-morning dose
measure: Ctrough of Ritonavir Following QHS Dosing
timeFrame: Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours; Days 5,6,7: pre-evening dose
measure: AUC (Tau) of Ritonavir Following Q12H Dosing
timeFrame: Days 1, 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours
measure: AUC (Tau) of Ritonavir Following QHS Dosing
timeFrame: Days 1, 8: pre-evening dose, 1,2,3,4,5,6,8 hours
measure: AUC (0-24) of Ritonavir Following Q12H Dosing
timeFrame: Day 8: pre-morning dose, 1,2,3,4,5,6,8,12, 13,14,15,16,17,18,20 hours
measure: AUC (0-24) of Ritonavir Following QHS Dosing
timeFrame: Day 8: pre-evening dose, 1,2,3,4,5,6,8 hours
measure: Accumulation Index of Ritonavir Following Q12H Dosing
timeFrame: Day 8: pre-morning dose, 1,2,3,4,5,6,8,12 hours; Day 8: 13,14,15,16,17,18,20 hours
measure: Accumulation Index of Ritonavir Following QHS Dosing
timeFrame: Day 8: pre-evening dose, 1,2,3,4,5,6,8 hours
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Landry I, Zhu L, Abu Tarif M, Hruska M, Sadler BM, Pitsiu M, Joshi S, Hanna GJ, Lataillade M, Boulton DW, Bertz RJ. Model-Based Phase 3 Dose Selection for HIV-1 Attachment Inhibitor Prodrug BMS-663068 in HIV-1-Infected Patients: Population Pharmacokinetics/Pharmacodynamics of the Active Moiety, BMS-626529. Antimicrob Agents Chemother. 2016 Apr 22;60(5):2782-9. doi: 10.1128/AAC.02503-15. Print 2016 May.
citation: Ray N, Hwang C, Healy MD, Whitcomb J, Lataillade M, Wind-Rotolo M, Krystal M, Hanna GJ. Prediction of virological response and assessment of resistance emergence to the HIV-1 attachment inhibitor BMS-626529 during 8-day monotherapy with its prodrug BMS-663068. J Acquir Immune Defic Syndr. 2013 Sep 1;64(1):7-15. doi: 10.1097/QAI.0b013e31829726f3.
citation: Nettles RE, Schurmann D, Zhu L, Stonier M, Huang SP, Chang I, Chien C, Krystal M, Wind-Rotolo M, Ray N, Hanna GJ, Bertz R, Grasela D. Pharmacodynamics, safety, and pharmacokinetics of BMS-663068, an oral HIV-1 attachment inhibitor in HIV-1-infected subjects. J Infect Dis. 2012 Oct 1;206(7):1002-11. doi: 10.1093/infdis/jis432. Epub 2012 Aug 14.