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Effects of Tipranavir/Ritonavir on the Pharmacokinetic Characteristics of Triple Drug Nucleoside and Non-nucleoside Reverse Transcriptase Inhibitor Therapy in HIV-1-infected Subjects

Primary Purpose

HIV Infections

Status
Completed
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Tipranavir low dose
Tipranavir medium dose
Tipranavir high dose
Ritonavir low dose
Ritonavir high dose
Sponsored by
Boehringer Ingelheim
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HIV Infections

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Signed informed consent prior to trial participation
  2. Between 18 and 75 years of age inclusive
  3. Female subjects of child bearing potential are required to use a barrier contraceptive method for at least 12 weeks prior to administration of study medication, during study medication administration, and for 28 days after the end of the study
  4. Ability to swallow capsules without difficulty
  5. A Body Mass Index (BMI) between 11 and 50 kg/m2
  6. Reasonable probability for completion of the study
  7. Acceptable screening laboratory values. All laboratory values ≤ Grade I (e.g., creatine phosphokinase (CPK), amylase, triglycerides) are permissible if documentation of stability for 2 months or more is available. Abnormalities > Grade I are subject to approval by BI clinical monitor or designee
  8. Acceptable medical history, physical examination, ECG, and chest X-ray prior to entering the treatment phase of the study
  9. Willingness to abstain from alcohol from Day -2 to Day 23
  10. Willingness to abstain from ingesting grapefruit, grapefruit juice, Seville oranges or orange marmalade from Day -2 to Day 23
  11. Negative urine drug screen for drugs of abuse. Subjects on methadone or equivalent narcotic maintenance programs will be permitted to enter the study
  12. Documented HIV-1 RNA load (by PCR) at screening of ≤20,000 copies/mL for at least twelve weeks. Acceptable documentation would include laboratory data, a letter or a verbal report from another provider noted in the subject records.
  13. Stable doses of approved NRTIs and NNRTIs 2 for a minimum of twelve weeks prior to study Day 0. Subjects on efavirenz must be able to tolerate daily morning (8:00 a.m.) dosing starting at screening period and for 22 days of the study. Subjects receiving bid ddI must be willing to accept a change to the once a day delayed release (EC) formulation

Exclusion Criteria:

  1. Female subjects who:

    • have a positive serum pregnancy test at Screening Period Day -14 to -7
    • are breast feeding
  2. Receipt of any other investigational medicine for 30 days prior to Day 0
  3. Receipt of any known cytochrome P450 3A4 (CYP3A4) altering drug i.e. phenothiazines, cimetidine, barbiturates, ketoconazole, fluconazole, rifampin, steroids and herbal medications for 30 days prior to Day 0. No antibiotics permitted within 10 days prior to Day 0
  4. Ingestion of grapefruit, grapefruit juice, Seville oranges or orange marmalade within 2 days of study entry (Day 0)
  5. Blood or plasma donations (>100 ml total) for research or altruistic reasons within 30 days prior to Day 0
  6. Seated systolic blood pressure either <100 mm Hg or >150 mm Hg; resting heart rate either <50 beats/minute or >90 beats/minute
  7. History of any illness, including malabsorption, irregular food intake or gastrointestinal intolerance, or allergy that, in the opinion of the investigator, might confound the results of the study or pose additional risk in administering TPV/RTV
  8. Any acute illness within 2 weeks prior to Day 0
  9. Subjects who are currently taking any over-the-counter drug within 7 days prior to Day 0, or who are currently taking any prescription drug that, in the opinion of the investigator (in consultation with the BI medical monitor and/or pharmacokineticist), might interfere with either the absorption, distribution or metabolism of the TPV/RTV
  10. Hypersensitivity to TPV, RTV or sulfonamide containing drugs
  11. Using the adherence diary, subject has less than 100% documented adherence for the last 14 doses (7 days) of baseline antiretroviral medications prior to Day 0. Subjects has less than 100% adherence for the last 7 doses (7 days) of efavirenz and ddI (delayed release) prior to Day 0

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm Type

    Experimental

    Experimental

    Experimental

    Arm Label

    TPV/r low dose

    TPV/r medium dose

    TPV/r high dose

    Arm Description

    Outcomes

    Primary Outcome Measures

    Change in trough plasma concentration (Cmin,ss) for non-nucleoside reverse transcriptase inhibitor (NNRTI)
    stratified by substance
    Change in area under plasma concentration-time curve over dosing interval (AUC0-τ) for nucleoside reverse transcriptase inhibitor (NRTI)
    stratified by substance
    Change in area under plasma concentration-time curve from 0 to 12 hours for didanosine (ddI)

    Secondary Outcome Measures

    Cmin,ss
    stratified by substance
    AUC0-τ
    stratified by substance
    Maximum plasma concentration (Cmax)
    stratified by substance
    Time of maximum plasma concentration (Tmax)
    stratified by substance
    Oral clearance (Cl/F)
    stratified by substance
    Apparent terminal half life (t1/2)
    stratified by substance
    Change in CD4 cell count
    Change in HIV-1 RNA levels
    Number of patients with clinically significant findings in laboratory tests
    Number of patients with adverse events

    Full Information

    First Posted
    September 25, 2014
    Last Updated
    September 25, 2014
    Sponsor
    Boehringer Ingelheim
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    1. Study Identification

    Unique Protocol Identification Number
    NCT02251223
    Brief Title
    Effects of Tipranavir/Ritonavir on the Pharmacokinetic Characteristics of Triple Drug Nucleoside and Non-nucleoside Reverse Transcriptase Inhibitor Therapy in HIV-1-infected Subjects
    Official Title
    An Open Label Multinational Study of the Effects of Three Dose Pairs of Tipranavir/Ritonavir (b.i.d.) on the Pharmacokinetic Characteristics of Protocol -Defined, Baseline, Triple Drug Nucleoside and Non-nucleoside Reverse Transcriptase Inhibitor Therapy in HIV-1-infected Subjects.
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    September 2014
    Overall Recruitment Status
    Completed
    Study Start Date
    February 2001 (undefined)
    Primary Completion Date
    February 2002 (Actual)
    Study Completion Date
    undefined (undefined)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Boehringer Ingelheim

    4. Oversight

    5. Study Description

    Brief Summary
    Primary: Sequentially determine the effects of three dose combinations of tipranavir (TPV) / ritonavir (RTV) (administered b.i.d.), TPV 1250 mg/RTV 100 mg vs. TPV 750 mg/RTV 100 mg vs. TPV 250 mg/RTV 200 mg on the steady-state pharmacokinetics of zidovudine, lamivudine, stavudine, didanosine, abacavir, nevirapine and efavirenz at approved doses. The three treatment groups will be enrolled sequentially starting with the highest tipranavir dosage group first and ending with the lowest tipranavir dosage group. Secondary: A) To assess the effects of zidovudine, lamivudine, stavudine, didanosine, abacavir, nevirapine, and efavirenz on the pharmacokinetics of tipranavir/ritonavir compared to historical controls. B) To assess the safety of three tipranavir/ritonavir combinations when used in combination with protocol defined antiretrovirals.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    HIV Infections

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1, Phase 2
    Interventional Study Model
    Parallel Assignment
    Allocation
    Non-Randomized
    Enrollment
    208 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    TPV/r low dose
    Arm Type
    Experimental
    Arm Title
    TPV/r medium dose
    Arm Type
    Experimental
    Arm Title
    TPV/r high dose
    Arm Type
    Experimental
    Intervention Type
    Drug
    Intervention Name(s)
    Tipranavir low dose
    Intervention Type
    Drug
    Intervention Name(s)
    Tipranavir medium dose
    Intervention Type
    Drug
    Intervention Name(s)
    Tipranavir high dose
    Intervention Type
    Drug
    Intervention Name(s)
    Ritonavir low dose
    Intervention Type
    Drug
    Intervention Name(s)
    Ritonavir high dose
    Primary Outcome Measure Information:
    Title
    Change in trough plasma concentration (Cmin,ss) for non-nucleoside reverse transcriptase inhibitor (NNRTI)
    Description
    stratified by substance
    Time Frame
    baseline, up to day 23
    Title
    Change in area under plasma concentration-time curve over dosing interval (AUC0-τ) for nucleoside reverse transcriptase inhibitor (NRTI)
    Description
    stratified by substance
    Time Frame
    baseline, up to day 22
    Title
    Change in area under plasma concentration-time curve from 0 to 12 hours for didanosine (ddI)
    Time Frame
    baseline, up to day 22
    Secondary Outcome Measure Information:
    Title
    Cmin,ss
    Description
    stratified by substance
    Time Frame
    up to day 23
    Title
    AUC0-τ
    Description
    stratified by substance
    Time Frame
    up to day 23
    Title
    Maximum plasma concentration (Cmax)
    Description
    stratified by substance
    Time Frame
    up to day 23
    Title
    Time of maximum plasma concentration (Tmax)
    Description
    stratified by substance
    Time Frame
    up to day 23
    Title
    Oral clearance (Cl/F)
    Description
    stratified by substance
    Time Frame
    up to day 23
    Title
    Apparent terminal half life (t1/2)
    Description
    stratified by substance
    Time Frame
    up to day 23
    Title
    Change in CD4 cell count
    Time Frame
    up to day 23
    Title
    Change in HIV-1 RNA levels
    Time Frame
    up to day 23
    Title
    Number of patients with clinically significant findings in laboratory tests
    Time Frame
    up to 25 weeks
    Title
    Number of patients with adverse events
    Time Frame
    up to 25 weeks

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    75 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Signed informed consent prior to trial participation Between 18 and 75 years of age inclusive Female subjects of child bearing potential are required to use a barrier contraceptive method for at least 12 weeks prior to administration of study medication, during study medication administration, and for 28 days after the end of the study Ability to swallow capsules without difficulty A Body Mass Index (BMI) between 11 and 50 kg/m2 Reasonable probability for completion of the study Acceptable screening laboratory values. All laboratory values ≤ Grade I (e.g., creatine phosphokinase (CPK), amylase, triglycerides) are permissible if documentation of stability for 2 months or more is available. Abnormalities > Grade I are subject to approval by BI clinical monitor or designee Acceptable medical history, physical examination, ECG, and chest X-ray prior to entering the treatment phase of the study Willingness to abstain from alcohol from Day -2 to Day 23 Willingness to abstain from ingesting grapefruit, grapefruit juice, Seville oranges or orange marmalade from Day -2 to Day 23 Negative urine drug screen for drugs of abuse. Subjects on methadone or equivalent narcotic maintenance programs will be permitted to enter the study Documented HIV-1 RNA load (by PCR) at screening of ≤20,000 copies/mL for at least twelve weeks. Acceptable documentation would include laboratory data, a letter or a verbal report from another provider noted in the subject records. Stable doses of approved NRTIs and NNRTIs 2 for a minimum of twelve weeks prior to study Day 0. Subjects on efavirenz must be able to tolerate daily morning (8:00 a.m.) dosing starting at screening period and for 22 days of the study. Subjects receiving bid ddI must be willing to accept a change to the once a day delayed release (EC) formulation Exclusion Criteria: Female subjects who: have a positive serum pregnancy test at Screening Period Day -14 to -7 are breast feeding Receipt of any other investigational medicine for 30 days prior to Day 0 Receipt of any known cytochrome P450 3A4 (CYP3A4) altering drug i.e. phenothiazines, cimetidine, barbiturates, ketoconazole, fluconazole, rifampin, steroids and herbal medications for 30 days prior to Day 0. No antibiotics permitted within 10 days prior to Day 0 Ingestion of grapefruit, grapefruit juice, Seville oranges or orange marmalade within 2 days of study entry (Day 0) Blood or plasma donations (>100 ml total) for research or altruistic reasons within 30 days prior to Day 0 Seated systolic blood pressure either <100 mm Hg or >150 mm Hg; resting heart rate either <50 beats/minute or >90 beats/minute History of any illness, including malabsorption, irregular food intake or gastrointestinal intolerance, or allergy that, in the opinion of the investigator, might confound the results of the study or pose additional risk in administering TPV/RTV Any acute illness within 2 weeks prior to Day 0 Subjects who are currently taking any over-the-counter drug within 7 days prior to Day 0, or who are currently taking any prescription drug that, in the opinion of the investigator (in consultation with the BI medical monitor and/or pharmacokineticist), might interfere with either the absorption, distribution or metabolism of the TPV/RTV Hypersensitivity to TPV, RTV or sulfonamide containing drugs Using the adherence diary, subject has less than 100% documented adherence for the last 14 doses (7 days) of baseline antiretroviral medications prior to Day 0. Subjects has less than 100% adherence for the last 7 doses (7 days) of efavirenz and ddI (delayed release) prior to Day 0

    12. IPD Sharing Statement

    Links:
    URL
    http://trials.boehringer-ingelheim.com
    Description
    Related Info

    Learn more about this trial

    Effects of Tipranavir/Ritonavir on the Pharmacokinetic Characteristics of Triple Drug Nucleoside and Non-nucleoside Reverse Transcriptase Inhibitor Therapy in HIV-1-infected Subjects

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