Tipranavir/Ritonavir Low Dose Pharmacokinetics in Treatment Naive Patients

A Multicenter, Randomized, Open Label, Clinical Trial to Evaluate Three Doses of Tipranavir Boosted With Ritonavir (500 mg/200 mg qd, 250 mg/100 mg Bid and 500 mg/100 mg Bid) by Assessing the Steady-state Pharmacokinetics and Short-term Efficacy and Safety in HIV-1 Positive Treatment naïve Patients

The purpose of this study is to identify an optimal dose combination(s) of tipranavir (TPV) and ritonavir (RTV) for antiretroviral treatment naïve HIV-1 infected patients that can be used in pivotal trial by assessing the steady-state pharmacokinetics and short-term efficacy and safety

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: tipranavir; Drug: ritonavir

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany
    • 1182.107.49002 Boehringer Ingelheim Investigational Site
  • Berlin, Germany
    • 1182.107.49004 Boehringer Ingelheim Investigational Site
  • Frankfurt/Main, Germany
    • 1182.107.49003 Boehringer Ingelheim Investigational Site
  • München, Germany
    • 1182.107.49001 Boehringer Ingelheim Investigational Site
• Italy
  • Antella (fi), Italy
    • 1182.107.39001 Boehringer Ingelheim Investigational Site
  • Bari, Italy
    • 1182.107.39009 Boehringer Ingelheim Investigational Site
  • Ferrara, Italy
    • 1182.107.39007 Boehringer Ingelheim Investigational Site
  • Palermo, Italy
    • 1182.107.39011 Boehringer Ingelheim Investigational Site
• Spain
  • Barcelona, Spain
    • 1182.107.34001 Boehringer Ingelheim Investigational Site
  • Barcelona, Spain
    • 1182.107.34002 Boehringer Ingelheim Investigational Site
  • L'Hospitalet de Llobregat, Spain
    • 1182.107.34003 Boehringer Ingelheim Investigational Site
  • Madrid, Spain
    • 1182.107.34004 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed informed consent in accordance with GCP and local regulatory requirements prior to trial participation.
• HIV-1 infected men and non-pregnant women who are treatment naïve, with positive serology (EIA) confirmed by Western blot.
• Age > 18 and < 65 years.
• CD4 > 200 cells/mm3
• Viral load (HIV-1 mRNA viral load) > 5,000 copies/mL.
• Ability to swallow multiple large capsules without difficulty.
• Acceptable laboratory values that indicate adequate baseline organ function at screening visit.
• Laboratory values are considered to be acceptable if the severity of any parameter is = < Grade 2, based on the DAIDS/ACTG Grading Scale (see Appendix 10.2).
• Acceptable medical history, physical examination, and 12-lead ECG at screening

• Willingness to abstain from the following starting 2 weeks prior to administration of any study medication and up until the end of the study:

  o Grapefruit or grapefruit juice, Seville oranges, St. John's Wort, and Milk Thistle.

• Willingness to abstain from alcohol 3 days prior to administration of any study medication up to the end of the study.

• Willingness to abstain from the following starting 3 days prior to PK sampling:

  o Garlic supplements and methylxanthine containing foods or drinks (including coffee, tea, cola, energy drinks, chocolate, etc.).

• Willingness to abstain from over-the-counter herbal medications for the duration of the study.
• Willingness to abstain from any over the counter medication 7 days prior to administration of any study medication (including vitamins, minerals, dietary supplements and antacids) during the study until completion of the post study assessments.

Exclusion Criteria:

• Female patients of reproductive potential who:

  • Have positive serum pregnancy test.
  • Have not been using a barrier method of contraception for at least 3 months prior to participation in the study.
  • Are not willing to use a reliable method of barrier contraception (such as diaphragm with spermicidal cream/jelly or condoms with spermicidal foam), during and 60 days after completion/termination of the trial.
  • Are breast-feeding.
• Suspected or documented seroconversion within last 6 months
• Participation in another trial with an investigational medicine within 2 months prior to Day 0 of this study.
• Use of any pharmacological contraceptive (including oral, patch or injectable contraceptives) within 1 month prior to Day 0 and for the duration of the study.
• Use of hormone replacement therapy within 1 month prior to Day 0 and anytime during the study.
• History of acute illness within 30 days prior to Day 0.
• Have evidence of active or acute HBV or HCV.
• Alcohol or substance abuse within 1 year prior to screening or during the study.
• Patients with a history of any illness or allergy that, in the opinion of the investigator, might confound the results of the study or pose additional risk in administering TPV.
• Patients who have taken (within 7 days prior to Day 0) any over-the-counter or prescription medication that, in the opinion of the investigator in consultation with the BI clinical monitor, might interfere with absorption, distribution, or metabolism of the study medications.
• Known hypersensitivity to any ingredients of the test drug.
• Inability to adhere to the protocol.
• Genotypic resistance to tipranavir (defined as a TPV mutation score > 4).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Interventional Model: Parallel Assignment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Viral Load (log10 Copies/mL) Change From Baseline (Last Observation Carried Forward (LOCF))	Baseline (Day 0) to Final (Day 14)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apparent Oral Clearance I(Cl/F) of Tipranavir	Tipranavir pharmacokinetics - Clearance (CL) is defined as the dose of a drug divided by the area-under-the-concentration-time curve (AUC), ie. CL = Dose / AUC. For extravascu-lar models the fraction of dose absorbed cannot be estimated, therefore "clear-ance" for these models is actually Cl/F where F is the fraction of the drug dose which is absorbed.	Final (Day 14)
Area Under the Curve(AUC) of Tipranavir 24 h for Once Daily (QD) and AUC 12 h for Twice Daily (BID)	Tipranavir (TPV) pharmacokinetics	Final (Day 13 for QD, Day 14 for BID)
Concentration-24 Hour (hr) Post Dose of Tipranavir - (Cp 24 h for QD and 12 hr Post Dose (CP 12h) for BID	TPV pharmacokinetics	Final (Day 13 for QD, Day 14 for BID)
Trough Concentration (Cmin) of Tipranavir	TPV pharmacokinetics	Final (Day 13 for QD, Day 14 for BID)
Maximum Concentration (Cmax) of Tipranavir	TPV pharmacokinetics	Final (Day 13 for QD, Day 14 for BID)
Volume of Distribution (V/F) of Tipranavir	Tipranavir pharmacokinetics	Final (Day 14)
Terminal Half-Life (t1/2) of Tipranavir	Tipranavir pharmacokinetics	Final (Day 14)
Time to Cmax (Tmax) of Tipranavir	Tipranavir pharmacokinetics	Final (Day 14)
AUC 24 of Ritonavir for QD and AUC 12 of Ritonavir for BID	Ritonavir pharmacokinetics	Final (Day 13 for QD, Day 14 for BID)
Cp 24 h of Ritonavir for QD and CP 12 h of Ritonavir for BID	Ritonavir pharmacokinetics	Final (Day 13 for QD, Day 14 for BID)
Apparent Oral Clearance I(Cl/F) of Ritonavir	Ritonavir pharmacokinetics	Final (Day 13 for QD, Day 14 for BID)
Volume of Distribution (V/F) of Ritonavir	Ritonavir pharmacokinetics	Final (Day 14)
Terminal Half-Life (t1/2) of Ritonavir	Ritonavir pharmacokinetics	Final (Day 14)
Tmax of Ritonavir	Ritonavir pharmacokinetics	Final (Day 14)
Cmax of Ritonavir	Ritonavir pharmacokinetics	Visits baseline, 5, 7, 9 and 13 or 14
Clinical Abnormal Findings in Laboratory and Physical Examination		Screening through the end of the study (14 days)

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: October 1, 2007
• Primary Completion (Actual): May 1, 2008

Study Registration Dates

• First Submitted: September 17, 2007
• First Submitted That Met QC Criteria: September 17, 2007
• First Posted (Estimate): September 18, 2007

Study Record Updates

• Last Update Posted (Estimate): June 6, 2014
• Last Update Submitted That Met QC Criteria: May 27, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Tipranavir
• Other Study ID Numbers: 1182.107