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

Study Overview
=================
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.

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.

Conditions
-----------------
HIV Infections

Intervention / Treatment
-----------------
* Drug: Tipranavir low dose
* Drug: Tipranavir medium dose
* Drug: Tipranavir high dose
* Drug: Ritonavir low dose
* Drug: Ritonavir high dose


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TPV/r low dose<br> | Drug: Tipranavir low dose<br> <br> Drug: Ritonavir high dose<br> <br> |
| Experimental: TPV/r medium dose<br> | Drug: Tipranavir medium dose<br> <br> Drug: Ritonavir low dose<br> <br> |
| Experimental: TPV/r high dose<br> | Drug: Tipranavir high dose<br> <br> Drug: Ritonavir low dose<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in trough plasma concentration (Cmin,ss) for non-nucleoside reverse transcriptase inhibitor (NNRTI) | stratified by substance | baseline, up to day 23 | 
| Change in area under plasma concentration-time curve over dosing interval (AUC0-τ) for nucleoside reverse transcriptase inhibitor (NRTI) | stratified by substance | baseline, up to day 22 | 
| Change in area under plasma concentration-time curve from 0 to 12 hours for didanosine (ddI) |  | baseline, up to day 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmin,ss | stratified by substance | up to day 23 | 
| AUC0-τ | stratified by substance | up to day 23 | 
| Maximum plasma concentration (Cmax) | stratified by substance | up to day 23 | 
| Time of maximum plasma concentration (Tmax) | stratified by substance | up to day 23 | 
| Oral clearance (Cl/F) | stratified by substance | up to day 23 | 
| Apparent terminal half life (t1/2) | stratified by substance | up to day 23 | 
| Change in CD4 cell count |  | up to day 23 | 
| Change in HIV-1 RNA levels |  | up to day 23 | 
| Number of patients with clinically significant findings in laboratory tests |  | up to 25 weeks | 
| Number of patients with adverse events |  | up to 25 weeks |