Rollover Trial Safety and Tolerability of Combination Tipranavir and Ritonavir Use in HIV 1 Infected Subjects

Study Overview
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Brief Summary
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The objective of this study is to determine the long term safety and tolerability of multiple oral doses of tipranavir (Aptivus) and ritonavir with a focus on the long term safety of the development dose (500 mg tipranavir/200 mg ritonavir BID) when administered with other antiretroviral medications.

Official Title
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A Long Term Open Label Rollover Trial Assessing the Safety and Tolerability of Combination Tipranavir and Ritonavir Use in HIV-1 Infected Subjects

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Tipranavir


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Ability and willingness to give written informed consent in accordance with institutional and federal guidelines and to comply with the investigational nature of the study and the related requirements. All subjects must have successfully completed participation in a combination tipranavir/ritonavir trial or have confirmed virologic failure in the 1182.12 or 1182.48 trials and are not able to obtain TPV by prescription. Successful completion of participation is defined as conclusion of required subject-weeks on assigned dosing (trial specific) and completion of required visits. Male and female subjects 18 years and over. Presence of Human Immunodeficiency Virus 1 (HIV-1) infection as documented by any licensed Enzyme Linked immunosorbent Assay (ELISA) test kit and confirmed by Western Blot, or HIV-1 culture, or HIV-1 antigen, or plasma HIV 1 Ribonucleic Acid (RNA) or a second antibody test by a method other than ELISA at any time prior to study entry. Adherence to previous tipranavir/ritonavir dosing protocol and adherence to visit requirements of previous protocol (as assessed by principal investigator). Acceptable screening laboratory values that indicate adequate baseline organ function. Laboratory values are considered to be acceptable if the following apply: Total Cholesterol ≤400 mg/dl (<Common Toxicity Criteria (CTC) Grade 2). Total Triglycerides ≤750 mg/dl (<Division of AIDS (DAIDS) Grade 2). Alanine aminotransferase (ALT) ≤3.0x upper limit of normal (ULN) and Aspartate aminotransferase (AST) ≤2.5x ULN (<DAIDS Grade 1). Any Grade Gamma Glutamyl transpeptidase(GGT) is acceptable. Any Grade creatinine kinase is acceptable as long as there is no concurrent myopathy. All other laboratory test values ≤DAIDS Grade 1. EXCLUSION CRITERIA Female subjects who are of reproductive potential who: Have a positive serum beta human chorionic gonadotropin (B HCG) at Screening/Enrollment Visit. Are not willing to use a reliable method of barrier contraception (such as diaphragm or condoms). Are breast-feeding. Subjects who are actively using injection drugs or other substance abuse (such as extensive alcohol or narcotic use) which is considered by the investigator to be a significant impairment to health and to protocol adherence. Any medical condition(s) which, in the opinion of the investigator, would interfere with the subject's ability to participate in or adhere to the requirements of this protocol. History of any illness or drug allergy which, in the opinion of the investigator, might confound the results of the study or pose additional risk in administering tipranavir/ritonavir to the subject. Active use of any of the following: Investigational HIV-1 vaccines. Any new investigational antiretroviral agent that was not approved for use in the patients prior tipranavir trial. Medications excluded during the trial period (see Section 4.2). Herbal medications (e.g., St. John's Wort). Active HIV-related or non HIV-related illness that may be negatively affected by use of tipranavir/ritonavir as determined by the investigator. If a subject must temporarily discontinue tipranavir/ritonavir at the recommendation of the investigator (at the completion of the previous tipranavir trial), then the subject may enroll in 1182.17 once the clinical illness has resolved, and after approval from the Boehringer Ingelheim Clinical Monitor or Local Clinical Monitor. Clinically significant liver disease in the 90 days prior to baseline visit, regardless of baseline AST and/or ALT values. Hypersensitivity to tipranavir or ritonavir. Voluntary discontinuation of antiretroviral therapy (including tipranavir/ritonavir) for more than seven days from completion of previous tipranavir trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Patients With Varying Degrees of Tipranavir Treatment Experience | Drug: Tipranavir<br> <br> |
| Experimental: Group 2<br>Highly Tipranavir Treatment Experienced Patients | Drug: Tipranavir<br> <br> |
| Experimental: Group 3<br>Tipranavir Treatment Naive Patients | Drug: Tipranavir<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Haemoglobin | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - White Blood Cell ct. | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Platelets | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Prothrombin Time | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Sodium | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Potassium | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Calcium | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Phosphate | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Carbon Dioxide | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Aspartate Aminotransferase (AST/GOT,SGOT) | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Alanine Aminotransferase (ALT/GPT,SGPT) | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Alkaline Phosphatase | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Amylase | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Creatine Phosphokinase | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Lipase | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Glucose | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Cholesterol, Total | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Creatinine | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Bilirubin, Total | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Triglycerides | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Uric Acid | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 - Albumin | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade 3 or 4 -Low-density Lipoprotein (LDL) | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 
| Number of Patients With Adverse Events Leading to Death | NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004. | End of Trial (>288 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Human Immunodeficiency Virus-Ribonucleic Acid (HIV-RNA) Viral Load - Last Observation Carried Forward (LOCF) | Change from baseline in Human Immunodeficiency Virus-Ribonucleic Acid (HIV-RNA) viral load with last observation carried forward (LOCF) | Baseline to 192-240 week time interval | 
| Change From Baseline in CD4 Cell Count (LOCF) | Change from baseline in CD4 cell count with last observation carried forward(LOCF). | Baseline to 192-240 week time interval |