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

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

Status

Completed

Phases

Phase 2Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00146328

Enrollment

997

Registered

2005-09-07

Start date

2001-04-30

Completion date

Unknown

Last updated

2014-03-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

HIV Infections

Brief summary

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.

Interventions

DRUGTipranavir

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. 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. 2. 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. 3. Male and female subjects 18 years and over. 4. 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. 5. Adherence to previous tipranavir/ritonavir dosing protocol and adherence to visit requirements of previous protocol (as assessed by principal investigator). 6. 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

1. 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. 2. 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. 3. 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. 4. 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. 5. 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). 6. 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. 7. Clinically significant liver disease in the 90 days prior to baseline visit, regardless of baseline AST and/or ALT values. 8. Hypersensitivity to tipranavir or ritonavir. 9. Voluntary discontinuation of antiretroviral therapy (including tipranavir/ritonavir) for more than seven days from completion of previous tipranavir trial.

Design outcomes

Primary

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

Secondary

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

Countries

Argentina, Australia, Austria, Belgium, Brazil, Canada, Denmark, France, Germany, Greece, Italy, Mexico, Netherlands, Portugal, Spain, Switzerland, United Kingdom, United States

Participant flow

Participants by arm

Arm	Count
Group 1 (Patients With Varying Degrees of Treatment Experience A total of 995 patients who entered 1182.17 from a 'core' TPV/r trial were treated with TPV/r and were included in the integrated database. Of the 995 patients from 241 sites in 19 countries worldwide, 291 patients were categorized into Group 1. Group 1: TPV/r patients who rolled over from Trials 1182.2, 1182.4, 1182.6, 1182.52, 1182.12 and 1182.48.	291
Group 2 (Highly Treatment Experienced Patients) A total of 995 patients who entered 1182.17 from a 'core' TPV/r trial were treated with TPV/r and were included in the integrated database. Of the 995 patients from 241 sites in 19 countries worldwide, 255 patients were categorized into Group 2. Group 2: Patients from 1182.51 who rolled over into 1182.17.	255
Group 3 (Tipranavir naïve Patients) A total of 995 patients who entered 1182.17 from a 'core' TPV/r trial were treated with TPV/r and were included in the integrated database. Of the 995 patients from 241 sites in 19 countries worldwide, 449 patients were categorized into Group 3. Group 3: PI comparator arm patients from 1182.4, 1182.12 and 1182.48 who virologically failed and who then rolled into 1182.17.	449
Total	995

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	39	48	79
Overall Study	Death	0	1	1
Overall Study	Enroll into other trial	2	4	2
Overall Study	Interaction with other medication	2	0	1
Overall Study	Lost to Follow-up	7	4	7
Overall Study	Moved	2	0	0
Overall Study	Patient decision to end	0	1	6
Overall Study	Protocol Violation	11	6	12
Overall Study	Trial ended/site closed	8	2	19
Overall Study	Virologic Failure/lack of efficacy	54	72	142
Overall Study	Withdrawal by Subject	16	16	22

Baseline characteristics

Characteristic	Group 1 (Patients With Varying Degrees of Treatment Experience	Group 2 (Highly Treatment Experienced Patients)	Group 3 (Tipranavir naïve Patients)	Total
Age, Continuous	43.7 years STANDARD_DEVIATION 8	45.6 years STANDARD_DEVIATION 8.2	43.5 years STANDARD_DEVIATION 7.7	44.1 years STANDARD_DEVIATION 8
Sex: Female, Male Female	35 Participants	20 Participants	44 Participants	99 Participants
Sex: Female, Male Male	256 Participants	235 Participants	405 Participants	896 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	284 / —	250 / —	406 / —
serious Total, serious adverse events	100 / —	91 / —	135 / —

Outcome results

Primary

Number of Patients With Adverse Events Leading to Death

NIH Division of AIDS (DAIDS) Table for Grading Severity of Adult Adverse Experiences, December 2004.