Tipranavir/Ritonavir vs. Genotypically Defined Protease Inhibitor/Ritonavir in HIV Patients (RESIST-2)

Phase 3

Completed

• Conditions: HIV Infections
• Interventions: Drug: Tipranavir (with low dose ritonavir); Drug: Comparator protease inhibitor(CPI)/low dose ritonavir(r)

• Registration Number: NCT00144170
• Lead Sponsor: Boehringer Ingelheim

Brief Summary

The objective of this study is to demonstrate the safety and efficacy of tipranavir/ritonavir versus an active control arm in highly treatment experienced Human immunodeficiency virus-1 infected patients. Patients must have a viral load \> =1000 cells/mL, and genotype indicating at least one resistance conferring protease inhibitor-mutation as determined from a predefined panel of mutations. Any CD4+ count is acceptable.

Detailed Description

Not available

Study Timeline

• Study Start: 2003-02
• Study First Submitted: 2005-09-02
• Study First Submitted QC: 2005-09-02
• Study First Posted: 2005-09-05
• Primary Completion: 2008-10
• Results First Submitted: 2009-09-11
• Results First Submitted QC: 2009-11-17
• Results First Posted: 2009-12-23
• Status Verified: 2014-04
• Last Update Submitted: 2014-06-23
• Last Update Posted: 2014-07-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 882

Inclusion Criteria

1. Signed informed consent prior to trial participation.

2. Human immunodeficiency virus-1 infected males or females >=18 years of age.

3. Screening genotypic resistance report indicating both of the following:

   • at least one primary protease mutation at the following sites 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V or 90M , and
   • no more than two protease mutations on codons 33, 82, 84, or 90.

4. At least 3 consecutive months experience taking antiretrovirals from each of the classes of Nucleoside reverse transcriptase inhibitor(s), Non-nucleoside reverse transcriptase inhibitor(s), and Protease inhibitor(s) at some point in treatment history,

   • with at least 2 Protease inhibitor-based regimens (minimum 3 months of exposure of each), one of which must be part of the current regimen, and
   • current Protease inhibitor-based antiretroviral medication regimen for at least 3 months prior to randomisation.

5. Human immunodeficiency virus-1 viral load >=1000 copies/mL at screening.

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 or 10,36 mm/L.
   • Total triglycerides <=750 mg/dl or 8,5 mm/L.
   • Alanine aminotransferase <=3x upper limit of normal and aspartate aminotransferase <=2.5x upper limit of normal.
   • Any Grade gamma-glutamyl transpeptidase is acceptable.
   • Any Grade creatinine kinase is acceptable as long as there is no concurrent myopathy.
   • All other laboratory test values <= Grade 1(Division of Acquired immune deficiency syndrome, National Institute of Health grading scale).

7. Acceptable medical history, as assessed by the investigator, with chest X-ray and electrocardiogram within 1 year of study participation.

8. Willingness to abstain from ingesting substances during the study which may alter plasma study drug levels by interaction with the cytochrome P450 system.

9. A prior Acquired immune deficiency syndrome-defining event is acceptable as long as it has resolved or the patient has been on stable treatment for at least 2 months (Acquired immune deficiency syndrome related complex is acceptable).

Exclusion Criteria

1. Antiretroviral medication naïve.

2. Patients on recent drug holiday, defined as off antiretroviral medications for at least 7 consecutive days within the last 3 months.

3. Alanine aminotransferase >3x upper limit of normal and aspartate aminotransferase >2.5x upper limit of normal at either screening visit.

4. Female patients of child-bearing potential who:

   • have a positive serum pregnancy test at screening or during the study,
   • are breast feeding
   • are planning to become pregnant, or
   • are not willing to use a barrier method of contraception, or
   • require ethinyl estradiol administration

5. Prior tipranavir use.

6. Use of investigational medications within 30 days before study entry or during the trial. (T-20 [enfuvirtide] and Tenofovir (Viread), investigational at the time of writing of this protocol, will be allowed.)

7. Use of immunomodulatory drugs within 30 days before study entry or during the trial (e.g. interferon, cyclosporin, hydroxyurea, interleukin 2).

8. Inability to adhere to the requirements of the protocol, including active substance abuse as assessed by the investigator.

9. In the opinion of the investigator, likely survival of less than 12 months because of underlying disease.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tipranavir(TPV)/low dose ritonavir(r)	Tipranavir (with low dose ritonavir)	-
Comparator protease inhibitor(CPI)/low dose ritonavir(r)	Comparator protease inhibitor(CPI)/low dose ritonavir(r)	-

Primary Outcome Measures

Name	Time	Method
Treatment Response at Week 48	after 48 weeks of treatment	Patients who experienced treatment response. Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound
Time to Treatment Failure Through 48 Weeks of Treatment	after 48 weeks of treatment	Time to treatment failure is defined as 0 for patients who never achieve TR otherwise time to treatment failure is the earliest time of death, discontinuation of the study drug or introduction of a new anti-retroviral drug to the regimen if it is not solely related to either toxicity or intolerance clearly attributable to a background, or the first of two consecutive visits with Log(baseline Viral Load) - Log(on-treatment Viral Load) \< 1.

Secondary Outcome Measures

Name	Time	Method
Mean Change From Baseline in CD4+ Cell Count (Week 48)	Baseline to Week 48
Mean Change From Baseline in CD4+ Cell Count (Week 56)	Baseline to Week 56
Mean Change From Baseline in CD4+ Cell Count (Week 64)	Baseline to Week 64
Mean Change From Baseline in CD4+ Cell Count (Week 72)	Baseline to Week 72
Mean Change From Baseline in CD4+ Cell Count (Week 80)	Baseline to Week 80
Treatment Response at Week 32	week 32	Patients who experienced treatment response. Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound
Treatment Response at Week 72	week 72	Patients who experienced treatment response. Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound
Treatment Response at Week 2	week 2	Patients who experienced treatment response. Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound
Treatment Response at Week 4	week 4	Patients who experienced treatment response. Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound
Treatment Response at Week 8	week 8	Patients who experienced treatment response. Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound
Treatment Response at Week 16	week 16	Patients who experienced treatment response. Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound
Treatment Response at Week 24	Week 24	Patients who experienced treatment response. Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound
Treatment Response at Week 40	week 40	Patients who experienced treatment response. Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound
Treatment Response at Week 56	week 56	Patients who experienced treatment response. Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound
Treatment Response at Week 64	week 64	Patients who experienced treatment response. Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound
Treatment Response at Week 80	week 80	Patients who experienced treatment response. Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound
Treatment Response at Week 88	week 88	Patients who experienced treatment response. Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound
Treatment Response at Week 96	after 96 weeks of treatment	Patients who experienced treatment response. Treatment response (TR) is defined as two consecutive VL ≥ 1 log10 below baseline without discontinuation of study drug, change in anti-retroviral background, or rebound
Time to Treatment Failure Through 96 Weeks of Treatment	after 96 weeks of treatment	Time to treatment failure is defined as 0 for patients who never achieve TR otherwise time to treatment failure is the earliest time of death, discontinuation of the study drug or introduction of a new anti-retroviral drug to the regimen if it is not solely related to either toxicity or intolerance clearly attributable to a background, or the first of two consecutive visits with Log(baseline Viral Load) - Log(on-treatment Viral Load) \< 1.
Time to Confirmed Virologic Failure Through 48 Weeks of Treatment	after 48 weeks of treatment	Time to virologic failure is defined as the time from the start of treatment to the last measurement where the Log(baseline viral load)-Log(on-treatment viral load)\>1 before a 2 consecutive measurements where Log(baseline viral load)-Log(on-treatment viral load)\<1.
Time to Confirmed Virologic Failure Through 96 Weeks of Treatment	after 96 weeks of treatment	Time to virologic failure is defined as the time from the start of treatment to the last measurement where the Log(baseline viral load)-Log(on-treatment viral load)\>1 before a 2 consecutive measurements where Log(baseline viral load)-Log(on-treatment viral load)\<1.
Virologic Response	Week 2 through Week 96 (at any point during trial)	Virologic response defined as Viral Load\<50 copies/mL
Virologic Response at Week 8	Week 8	Virologic response defined as Viral Load\<50 copies/mL
Virologic Response at Week 2	Week 2	Virologic response defined as Viral Load\<50 copies/mL
Virologic Response at Week 4	Week 4	Virologic response defined as Viral Load\<50 copies/mL
Virologic Response at Week 16	Week 16	Virologic response defined as Viral Load\<50 copies/mL
Virologic Response at Week 24	Week 24	Viral Load \< 50 copies/mL
Virologic Response at Week 32	Week 32	Virologic response defined as Viral Load\<50 copies/mL
Virologic Response at Week 40	Week 40	Virologic response defined as Viral Load\<50 copies/mL
Virologic Response at Week 48	Week 48	Virologic response defined as Viral Load\<50 copies/mL
Virologic Response at Week 56	Week 56	Virologic response defined as Viral Load\<50 copies/mL
Virologic Response at Week 64	Week 64	Virologic response defined as Viral Load\<50 copies/mL
Virologic Response at Week 72	Week 72	Virologic response defined as Viral Load\<50 copies/mL
Virologic Response at Week 80	Week 80	Virologic response defined as Viral Load\<50 copies/mL
Virologic Response at Week 88	Week 88	Virologic response defined as Viral Load\<50 copies/mL
Virologic Response at Week 96	Week 96	Virologic response defined as Viral Load\<50 copies/mL
Median Change From Baseline in Viral Load (Week 2)	Baseline to Week 2
Median Change From Baseline in Viral Load (Week 4)	Baseline to Week 4
Median Change From Baseline in Viral Load (Week 8)	Baseline to Week 8
Median Change From Baseline in Viral Load (Week 16)	Baseline to Week 16
Median Change From Baseline in Viral Load (Week 24)	Baseline to Week 24
Median Change From Baseline in Viral Load (Week 32)	Baseline to Week 32
Median Change From Baseline in Viral Load (Week 40)	Baseline to Week 40
Median Change From Baseline in Viral Load (Week 48)	Baseline to Week 48
Median Change From Baseline in Viral Load (Week 56)	Baseline to Week 56
Median Change From Baseline in Viral Load (Week 64)	Baseline to Week 64
Median Change From Baseline in Viral Load (Week 72)	Baseline to Week 72
Median Change From Baseline in Viral Load (Week 80)	Baseline to Week 80
Median Change From Baseline in Viral Load (Week 88)	Baseline to Week 88
Median Change From Baseline in Viral Load (Week 96)	Baseline to Week 96
Virologic Response at Viral Load Nadir During Study Treatment Through 96 Weeks	Week 2 through Week 96 (at any point during trial)	Virologic response defined as Viral Load\<400 copies/mL
Mean Change From Baseline in CD4+ Cell Count (Week 2)	Baseline to Week 2
Mean Change From Baseline in CD4+ Cell Count (Week 4)	Baseline to Week 4
Mean Change From Baseline in CD4+ Cell Count (Week 8)	Baseline to Week 8
Mean Change From Baseline in CD4+ Cell Count (Week 16)	Baseline to Week 16
Mean Change From Baseline in CD4+ Cell Count (Week 24)	Baseline to Week 24
Mean Change From Baseline in CD4+ Cell Count (Week 32)	Baseline to Week 32
Mean Change From Baseline in CD4+ Cell Count (Week 40)	Baseline to Week 40
Mean Change From Baseline in CD4+ Cell Count (Week 88)	Baseline to Week 88
Mean Change From Baseline in CD4+ Cell Count (Week 96)	Baseline to Week 96
Time to New Centers for Disease Control (CDC) Class C Progression Event or Death.	up to 75 weeks of treatment	Time to death or occurrence of AIDS-defining condition according to the US Centers for Disease Control and Prevention case definition.; The median and quartiles are underestimated since more than 92% of the observations (in both treatment arms) were censored and the estimation was restricted to the largest observed event time.

Trial Locations

Locations (174)

1182.48.5401 Fundación Huésped; 🇦🇷 Buenos Aires, Argentina

1182.48.5402 Fundación Huésped; 🇦🇷 Buenos Aires, Argentina

1182.48.5403 Servicio de Infecciosas; 🇦🇷 Buenos Aires, Argentina

1182.48.5404 Servicio de Infecciosas; 🇦🇷 Buenos Aires, Argentina

1182.48.5405 Hospital Muniz; 🇦🇷 Buenos Aires, Argentina

1182.48.5406 Servicio de Immunocomprometido; 🇦🇷 Buenos Aires, Argentina

1182.48.4301 Boehringer Ingelheim Investigational Site; 🇦🇹 Wien, Austria

1182.48.3209 Boehringer Ingelheim Investigational Site; 🇧🇪 Antwerpen, Belgium

1182.48.3201 Boehringer Ingelheim Investigational Site; 🇧🇪 Bruxelles, Belgium

1182.48.3202 Boehringer Ingelheim Investigational Site; 🇧🇪 Bruxelles, Belgium

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