SPRING: Safety, Efficacy, Pharmacokinetics of tipRanavir/r IN Race/Gender HIV+ Patients Randomized to TDM or SoC

Phase 3

Terminated

• Conditions: HIV Infections
• Interventions: Drug: tipranavir; Drug: ritonavir; Drug: Optimized Background Regimen (OBR)

• Registration Number: NCT00440271
• Lead Sponsor: Boehringer Ingelheim

Brief Summary

The primary purpose of this study is to:

1. Demonstrate the safety and efficacy of tipranavir/ritonavir (TPV/r) among a racially diverse HIV+ population (males and females) who are three-class (nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), and protease inhibitor (PI)) experienced with documented resistance to more than one PI.

2. Determine pharmacokinetic data in this racially and gender diverse population.

3. Determine the potential utility of using therapeutic drug monitoring (TDM) in improving efficacy outcomes.

Detailed Description

Not available

Study Timeline

• Study Start: 2007-02
• Study First Submitted: 2007-02-26
• Study First Submitted QC: 2007-02-26
• Study First Posted: 2007-02-27
• Primary Completion: 2008-10
• Results First Submitted: 2009-10-20
• Results First Submitted QC: 2009-10-20
• Results First Posted: 2009-11-26
• Status Verified: 2014-01
• Last Update Submitted: 2014-06-17
• Last Update Posted: 2014-06-27

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 33

Inclusion Criteria

Main inclusion criteria for the study are:

1. HIV-1 infected adults, men and women at least 18 years of age.
2. 3-class (nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), and protease inhibitor (PI)) treatment-experienced (min of 3-months duration for each class) with resistance to more than one PI (on screening resistance testing). NNRTI-naïve patients who have genotypically documented NNRTI-resistance mutations on past or screening resistance testing would be eligible.
3. CD4+ T lymphocyte count >=50 cells/mm3.
4. HIV-1 viral load >=1,000 copies/mL at screening.
5. The antiretroviral (ARV) study treatment regimen must consist of TPV/r in combo with an optimized background regimen (OBR) of 2-4 agents: N(t)RTIs (NRTI or NtRTI), enfuvirtide (ENF), and/or, where available, a trial approved expanded access program (EAP) investigational agent.
6. Acceptable screening laboratory values that indicate adequate baseline organ function.
7. Acceptable medical history with a chest X-ray without evidence of active disease and an electrocardiogram (ECG) without clinically important abnormalities within one year of the study.
8. A reliable method of barrier contraception will be used by all female patients who are of childbearing potential.

Exclusion Criteria

Main exclusion criteria for the study are:

1. Known hypersensitivity to the tipranavir (TPV) or ritonavir (RTV).
2. ARV medication naïve.
3. Genotypic resistance to TPV (defined as a TPV mutation score >7).
4. Patients on recent drug holiday, defined as off antiretroviral (ARV) medications for at least 7 consecutive days within the month prior to screening.
5. Prior tipranavir use.
6. Inability to adhere to the requirements of the protocol.
7. Patients with prior history of hemorrhagic stroke or intracranial aneurysm.
8. Patients with a history of ischemic stroke, neurosurgery or skull trauma within 4 weeks prior to screening.
9. History of Progressive Multifocal Leukoencephalopathy, Visceral Kaposi's Sarcoma, and/or any malignancy.
10. Any acquired immunodeficiency syndrome (AIDS) defining illness that is unresolved, symptomatic or not stable on treatment for at least 12 weeks at screening visit.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard of Care (SoC)	Optimized Background Regimen (OBR)	Standard of Care (SOC) Arm = Tipranavir/ritonavir (TPV/r) capsules taken orally at a dose of 500 mg/200 mg twice a day (BID) plus optimized background regimen (OBR). No TPV/r dose changes were permitted.
Therapeutic Drug Monitoring (TDM)	ritonavir	Therapeutic Drug Monitoring (TDM) Arm = Patients began by receiving standard of care (SOC) tipranavir/ritonavir (TPV/r) capsules orally at a dose of 500 mg/200 mg twice a day (BID) plus optimized background regimen (OBR) followed, if needed, by TPV or ritonavir (RTV) dose adjustments at Week 4, 6, 10, 14, 18, 22, 26 and 30 based on viral response, phenotypic inhibitory quotient (IQ), and TPV trough concentrations.
Therapeutic Drug Monitoring (TDM)	Optimized Background Regimen (OBR)	Therapeutic Drug Monitoring (TDM) Arm = Patients began by receiving standard of care (SOC) tipranavir/ritonavir (TPV/r) capsules orally at a dose of 500 mg/200 mg twice a day (BID) plus optimized background regimen (OBR) followed, if needed, by TPV or ritonavir (RTV) dose adjustments at Week 4, 6, 10, 14, 18, 22, 26 and 30 based on viral response, phenotypic inhibitory quotient (IQ), and TPV trough concentrations.
Standard of Care (SoC)	ritonavir	Standard of Care (SOC) Arm = Tipranavir/ritonavir (TPV/r) capsules taken orally at a dose of 500 mg/200 mg twice a day (BID) plus optimized background regimen (OBR). No TPV/r dose changes were permitted.
Therapeutic Drug Monitoring (TDM)	tipranavir	Therapeutic Drug Monitoring (TDM) Arm = Patients began by receiving standard of care (SOC) tipranavir/ritonavir (TPV/r) capsules orally at a dose of 500 mg/200 mg twice a day (BID) plus optimized background regimen (OBR) followed, if needed, by TPV or ritonavir (RTV) dose adjustments at Week 4, 6, 10, 14, 18, 22, 26 and 30 based on viral response, phenotypic inhibitory quotient (IQ), and TPV trough concentrations.
Standard of Care (SoC)	tipranavir	Standard of Care (SOC) Arm = Tipranavir/ritonavir (TPV/r) capsules taken orally at a dose of 500 mg/200 mg twice a day (BID) plus optimized background regimen (OBR). No TPV/r dose changes were permitted.

Primary Outcome Measures

Name	Time	Method
Treatment Response at Week 48	after 48 weeks of treatment	percentage of participants whose viral load \<50 copies/mL at Week 48

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Whose Viral Load <50 Copies/mL at Each Visit Including Visits at Weeks 24 and 48	after 2 weeks of treatment (Weeks 2, 4, 8, 12, 24, 36, and 48)
Percentage of Participants Whose Viral Load <400 Copies/mL at Each Visit Including Visits at Weeks 24 and 48	after 2 weeks of treatment (Weeks 2, 4, 8, 12, 24, 36, and 48)
Percentage of Participants Whose ≥1 log10 Drop in Viral Load From Baseline at All Visits, Including Visits at Weeks 24 and 48	after 2 weeks of treatment (Weeks 2, 4, 8, 12, 24, 36, and 48)
Change in Viral Load From Baseline at Each Visit	after 2 weeks of treatment (Weeks 2, 4, 8, 12, 24, 36, and 48)
Time to Treatment Failure	after Day 1 of treatment	For patients who never achieve a confirmed virologic response, time to treatment failure is defined as 0. For patients who achieve a confirmed virologic response, time to treatment failure is the earliest time of either: death, permanent discontinuation of the study drug or loss to follow-up, 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 drug, but not the study drug, or first occurrence of a VL \>50 copies/mL at two consecutive measurements after having achieved a VL \<50 copies/mL.
Time to New AIDS or AIDS Related Progression Event or Death	after Day 1 of treatment
Change in CD4+ and CD8+ Cell Counts From Baseline at Each Visit Including Visits at Week 24 and Week 48	after 2 weeks of treatment till Week 48 (Weeks 2, 4, 8, 12, 24, 36, and 48)
Change in Ratio of CD38+/CD8+ From Baseline to Week 48	after 2 weeks of treatment till Week 48 (Weeks 2, 4, 8, 12, 24, 36, and 48)
Tipranavir (TPV) and Ritonavir (RTV) Trough Concentrations at Week 2, Week 4, Week 8, Week 12, Week 24, Week 36 and Week 48	after 2 weeks of treatment till Week 48 (Weeks 2, 4, 8, 12, 24, 36, and 48)
Patients Adherence With Study Medication Based on Pill Count	after 4 weeks of treatment
Occurrence of TPV Inhibitory Quotient (IQ) >60 at Each Visit Where TPV Concentration is Measured	after 2 weeks of treatment (Weeks 2, 4, 8, 12, 24, 36, and 48)
Occurrence of TPV Trough Concentration >120 μM	after 2 weeks of treatment (Weeks 2, 4, 8, 12, 24, 36, and 48)
Post-dose TPV and RTV Concentrations at Week 4	Week 4

Trial Locations

Locations (30)

1182.98.018 Boehringer Ingelheim Investigational Site; 🇺🇸 Clearwater, Florida, United States

1182.98.014 Boehringer Ingelheim Investigational Site; 🇺🇸 Fort Lauderdale, Florida, United States

1182.98.004 Boehringer Ingelheim Investigational Site; 🇺🇸 Decatur, Georgia, United States

1182.98.034 Boehringer Ingelheim Investigational Site; 🇺🇸 Stony Brook, New York, United States

1182.98.029 Boehringer Ingelheim Investigational Site; 🇺🇸 Philadelphia, Pennsylvania, United States

1182.98.3907 Boehringer Ingelheim Investigational Site; 🇮🇹 Torino, Italy

1182.98.023 Boehringer Ingelheim Investigational Site; 🇺🇸 Austin, Texas, United States

1182.98.3406; 🇪🇸 Madrid, Spain

1182.98.007 Boehringer Ingelheim Investigational Site; 🇺🇸 Cincinnati, Ohio, United States

1182.98.3405; 🇪🇸 Madrid, Spain

1182.98.4903 Boehringer Ingelheim Investigational Site; 🇩🇪 Bochum, Germany

1182.98.4908 Boehringer Ingelheim Investigational Site; 🇩🇪 Hamburg, Germany

1182.98.5405 CENTRO de INFECTOLOGIA y ASISTENCIA (CIAS); 🇦🇷 Capital Federal ,Buenos Aires, Argentina

1182.98.55001 Universidade Federal de Sao Paulo; 🇧🇷 Sao Paulo, Brazil

1182.98.1007 Boehringer Ingelheim Investigational Site; 🇨🇦 Quebec, Ste Foy, Quebec, Canada

1182.98.55003 Centro de Referência e Treinamento - DST/AIDS; 🇧🇷 Vila Mariana - Sao Paulo, Brazil

1182.98.009 Boehringer Ingelheim Investigational Site; 🇺🇸 Houston, Texas, United States

1182.98.5403 Centro Hospital Higa - Dr Oscar Alende; 🇦🇷 Mar del Plata, Argentina

1182.98.006 Boehringer Ingelheim Investigational Site; 🇺🇸 Akron, Ohio, United States

1182.98.55002 Hospital DIA; 🇧🇷 Sacomã - São Paulo, Brazil

1182.98.040 Boehringer Ingelheim Investigational Site; 🇺🇸 Huntersville, North Carolina, United States

1182.98.020 Boehringer Ingelheim Investigational Site; 🇺🇸 Oklahoma City, Oklahoma, United States

1182.98.033 Boehringer Ingelheim Investigational Site; 🇺🇸 Washington, District of Columbia, United States

1182.98.041 Boehringer Ingelheim Investigational Site; 🇺🇸 Orlando, Florida, United States

1182.98.016 Boehringer Ingelheim Investigational Site; 🇺🇸 New York, New York, United States

1182.98.002 Boehringer Ingelheim Investigational Site; 🇺🇸 Kansas City, Missouri, United States

1182.98.026 Boehringer Ingelheim Investigational Site; 🇺🇸 New York, New York, United States

1182.98.55004 Unidade de Referência em doenças Infecciosas Preveníveis; 🇧🇷 Santo André, Brazil

1182.98.5402 Caici; 🇦🇷 Rosario, Argentina

1182.98.3402; 🇪🇸 Barcelona, Spain