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

SPRING: Safety, Efficacy, Pharmacokinetics of tipRanavi/r IN Race/Gender HIV+ Patients Randomized to Therapeutic Drug Monitoring or Standard of Care

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.

Study Overview

• Status: Terminated
• Conditions: HIV Infections
• Intervention / Treatment: Drug: tipranavir; Drug: ritonavir; Drug: Optimized Background Regimen (OBR)

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Capital Federal ,Buenos Aires, Argentina
    • 1182.98.5405 CENTRO de INFECTOLOGIA y ASISTENCIA (CIAS)
  • Mar del Plata, Argentina
    • 1182.98.5403 Centro Hospital Higa - Dr Oscar Alende
  • Rosario, Argentina
    • 1182.98.5402 Caici
• Brazil
  • Sacomã - São Paulo, Brazil
    • 1182.98.55002 Hospital DIA
  • Santo André, Brazil
    • 1182.98.55004 Unidade de Referência em doenças Infecciosas Preveníveis
  • Sao Paulo, Brazil
    • 1182.98.55001 Universidade Federal de Sao Paulo
  • Vila Mariana - Sao Paulo, Brazil
    • 1182.98.55003 Centro de Referência e Treinamento - DST/AIDS
• Canada
  • Quebec
    • Quebec, Ste Foy, Quebec, Canada
      • 1182.98.1007 Boehringer Ingelheim Investigational Site
• Germany
  • Bochum, Germany
    • 1182.98.4903 Boehringer Ingelheim Investigational Site
  • Hamburg, Germany
    • 1182.98.4908 Boehringer Ingelheim Investigational Site
• Italy
  • Torino, Italy
    • 1182.98.3907 Boehringer Ingelheim Investigational Site
• Spain
  • Barcelona, Spain
    • 1182.98.3402
  • Madrid, Spain
    • 1182.98.3405
  • Madrid, Spain
    • 1182.98.3406
• United States
  • District of Columbia
    • Washington, District of Columbia, United States
      • 1182.98.033 Boehringer Ingelheim Investigational Site
  • Florida
    • Clearwater, Florida, United States
      • 1182.98.018 Boehringer Ingelheim Investigational Site
    • Fort Lauderdale, Florida, United States
      • 1182.98.014 Boehringer Ingelheim Investigational Site
    • Orlando, Florida, United States
      • 1182.98.041 Boehringer Ingelheim Investigational Site
  • Georgia
    • Decatur, Georgia, United States
      • 1182.98.004 Boehringer Ingelheim Investigational Site
  • Missouri
    • Kansas City, Missouri, United States
      • 1182.98.002 Boehringer Ingelheim Investigational Site
  • New York
    • New York, New York, United States
      • 1182.98.016 Boehringer Ingelheim Investigational Site
    • New York, New York, United States
      • 1182.98.026 Boehringer Ingelheim Investigational Site
    • Stony Brook, New York, United States
      • 1182.98.034 Boehringer Ingelheim Investigational Site
  • North Carolina
    • Huntersville, North Carolina, United States
      • 1182.98.040 Boehringer Ingelheim Investigational Site
  • Ohio
    • Akron, Ohio, United States
      • 1182.98.006 Boehringer Ingelheim Investigational Site
    • Cincinnati, Ohio, United States
      • 1182.98.007 Boehringer Ingelheim Investigational Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • 1182.98.020 Boehringer Ingelheim Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • 1182.98.029 Boehringer Ingelheim Investigational Site
  • Texas
    • Austin, Texas, United States
      • 1182.98.023 Boehringer Ingelheim Investigational Site
    • Houston, Texas, United States
      • 1182.98.009 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Standard of Care (SoC); 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.	Drug: tipranavir; Drug: ritonavir; Drug: Optimized Background Regimen (OBR); Patients received between two and four active anti-retroviral medications based on resistance testing results, as background treatment, and remained on these for the duration of the trial.; Other Names: Nucleoside Reverse Transcriptase Inhibitors (NRTIs),; Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs),; Enfuvirtide,; Maraviroc,; Raltegravir
Other: Therapeutic Drug Monitoring (TDM); 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.	Drug: tipranavir; Drug: ritonavir; Drug: Optimized Background Regimen (OBR); Patients received between two and four active anti-retroviral medications based on resistance testing results, as background treatment, and remained on these for the duration of the trial.; Other Names: Nucleoside Reverse Transcriptase Inhibitors (NRTIs),; Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs),; Enfuvirtide,; Maraviroc,; Raltegravir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Response at Week 48	percentage of participants whose viral load <50 copies/mL at Week 48	after 48 weeks of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	after Day 1 of treatment
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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start: February 1, 2007
• Primary Completion (Actual): October 1, 2008
• Study Completion: December 6, 2022

Study Registration Dates

• First Submitted: February 26, 2007
• First Submitted That Met QC Criteria: February 26, 2007
• First Posted (Estimate): February 27, 2007

Study Record Updates

• Last Update Posted (Estimate): June 27, 2014
• Last Update Submitted That Met QC Criteria: June 17, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Integrase Inhibitors; Integrase Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; CCR5 Receptor Antagonists; Raltegravir Potassium; Ritonavir; Maraviroc; Tipranavir; Enfuvirtide; Reverse Transcriptase Inhibitors
• Other Study ID Numbers: 1182.98; EudraCT No.: 2005-005264-86

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No