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A Multicenter Study to Assess the Tolerability of Once Daily Lopinavir/Ritonavir (LPV/r) Liquid Versus Capsules

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ClinicalTrials.gov Identifier: NCT00281606
Recruitment Status : Completed
First Posted : January 25, 2006
Last Update Posted : June 30, 2020
Sponsor:
Collaborator:
Abbott
Information provided by (Responsible Party):
J Allen McCutchan, University of California, San Diego

Brief Summary:
Guidelines have continued to list lopinavir/ritonavir as a preferred protease inhibitor-containing regimen for HIV-infected individuals. There has recently been increasing interest in once daily therapy. While lopinavir/ritonavir has recently been approved as a once daily therapy it was associated with considerable diarrhea in those treated with soft gel capsules. It is the hope that alternative formulations of lopinavir/ritonavir may provide similar pharmacokinetics with improved tolerability. This includes the possibility of using liquid or newly released tablets. This study will treat people tolerating their current regimen with up to four weeks of each formulation with several assessments of pharmacokinetics and tolerability for each.

Condition or disease Intervention/treatment Phase
HIV Infection Drug: Different formulations of once-daily lopinavir/ritonavir Phase 4

Detailed Description:
This study is designed to assess the tolerability of different forms (liquid, capsules or tablets) of lopinavir/ritonavir given once-daily as part of combination therapy for HIV infection. Study subjects will be those tolerating a stable regimen of HIV medications with undetectable levels of HIV in their blood. They will be assigned by chance to receive once daily liquid or soft gel capsules of lopinavir/ritonavir for up to four weeks. At that time they will receive the alternative formulation for up to four weeks. They will then be given once daily lopinavir/ritonavir in the recently released tablet formulation. After up to four weeks of each of these formulations several assessments will be made of the overall tolerability of the drug. After four weeks of tablets they will be allowed to take whatever regimen they want and will be followed for an additional 36 weeks for a total duration of study of up to 48 weeks. The pharmacokinetics of each formulation of lopinavir/ritonavir given once daily will also be assessed in a subset of study subjects.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 65 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase IV, Randomized, Open-label Study of the Tolerability of Once Daily Lopinavir/Ritonavir (LPV/r) Liquid Versus Capsules
Actual Study Start Date : February 14, 2006
Actual Primary Completion Date : October 16, 2007
Actual Study Completion Date : June 13, 2012


Arm Intervention/treatment
Active Comparator: LPV/r (800/200 mg) 10 ml liquid
Once daily Lopinovir/ritonavir (800/200 mg) taken as a 10 ml liquid
Drug: Different formulations of once-daily lopinavir/ritonavir
CCTG585 is a randomized, open-label, two arm cross-over study to compare the tolerability of once daily LPV/r liquid versus capsules
Other Name: Lopinavir/Ritonavir (LPV/r)

Active Comparator: LPV/r (800/200 mg) 6 gel capsules
Once daily Lopinavir/ritonavir (800/200 mg) as 6 gel capsules
Drug: Different formulations of once-daily lopinavir/ritonavir
CCTG585 is a randomized, open-label, two arm cross-over study to compare the tolerability of once daily LPV/r liquid versus capsules
Other Name: Lopinavir/Ritonavir (LPV/r)




Primary Outcome Measures :
  1. Measuring whether the subject has severity of diarrhea grade 2 or higher or exhibits treatment-limiting toxicity when treated with once daily Lopinavir/ritonavir [LPV/r] (800/200 mg) as 10 ml liquid vs. 6 soft gel capsules. [ Time Frame: Baseline to week 48 ]
    To assess the comparative tolerability of once daily Lopinavir/ritonavir [LPV/r] (800/200 mg) as 10 ml liquid vs. 6 soft gel capsules by measuring incidence rates as assessed by the CTCAE v4.0 in each arm of: a) grade 2 or higher diarrhea plus b) dose limiting toxicity of any kind.


Secondary Outcome Measures :
  1. Incidence Measures of Treatment-limiting toxicity [ Time Frame: Baseline to week 48 ]
    Separately evaluating at the end of week 4 or at the time therapy is discontinued for treatment-limiting toxicity of the two 4 week phases of the cross-over trial (Steps 1 and 2).

  2. Incidence Measures of Drug-related diarrhea [ Time Frame: Baseline to week 48 ]
    Separately evaluating at the end of week 4 or at the time therapy is discontinued for drug-related diarrhea of the two 4 week phases of the cross-over trial (Steps 1 and 2).

  3. Incidence Measures of the Use of antiemetic and/or antimotility therapy [ Time Frame: Baseline to week 48 ]
    Separately evaluating at the end of week 4 or at the time therapy is discontinued for antiemetic and/or antimotility therapy of the two 4 week phases of the cross-over trial (Steps 1 and 2).

  4. Incidence Measures of Adverse events other than nausea and diarrhea [ Time Frame: Baseline to week 48 ]
    Separately evaluating at the end of week 4 or at the time therapy is discontinued for adverse events other than nausea and diarrhea of the two 4 week phases of the cross-over trial (Steps 1 and 2).

  5. Incidence Measures of Laboratory abnormalities, e.g. lipids, liver enzymes [ Time Frame: Baseline to week 48 ]
    Separately evaluating at the end of week 4 or at the time therapy is discontinued for laboratory abnormalities of the two 4 week phases of the cross-over trial (Steps 1 and 2).

  6. Incidence Measures of HIV RNA suppression to <50 copies/ml [ Time Frame: Baseline to week 48 ]
    Separately evaluating at the end of week 4 or at the time therapy is discontinued for HIV RNA suppression to <50 copies/ml of the two 4 week phases of the cross-over trial (Steps 1 and 2).

  7. Preference for Lopinavir/ritonavir liquid, capsules or tablets, and the degree of like or dislike of each [ Time Frame: Week 8 and week 48 ]
    The stated preference for LPV/r liquid, capsules or tablets, and the degree of like or dislike of each in those who choose an option other than once daily LPV/r tablets at start of Step 4

  8. Evaluating the proportion of screened individuals who choose not to be randomized after the liquid Lopinavir/ritonavir taste test [ Time Frame: Baseline ]
    Evaluating the proportion of screened individuals who choose not to be randomized after the liquid LPV/r taste test at the time of enrollment into the study

  9. Evaluating the severity of diarrhea [ Time Frame: Week 4, week 8 and week 48 ]
    Measuring sum of days with diarrhea weighted for highest level of severity (sum of event severity numbers = 1-5) on that day via the Division of AIDS Table for Grading Adult Adverse Experiences that can be found on the ROC Web site: http://rcc.tech-res-intl.com/

  10. Evaluating the severity of nausea [ Time Frame: Week 4, week 8 and week 48 ]
    Measuring days of nausea weighted for the highest level of severity (sum of event severity numbers = 1-5) on that day via the Division of AIDS Table for Grading Adult Adverse Experiences that can be found on the ROC Web site: http://rcc.tech-res-intl.com/

  11. Evaluating proportion with plasma HIV RNA <50 copies/mL at the end of Step 4 [ Time Frame: Week 4, week 8 and week 48 ]
    Evaluating the proportion of participants with plasma HIV RNA <50 copies/mL at the end of Step 4


Other Outcome Measures:
  1. Direct inspection of Pre-dose concentrations (Cpre-dose) for Lopinavir/ritonavir (LPV/r) [ Time Frame: Baseline and 12 weeks ]
    Direct inspection of the concentration data to assess Pre-dose concentrations (Cpre-dose) for Lopinavir/ritonavir (LPV/r) liquid, capsules and tablets

  2. Direct inspection of trough concentrations (Ctrough) for Lopinavir/ritonavir (LPV/r) [ Time Frame: Baseline and 12 weeks ]
    The magnitude of difference within patients of the two formulations will be assessed with the Wilcoxon signed-rank test. The trough concentrations of the Group 2 subjects may also be compared using the Wilcoxon signed-rank test to detect a difference between the formulations.

  3. Direct inspection of 24-hour post-dose concentrations (C24) for Lopinavir/ritonavir (LPV/r) [ Time Frame: Baseline and 12 weeks ]
    Model dependent and independent traditional pharmacokinetic approaches will be used to estimate pharmacokinetic parameters, such as the area under the concentration versus time curve from time 0 to 24 hours (AUC0-24).

  4. Direct inspection of maximum plasma concentrations (Cmax) for Lopinavir/ritonavir (LPV/r) [ Time Frame: Baseline and 12 weeks ]
    Determine TDF plasma and urine concentrations in Group 1 patients taking TDF concurrently with LPV/r (Group 3).

  5. Direct inspection of the corresponding time to Cmax (Tmax) for Lopinavir/ritonavir (LPV/r) [ Time Frame: Baseline and 12 weeks ]
    Model dependent and independent traditional pharmacokinetic approaches will be used to estimate pharmacokinetic parameters, such as the area under the concentration versus time curve from time 0 to 24 hours (AUC0-24), the terminal half-life (t1/2), the apparent clearance (CL/F), and the apparent volume of distribution (Vz/F).

  6. Estimation of concentration versus time curve from time 0 to 24 hours (AUC0-24) for Lopinavir/ritonavir (LPV/r) [ Time Frame: Baseline and 12 weeks ]
    Model dependent and independent traditional pharmacokinetic approaches will be used to estimate concentration versus time curve from time 0 to 24 hours (AUC0-24). The AUC0-24 and Cmax ratios of liquid to capsule LPV/r within subjects will be used to assess bioequivalence.

  7. Estimation of terminal half-life (t1/2) for Lopinavir/ritonavir (LPV/r) [ Time Frame: Baseline and 12 weeks ]
    Model dependent and independent traditional pharmacokinetic approaches will be used to estimate terminal half-life (t1/2)

  8. Estimation of apparent clearance (CL/F) for Lopinavir/ritonavir (LPV/r) [ Time Frame: Baseline and 12 weeks ]
    Model dependent and independent traditional pharmacokinetic approaches will be used to estimate apparent clearance (CL/F)

  9. Estimation of apparent volume of distribution (Vz/F) for Lopinavir/ritonavir (LPV/r) [ Time Frame: Baseline and 12 weeks ]
    Model dependent and independent traditional pharmacokinetic approaches will be used to estimate apparent volume of distribution (Vz/F)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Ability and willingness of subject or legal guardian/representative to give written informed consent.
  • HIV-1 infected.
  • At least 18 years of age
  • Have the last two HIV-1 RNA measurements performed prior to screening be <50 or 75 copies/mL within the last 180 days, as well as at the time of screening.
  • No evidence of primary PI mutations (defined by IAS-USA) documented on previous resistance testing, if ever performed and available, or suggested to be present by previous treatment history.
  • Laboratory values:

    • Absolute neutrophil count (ANC) >500/mm3.
  • -Hemoglobin >7.0 g/dL.

    • platelet count >50,000/mm3.
    • AST (SGOT), ALT (SGPT), and alkaline phosphatase <5 X ULN.
    • Total bilirubin <2.5 x ULN, unless on IDV or ATV in which case must be <1.5 x ULN of direct bilirubin.
    • Calculated creatinine clearance >50 mL/min as estimated by the Cockcroft-Gault equation
  • For women of reproductive potential, negative serum or urine pregnancy test within 7 days prior to initiating study medications. If participating in sexual activity that could lead to pregnancy, female study subjects must use two forms of contraception, one of which must be a barrier method. All subjects must continue to use contraception for 6 weeks after stopping the study medications.
  • Willingness to take an alcohol containing product.
  • Karnofsky performance score >70.

Exclusion Criteria:

  • Pregnancy or breast-feeding
  • Greater than Grade 1 diarrhea or nausea (as defined by protocol)
  • Use of a NNRTI within 12 weeks of screening
  • Use of antimotility or antiemetics during the 14 days prior to screening
  • Use of any of the prohibited medications (defined by protocol) within 30 days of study entry.
  • Need to continue the use of prohibited or select precautionary medications (defined by protocol)
  • Known hypersensitivity to lopinavir/ritonavir
  • Active drug or alcohol use or dependence which, in the Investigator's opinion, may interfere with adherence to study requirements or endanger subject's health while on the study
  • Serious illness requiring systemic treatment and/or hospitalization until subject either completes therapy or is clinically stable on therapy, in the opinion of the investigator, for at least 30 days prior to study entry.
  • Acute therapy for serious infection or other serious medical illnesses (in the judgment of the site investigator) requiring systemic treatment and/or hospitalization within 14 days prior to study entry.
  • Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV-1 vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00281606


Locations
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United States, California
UCI
Irvine, California, United States, 92668
USC
Los Angeles, California, United States, 90033
UCSD
San Diego, California, United States, 92103
Santa Clara Valley Medical Center
San Jose, California, United States, 95128
Harbor-UCLA Medical Center
Torrance, California, United States, 90502
Sponsors and Collaborators
University of California, San Diego
Abbott
Investigators
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Principal Investigator: Eric Daar, MD University of California, Los Angeles
Publications of Results:
1. Best B, Rieg G, Sun S, Jain S, Kemper C, Diamond C, Hermes A, Haubrich R, Daar E, and California Collaborative Treatment Group (CCTG) 585 Team. Increased lopinavir concentrations on once-daily tablets as compared with capsules and liquid formulations. 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, MA. Abstract 766a. 2. CDB088 Abstract Switching to once-daily (QD) lopinavir/ritonavir (LPV/r) liquid (Liq), capsules (caps) and tablets (tabs): a randomized, ppen label, cross-over study (CCTG 585). 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention; Cape Town 2009 G. Rieg1, S. Jain2, S. Sun2, R. Larsen3, C. Kemper4, C. Diamond5, S. Schneider6, D. Shamblaw7, A. Hermes8, R. Haubrich9, E. Daar10, California Collaborative Treatment Group (CCTG)

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Responsible Party: J Allen McCutchan, Prof Emeritus, University of California, San Diego
ClinicalTrials.gov Identifier: NCT00281606    
Other Study ID Numbers: CCTG 585
First Posted: January 25, 2006    Key Record Dates
Last Update Posted: June 30, 2020
Last Verified: June 2020
Keywords provided by J Allen McCutchan, University of California, San Diego:
Lopinavir
antiretroviral therapy
cross-over
tolerability
Additional relevant MeSH terms:
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HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Ritonavir
Lopinavir
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors