Clinical trial NCT00281606: A Multicenter Study to Assess the Tolerability of Once Daily Lopinavir/Ritonavir (LPV/r) Liquid Versus Capsules
Official title: A Phase IV, Randomized, Open-label Study of the Tolerability of Once Daily Lopinavir/Ritonavir (LPV/r) Liquid Versus Capsules
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Infection
Keywords: Lopinavir
antiretroviral therapy
cross-over
tolerability
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
Collaborators: name: Abbott
First posted: 2006-01-25
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: 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.
timeFrame: Baseline to week 48
Secondary outcomes:
measure: Incidence Measures of Treatment-limiting toxicity
timeFrame: Baseline to week 48
measure: Incidence Measures of Drug-related diarrhea
timeFrame: Baseline to week 48
measure: Incidence Measures of the Use of antiemetic and/or antimotility therapy
timeFrame: Baseline to week 48
measure: Incidence Measures of Adverse events other than nausea and diarrhea
timeFrame: Baseline to week 48
measure: Incidence Measures of Laboratory abnormalities, e.g. lipids, liver enzymes
timeFrame: Baseline to week 48
measure: Incidence Measures of HIV RNA suppression to <50 copies/ml
timeFrame: Baseline to week 48
measure: Preference for Lopinavir/ritonavir liquid, capsules or tablets, and the degree of like or dislike of each
timeFrame: Week 8 and week 48
measure: Evaluating the proportion of screened individuals who choose not to be randomized after the liquid Lopinavir/ritonavir taste test
timeFrame: Baseline
measure: Evaluating the severity of diarrhea
timeFrame: Week 4, week 8 and week 48
measure: Evaluating the severity of nausea
timeFrame: Week 4, week 8 and week 48
measure: Evaluating proportion with plasma HIV RNA <50 copies/mL at the end of Step 4
timeFrame: Week 4, week 8 and week 48
Other outcomes:
measure: Direct inspection of Pre-dose concentrations (Cpre-dose) for Lopinavir/ritonavir (LPV/r)
timeFrame: Baseline and 12 weeks
measure: Direct inspection of trough concentrations (Ctrough) for Lopinavir/ritonavir (LPV/r)
timeFrame: Baseline and 12 weeks
measure: Direct inspection of 24-hour post-dose concentrations (C24) for Lopinavir/ritonavir (LPV/r)
timeFrame: Baseline and 12 weeks
measure: Direct inspection of maximum plasma concentrations (Cmax) for Lopinavir/ritonavir (LPV/r)
timeFrame: Baseline and 12 weeks
measure: Direct inspection of the corresponding time to Cmax (Tmax) for Lopinavir/ritonavir (LPV/r)
timeFrame: Baseline and 12 weeks
measure: Estimation of concentration versus time curve from time 0 to 24 hours (AUC0-24) for Lopinavir/ritonavir (LPV/r)
timeFrame: Baseline and 12 weeks
measure: Estimation of terminal half-life (t1/2) for Lopinavir/ritonavir (LPV/r)
timeFrame: Baseline and 12 weeks
measure: Estimation of apparent clearance (CL/F) for Lopinavir/ritonavir (LPV/r)
timeFrame: Baseline and 12 weeks
measure: Estimation of apparent volume of distribution (Vz/F) for Lopinavir/ritonavir (LPV/r)
timeFrame: Baseline and 12 weeks
Locations:
city: Irvine
country: United States
facility: UCI
state: California
city: Los Angeles
country: United States
facility: USC
state: California
city: San Diego
country: United States
facility: UCSD
state: California
city: San Jose
country: United States
facility: Santa Clara Valley Medical Center
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Medical Center
state: California
Study officials:
affiliation: University of California, Los Angeles
name: Eric Daar, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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)