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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase IV, Randomized, Open-label Study of the Tolerability of Once Daily Lopinavir/Ritonavir (LPV/r) Liquid Versus Capsules

Conditions
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HIV Infection

Intervention / Treatment
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* Drug: Different formulations of once-daily lopinavir/ritonavir


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: LPV/r (800/200 mg) 10 ml liquid<br>Once daily Lopinovir/ritonavir (800/200 mg) taken as a 10 ml liquid | Drug: Different formulations of once-daily lopinavir/ritonavir<br>* CCTG585 is a randomized, open-label, two arm cross-over study to compare the tolerability of once daily LPV/r liquid versus capsules<br>* Other names: Lopinavir/Ritonavir (LPV/r);|
| Active Comparator: LPV/r (800/200 mg) 6 gel capsules<br>Once daily Lopinavir/ritonavir (800/200 mg) as 6 gel capsules | Drug: Different formulations of once-daily lopinavir/ritonavir<br>* CCTG585 is a randomized, open-label, two arm cross-over study to compare the tolerability of once daily LPV/r liquid versus capsules<br>* Other names: Lopinavir/Ritonavir (LPV/r);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | Baseline to week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Measures of Treatment-limiting toxicity | 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). | Baseline to week 48 | 
| Incidence Measures of Drug-related diarrhea | 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). | Baseline to week 48 | 
| Incidence Measures of the Use of antiemetic and/or antimotility therapy | 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). | Baseline to week 48 | 
| Incidence Measures of Adverse events other than nausea and diarrhea | 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). | Baseline to week 48 | 
| Incidence Measures of Laboratory abnormalities, e.g. lipids, liver enzymes | 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). | Baseline to week 48 | 
| Incidence Measures of HIV RNA suppression to <50 copies/ml | 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). | Baseline to week 48 | 
| Preference for Lopinavir/ritonavir liquid, capsules or tablets, and the degree of like or dislike of each | 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 | Week 8 and week 48 | 
| Evaluating the proportion of screened individuals who choose not to be randomized after the liquid Lopinavir/ritonavir taste test | 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 | Baseline | 
| Evaluating the severity of diarrhea | 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/ | Week 4, week 8 and week 48 | 
| Evaluating the severity of nausea | 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/ | Week 4, week 8 and week 48 | 
| Evaluating proportion with plasma HIV RNA <50 copies/mL at the end of Step 4 | Evaluating the proportion of participants with plasma HIV RNA <50 copies/mL at the end of Step 4 | Week 4, week 8 and week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lopinavir, antiretroviral therapy, cross-over, tolerability