Dose-ranging Efficacy and Pharmacokinetics Study of Intravenous Atorvastatin in Hypercholesterolemic Patients

Study Overview
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Brief Summary
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Open-label study will titrate doses of intravenous atorvastatin and monitor respective LDL-C levels in hypercholesterolemic patients previously controlled on oral atorvastatin.

Official Title
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Phase II, Dose-ranging Study to Evaluate the Efficacy Dose Response and Pharmacokinetics of Intravenous Atorvastatin in Hypercholesterolemic Patients Previously Controlled With Oral Atorvastatin

Conditions
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Hypercholesterolemia, Dyslipidemias

Intervention / Treatment
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* Drug: Atorvastatin injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: On stable dose of daily oral atorvastatin for >= 5 weeks (oral atorvastatin may be provided during a lead-in period for subjects not previously taking atorvastatin) Stable LDL-C confirmed in the previous 7 to 10 days prior to enrollment into the treatment phase. Exclusion Criteria: History of myopathy or rhabdomyolysis Liver disease including current biliary disorders Positive for HIV, Hepatitis B or Hepatitis C Virus Abuse of alcohol or non-prescribed drugs Unstable angina or arrhythmias or a cardiac event in the previous three months hypothyroidism, diabetes, or hypertension that is not under control pregnant or plans to be pregnant

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Cohort 1 = Baseline daily dose of 10 mg oral atorvastatin during lead-in, then IV study drug for up to 15 days | Drug: Atorvastatin injection<br>* statin (i.e., 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor) for injection<br>|
| Experimental: Cohort 2<br>Cohort 2 = Baseline daily dose of 20 mg oral atorvastatin during lead-in, then IV study drug for up to 15 days | Drug: Atorvastatin injection<br>* statin (i.e., 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor) for injection<br>|
| Experimental: Cohort 3<br>Cohort 3 = Baseline daily dose of 40 mg oral atorvastatin during lead-in, then IV study drug for up to 15 days | Drug: Atorvastatin injection<br>* statin (i.e., 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor) for injection<br>|
| Experimental: Cohort 4<br>Cohort 4 = Baseline daily dose of 20 mg oral atorvastatin during lead-in, then SC study drug for up to 15 days | Drug: Atorvastatin injection<br>* statin (i.e., 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor) for injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy, Number of Participants With Day 15 LDL-C Less Than or Equal to 125% of Baseline LDL-C | LDL-C levels were measured prior to and at the end of the 15 day treatment period to quantify the percent baseline LDL-C at 15 days. Efficacy is defined as eleven or more subjects in a dosing cohort with a Day 15 LDL-C not more than 125% of their baseline. | Baseline, 15 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy, Number of Participants With Day 15 HDL-C More Than or Equal to 75% Baseline HDL-C | HDL-C levels were measured prior to and at the end of the 15 day treatment period to quantify the percent baseline HDL-C at 15 days. Efficacy is defined as eleven or more subjects in a dosing cohort with a Day 15 HDL-C not less than 75% of their baseline. | Baseline, 15 Days | 
| Change in Baseline LDL-C Concentration | Mean change in LDL-C (mg/dL) from baseline at Day 15 | Baseline, 15 days | 
| Cmax IV | The maximum serum concentration of atorvastatin and the 2- and 4-hydroxy active metabolites following an intravenous injection to a patient at steady-state. | 3 to 7 minutes, 0.5h, 1h 2h, 4h, 6h, 8h, 24h post-dose | 
| Tmax IV | The time to maximum concentration of atorvastatin and the 2- and 4-hydroxy active metabolites following an intravenous injection to a patient at steady-state. | 3 to 7 minutes, 0.5h, 1h 2h, 4h, 6h, 8h, 24h post-dose | 
| AUC 0-24 | The AUC 0-24 of atorvastatin and the 2- and 4-hydroxy active metabolites following an intravenous injection to a patient at steady-state. | 3 to 7 minutes, 0.5h, 1h 2h, 4h, 6h, 8h, 24h post-dose | 
| AUC Inf | The AUCinf of atorvastatin following an intravenous injection to a patient at steady-state. | 3 to 7 minutes, 0.5h, 1h 2h, 4h, 6h, 8h, 24h post-dose | 
| VDss | The volume of distribution at steady state of atorvastatin following an intravenous injection to a patient. | 3 to 7 minutes, 0.5h, 1h 2h, 4h, 6h, 8h, 24h post-dose | 
| t 1/2 | The half-life of atorvastatin following an intravenous injection to a patient at a steady state. | 3 to 7 minutes, 0.5h, 1h 2h, 4h, 6h, 8h, 24h post-dose |