Dyslipidemias, Hypercholesterolemia
Conditions
Brief summary
Open-label study will titrate doses of intravenous atorvastatin and monitor respective LDL-C levels in hypercholesterolemic patients previously controlled on oral atorvastatin.
Interventions
DRUGAtorvastatin injection
statin (i.e., 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor) for injection
Sponsors
Cumberland Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy, Number of Participants With Day 15 LDL-C Less Than or Equal to 125% of Baseline LDL-C | Baseline, 15 Days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Baseline LDL-C Concentration | Baseline, 15 days | Mean change in LDL-C (mg/dL) from baseline at Day 15 |
| Cmax IV | 3 to 7 minutes, 0.5h, 1h 2h, 4h, 6h, 8h, 24h post-dose | The maximum serum concentration of atorvastatin and the 2- and 4-hydroxy active metabolites following an intravenous injection to a patient at steady-state. |
| Tmax IV | 3 to 7 minutes, 0.5h, 1h 2h, 4h, 6h, 8h, 24h post-dose | 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. |
| Efficacy, Number of Participants With Day 15 HDL-C More Than or Equal to 75% Baseline HDL-C | Baseline, 15 Days | 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. |
| AUC Inf | 3 to 7 minutes, 0.5h, 1h 2h, 4h, 6h, 8h, 24h post-dose | The AUCinf of atorvastatin following an intravenous injection to a patient at steady-state. |
| VDss | 3 to 7 minutes, 0.5h, 1h 2h, 4h, 6h, 8h, 24h post-dose | The volume of distribution at steady state of atorvastatin following an intravenous injection to a patient. |
| t 1/2 | 3 to 7 minutes, 0.5h, 1h 2h, 4h, 6h, 8h, 24h post-dose | The half-life of atorvastatin following an intravenous injection to a patient at a steady state. |
| AUC 0-24 | 3 to 7 minutes, 0.5h, 1h 2h, 4h, 6h, 8h, 24h post-dose | The AUC 0-24 of atorvastatin and the 2- and 4-hydroxy active metabolites following an intravenous injection to a patient at steady-state. |
Countries
United States
Participant flow
Recruitment details
Enrollment occurred between 07Aug2018 and 24Feb2020. Three types of patients, categorized by statin use prior to study participation were eligible: patients taking oral atorvastatin, patients taking statins other than atorvastatin, patient not taking any statins prior to study. In Amendment 03. the fourth 80mg dose was eliminated and the 15 days IV route administration was changed to subcutaneous administration.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Cohort 1 = Baseline daily dose of 10 mg oral atorvastatin receiving either IV or SC study drug | 14 |
| Cohort 2 Cohort 2 = Baseline daily dose of 20 mg oral atorvastatin receiving either IV or SC study drug | 14 |
| Cohort 3 Cohort 3 = Baseline daily dose of 40 mg oral atorvastatin receiving either IV or SC study drug | 2 |
| Cohort 4 Cohort 4 = Baseline daily dose of 20 mg oral atorvastatin receiving either SC study drug | 10 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 2: 15 Day Treatment | Inaccessible veins | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Cohort 4 | Cohort 3 | Cohort 2 | Cohort 1 |
|---|---|---|---|---|---|
| Age, Continuous | 48.6 years STANDARD_DEVIATION 9.9 | 50.4 years STANDARD_DEVIATION 10.47 | 46.0 years STANDARD_DEVIATION 18.38 | 51.4 years STANDARD_DEVIATION 8.21 | 44.8 years STANDARD_DEVIATION 9.74 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 4 Participants | 1 Participants | 5 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 6 Participants | 1 Participants | 9 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Prior Atorvastatin Use or Using Oral Atorvastatin No Prior Statin Use | 22 Participants | 5 Participants | 1 Participants | 9 Participants | 7 Participants |
| Prior Atorvastatin Use or Using Oral Atorvastatin Prior Atorvastatin Use or Using Oral Atorvastatin | 16 Participants | 5 Participants | 1 Participants | 4 Participants | 6 Participants |
| Prior Atorvastatin Use or Using Oral Atorvastatin Prior Statin Other than Atorvastatin Use | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 4 Participants | 0 Participants | 6 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 5 Participants | 2 Participants | 8 Participants | 9 Participants |
| Sex: Female, Male Female | 17 Participants | 5 Participants | 1 Participants | 5 Participants | 6 Participants |
| Sex: Female, Male Male | 23 Participants | 5 Participants | 1 Participants | 9 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 | 0 / 2 | 0 / 10 |
| other Total, other adverse events | 4 / 14 | 1 / 14 | 1 / 2 | 3 / 10 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 | 0 / 2 | 0 / 10 |
Outcome results
Primary
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.
Time frame: Baseline, 15 Days
Population: Efficacy Population: A completed group of subjects that 1) finished the two-week treatment period, 2) provided a Day 15 LDL-C level, and 3) took the final targeted dose for that cohort comprised the four efficacy populations.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Efficacy, Number of Participants With Day 15 LDL-C Less Than or Equal to 125% of Baseline LDL-C | 9 Participants |
| Cohort 2 | Efficacy, Number of Participants With Day 15 LDL-C Less Than or Equal to 125% of Baseline LDL-C | 9 Participants |
| Cohort 3 | Efficacy, Number of Participants With Day 15 LDL-C Less Than or Equal to 125% of Baseline LDL-C | 1 Participants |
| Cohort 4 | Efficacy, Number of Participants With Day 15 LDL-C Less Than or Equal to 125% of Baseline LDL-C | 7 Participants |
Secondary
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.
Time frame: 3 to 7 minutes, 0.5h, 1h 2h, 4h, 6h, 8h, 24h post-dose
Population: Pharmacokinetic Population: All subjects in the Efficacy Population who had no major protocol deviations and who had sufficient plasma atorvastatin concentration data for reliable estimates of the key PK variables for each of the four baseline cohorts.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | AUC 0-24 | 2-Hydroxy Atorvastatin | 3.35 ng*hr/mL | Standard Deviation 2.603 |
| Cohort 1 | AUC 0-24 | Atorvastatin | 72.12 ng*hr/mL | Standard Deviation 31.216 |
| Cohort 1 | AUC 0-24 | 4-Hydroxy Atorvastatin | NA ng*hr/mL | — |
| Cohort 2 | AUC 0-24 | 2-Hydroxy Atorvastatin | 16.76 ng*hr/mL | Standard Deviation 6.283 |
| Cohort 2 | AUC 0-24 | Atorvastatin | 137.04 ng*hr/mL | Standard Deviation 134.608 |
| Cohort 2 | AUC 0-24 | 4-Hydroxy Atorvastatin | 5.45 ng*hr/mL | Standard Deviation 3.691 |
| Cohort 3 | AUC 0-24 | Atorvastatin | 212.00 ng*hr/mL | Standard Deviation 89.095 |
| Cohort 3 | AUC 0-24 | 4-Hydroxy Atorvastatin | 12.65 ng*hr/mL | Standard Deviation 5.303 |
| Cohort 3 | AUC 0-24 | 2-Hydroxy Atorvastatin | 49.20 ng*hr/mL | Standard Deviation 26.698 |
Secondary
AUC Inf
The AUCinf of atorvastatin following an intravenous injection to a patient at steady-state.
Time frame: 3 to 7 minutes, 0.5h, 1h 2h, 4h, 6h, 8h, 24h post-dose
Population: Pharmacokinetic Population: All subjects in the Efficacy Population who had no major protocol deviations and who had sufficient plasma atorvastatin concentration data for reliable estimates of the key PK variables for each of the four baseline cohorts.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | AUC Inf | 72.19 ng*hr/mL | Standard Deviation 31.196 |
| Cohort 2 | AUC Inf | 167.32 ng*hr/mL | Standard Deviation 138.099 |
| Cohort 3 | AUC Inf | 217.00 ng*hr/mL | Standard Deviation 89.095 |
Secondary
Change in Baseline LDL-C Concentration
Mean change in LDL-C (mg/dL) from baseline at Day 15
Time frame: Baseline, 15 days
Population: Efficacy Population: A completed group of subjects that 1) finished the two-week treatment period, 2) provided a Day 15 LDL-C level, and 3) took the final targeted dose for that cohort comprised the four efficacy populations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Change in Baseline LDL-C Concentration | 12.36 mg/dL | Standard Deviation 14.74 |
| Cohort 2 | Change in Baseline LDL-C Concentration | 2.62 mg/dL | Standard Deviation 34.844 |
| Cohort 3 | Change in Baseline LDL-C Concentration | 27.50 mg/dL | Standard Deviation 14.849 |
| Cohort 4 | Change in Baseline LDL-C Concentration | 11.22 mg/dL | Standard Deviation 13.283 |
Secondary
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.
Time frame: 3 to 7 minutes, 0.5h, 1h 2h, 4h, 6h, 8h, 24h post-dose
Population: Pharmacokinetic Population: All subjects in the Efficacy Population who had no major protocol deviations and who had sufficient plasma atorvastatin concentration data for reliable estimates of the key PK variables for each of the four baseline cohorts.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Cmax IV | 2-Hydroxy Atorvastatin | 0.40 mg/mL | Standard Deviation 0.87 |
| Cohort 1 | Cmax IV | Atorvastatin | 284.33 mg/mL | Standard Deviation 189.54 |
| Cohort 1 | Cmax IV | 4-Hydroxy Atorvastatin | 0.24 mg/mL | Standard Deviation 0 |
| Cohort 2 | Cmax IV | 2-Hydroxy Atorvastatin | 1.23 mg/mL | Standard Deviation 0.45 |
| Cohort 2 | Cmax IV | Atorvastatin | 830.34 mg/mL | Standard Deviation 1141.919 |
| Cohort 2 | Cmax IV | 4-Hydroxy Atorvastatin | 0.30 mg/mL | Standard Deviation 0.163 |
| Cohort 3 | Cmax IV | Atorvastatin | 507.50 mg/mL | Standard Deviation 443.456 |
| Cohort 3 | Cmax IV | 4-Hydroxy Atorvastatin | 0.75 mg/mL | Standard Deviation 0.37 |
| Cohort 3 | Cmax IV | 2-Hydroxy Atorvastatin | 3.23 mg/mL | Standard Deviation 1.987 |
Secondary
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.
Time frame: Baseline, 15 Days
Population: Efficacy Population: A completed group of subjects that 1) finished the two-week treatment period, 2) provided a Day 15 LDL-C level, and 3) took the final targeted dose for that cohort comprised the four efficacy populations.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Efficacy, Number of Participants With Day 15 HDL-C More Than or Equal to 75% Baseline HDL-C | 11 Participants |
| Cohort 2 | Efficacy, Number of Participants With Day 15 HDL-C More Than or Equal to 75% Baseline HDL-C | 13 Participants |
| Cohort 3 | Efficacy, Number of Participants With Day 15 HDL-C More Than or Equal to 75% Baseline HDL-C | 1 Participants |
| Cohort 4 | Efficacy, Number of Participants With Day 15 HDL-C More Than or Equal to 75% Baseline HDL-C | 9 Participants |
Secondary
t 1/2
The half-life of atorvastatin following an intravenous injection to a patient at a steady state.
Time frame: 3 to 7 minutes, 0.5h, 1h 2h, 4h, 6h, 8h, 24h post-dose
Population: Pharmacokinetic Population: All subjects in the Efficacy Population who had no major protocol deviations and who had sufficient plasma atorvastatin concentration data for reliable estimates of the key PK variables for each of the four baseline cohorts.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | t 1/2 | 4.79 hours | Standard Deviation 4.311 |
| Cohort 2 | t 1/2 | 6.22 hours | Standard Deviation 1.884 |
| Cohort 3 | t 1/2 | 6.38 hours | Standard Deviation 0.085 |
Secondary
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.
Time frame: 3 to 7 minutes, 0.5h, 1h 2h, 4h, 6h, 8h, 24h post-dose
Population: Pharmacokinetic Population: All subjects in the Efficacy Population who had no major protocol deviations and who had sufficient plasma atorvastatin concentration data for reliable estimates of the key PK variables for each of the four baseline cohorts.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 | Tmax IV | 2-Hydroxy Atorvastatin | 6.00 hours |
| Cohort 1 | Tmax IV | Atorvastatin | 0.08 hours |
| Cohort 1 | Tmax IV | 4-Hydroxy Atorvastatin | 0.08 hours |
| Cohort 2 | Tmax IV | 2-Hydroxy Atorvastatin | 6.0 hours |
| Cohort 2 | Tmax IV | Atorvastatin | 0.08 hours |
| Cohort 2 | Tmax IV | 4-Hydroxy Atorvastatin | 6.0 hours |
| Cohort 3 | Tmax IV | Atorvastatin | 0.15 hours |
| Cohort 3 | Tmax IV | 4-Hydroxy Atorvastatin | 8.0 hours |
| Cohort 3 | Tmax IV | 2-Hydroxy Atorvastatin | 5.00 hours |
Secondary
VDss
The volume of distribution at steady state of atorvastatin following an intravenous injection to a patient.
Time frame: 3 to 7 minutes, 0.5h, 1h 2h, 4h, 6h, 8h, 24h post-dose
Population: Pharmacokinetic Population: All subjects in the Efficacy Population who had no major protocol deviations and who had sufficient plasma atorvastatin concentration data for reliable estimates of the key PK variables for each of the four baseline cohorts.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | VDss | 71.86 liter | Standard Deviation 81.475 |
| Cohort 2 | VDss | 135.53 liter | Standard Deviation 145.579 |
| Cohort 3 | VDss | 182.85 liter | Standard Deviation 140.219 |