Prolonged Infusion of Clevidipine Results in Safe and Predictable Blood Pressure Control in Patients with Acute Severe

Hypertension

Results from the VELOCITY Trial

Prolonged Infusion of Clevidipine Results in Safe and Predictable Blood Pressure Control in Patients with Acute Severe

Hypertension

Results from the VELOCITY Trial

J. Varon, MD, FCCP, W.F. Peacock, MD, N. Garrison, MD, R. Ebrahimi, MD, L. Dunbar, MD, P.

Acosta, MD, and C. Pollack, MD

2

DisclosuresDisclosures

This study was conducted with the support of a research grant by The Medicines Company

Dr. Varon was a PI in this trial and has served as a consultant for The Medicines Company.

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Treatment Goals for Hypertensive EmergencyTreatment Goals for Hypertensive Emergency

Prompt, but smooth reduction in BP

– Reduce BP by ≤25% during the first minute to 1 hour

– If stable, reduce BP in next 2–6 hours

– Gradual reductions toward normal BP over next 24–48 hours

– Exceptions requiring special care: ischemic stroke, stroke eligible for thrombolytic agents, aortic dissection

Avoid excessive drops in BP

– May cause renal, cerebral or coronary ischemia

– Need careful and close monitoring

– Use of an arterial catheter for monitoring BP routinely required

Choice of pharmacologic agent should be tailored to patient

– Based on risks, comorbidities and type of end-organ damage

US Department of Heath and Human Services. Bethesda, Md: National Institutes of Health. NIH Publication No. 04-5230. August 2004.

4

Cl

ClH

CH3OOC

H3C

COOCH2OOCC3H7

CH3N

H

ClevidipineClevidipine

t ½ ~1 min

Steady state achieved in ~2 mins

Protein binding >99.5%

High clearance rate (independent of dosing rate)

Arterial Selective

Small Vd = 0.17 L/kg

A rationally designed dihydropyridine calcium channel blocker characterized by its rapid onset and offset of BP lowering effect

5

Clevidipine: Metabolized by Plasma and Tissue EsterasesClevidipine: Metabolized by Plasma and Tissue Esterases

Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue to an inactive carboxylic acid metabolite

+OH

OHH

O

Clevidipine

Cl

OO

O

O

NH

Cl

O

O

*Esterases +O

O

NH

Cl

O

O

Cl

H

Primary metabolite

*The chiral center of clevidipine.

Reproduced from Ericsson H, et al. Eur J Clin Pharmacol. 1999;55:61-67.

Bailey JM, et al. Anesthesiology. 2002;96:1086-1094.

Ericsson H, et al. Drug Metab Dispos. 1999;27:558-564.

Ericsson H et al. Eur J Clin Pharmacol. 1999;55:61-67.

Ericsson H, et al. Eur J Pharm Sci. 1999;8:29-37.

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VELOCITY: RationaleVELOCITY: Rationale

Multi-center, Phase III, open-label, single-arm, study to confirm the safety of IV clevidipine for patients with acute hypertension requiring parenteral treatment for at least 18 hr

Phase III safety and efficacy study

– Evaluation: to confirm the safety and efficacy of clevidipine in patients with acute hypertension using a predefined, non-weight

based dosing algorithm

– Population: patients with acute hypertension (SBP >180 mmHg or DBP >115 mmHg) assessed at 2 successive occasions 15 min apart at baseline

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VELOCITY: ObjectivesVELOCITY: Objectives

Primary

Confirm the safety of a titration dosing regimen of an IV infusion of clevidipine for the treatment of acute hypertension

– Efficacy: percentage of patients in whom SBP fell within the SBP target range within 30 min of initiating infusion

– Safety: percentage of patients in whom SBP fell below the lower limit of the initial SBP target range within 3 min of initiating infusion

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VELOCITY: ObjectivesVELOCITY: Objectives

Secondary

Efficacy:

– Time to attainment of 30-min SBP target range

Safety:

– Change in heart rate during the 30-min period from initiation of infusion

– Dose of clevidipine during the treatment period

– Of the patients converted to oral antihypertensive therapy, the proportion of those with successful transition, defined as SBP within the last specified target range at 6 hr after cessation of clevidipine infusion

– Safety of prolonged infusion of clevidipine (≥18 hr)

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VELOCITY: Enrollment CriteriaVELOCITY: Enrollment Criteria

Inclusion Criteria

– Age 18 years and older

– Systolic BP >180 mmHg and/or diastolic BP >115 mmHg assessed on 2 successive occasions, 15 min apart

– Provide written informed consent before initiation of any study-related procedures

Exclusion Criteria

– SBP ≤180 mmHg and DBP ≤115 mmHg

– Expectation that the patient will not tolerate IV antihypertensive therapy for a minimum of 18 hr

– Known or suspected aortic dissection

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VELOCITY: TreatmentVELOCITY: Treatment

Clevidipine

– Selection of SBP Initial Target Range (ITR) was determined prior to the initiation of clevidipine

– ITR was determined for each individual patient

– The difference between the upper and lower ITR was between 20 mmHg and 40 mmHg

– BP monitoring was done with a BP cuff

– Clevidipine initiated at 2 mg/hr via peripheral vein

– Titrated in doubling increments Q3 min, not to exceed 32 mg/hr, to achieve pre-specified ITR

– Infusion rate could have been decreased at the investigators discretion in order to achieve the target SBP

– Infusion was maintained or further titrated after the first 30 min to achieve the desired long-term reduction in SBP

– Treatment duration for at least 18 hr and not exceeding 96 hr

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VELOCITY: Treatment – Transition to Oral TherapyVELOCITY: Treatment – Transition to Oral Therapy

If transition to an oral antihypertensive agent was required, the agent could be given 1 hr prior to the anticipated cessation of clevidipine infusion but not before the 18 hr time point

At any time following the administration of the oral agent, the clevidipine infusion could have been down-titrated or terminated in order to achieve the desired BP level

If the BP rose to an undesirable level upon cessation of the infusion, additional oral therapy may have been added or clevidipine infusion may have been restarted

Successful transition to oral therapy was defined as achieving a target BP within 6 hours of cessation of clevidipine infusion

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VELOCITY: Patient DispositionVELOCITY: Patient Disposition

DNC=did not complete.

mITT Population(patients with

SBP >UL of target range)N=117

Total patients enrolledN=131

Safety Population(patients who

received at least 1 dose)N=126

No clevidipine

n=5

SBP ≤UL of target rangen=14

≥18 hr continuous infusionn=117

<18 hr treatmentn=9

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VELOCITY: Results – Patient DemographicsVELOCITY: Results – Patient Demographics

Parameter Value

Age (yrs) 53.5 ± 15

Gender (%)

Male 48

Female 52

BMI (kg/m2) 30 ± 7.6

Race (%)

African American 77

White 16

Hispanic 6

Asian 1

SBP (mmHg) 202 ± 22

DBP (mmHg) 111 ± 21

ITR (high, low) 175, 143

Mean ± SDSafety Population, N=126.

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VELOCITY: Results – Medical History, Comorbidity, and End-Organ Dysfunction

VELOCITY: Results – Medical History, Comorbidity, and End-Organ Dysfunction

Medical History Percent (%)

End organ injury 81

Myocardial infarction 5

Renal disease 25

Dialysis dependent 11

Coronary artery disease 28

Hypertension 97

Previous hospitalization for hypertension 31

Congestive heart failure 18

Dyslipidemia 37

Smoker

Current / Former 39 / 21

Diabetes 31

Stroke 11

Safety Population, N=126.

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VELOCITY: Efficacy ResultsVELOCITY: Efficacy Results

Initial infusion rate 2 mg/hr (4 mL/hr)

Time to first achievement to Initial Target Range (ITR)

– 10.9 min (95% CI 9.0, 15.0)

– Median dose rate 4 mg/hr (mean 6 mg/hr)

mITT population

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VELOCITY: Efficacy ResultsVELOCITY: Efficacy Results

89% of patients achieved pre-specified ITR within 30 min

– An additional 7% of patients achieved ITR after 30 min

– Of the 96% of patients who did not have protocol violations with selection of ITR, 90% achieved the ITR within 30 min

From drug initiation to 30 min

– Median infusion rate 7 mg/hr (mean 9.5mg/hr)

Time to a 15% drop in blood pressure 9.5 min

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VELOCITY: Probability of Having Attained SBP Initial Target RangeVELOCITY: Probability of Having Attained SBP Initial Target Range

K-M Analysis

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

0

10

20

30

40

50

60

70

80

90

10091%

Minutes

Per

cent

of

Pat

ient

s

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VELOCITY: Efficacy Results – Change in BP (30 min)VELOCITY: Efficacy Results – Change in BP (30 min)

mITT population

Time after start of infusion (min.)

% R

educ

tion

from

Bas

elin

e S

BP

(Mea

n ±

SE

)

3 6 9 12 15 18 21 24 27 30-25

-20

-15

-10

-5

0

-6%

-16.5%-21%

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VELOCITY: Results – Long-term InfusionVELOCITY: Results – Long-term Infusion

92.9% of patients were administered clevidipine for ≥18 hours

– The infusion rate was maintained or further titrated after 30 min to the desired long-term (≥18 h) SBP target

– SBP reduction at 18 hours was -27% (-55 mmHg) from baseline

– Patients were maintained on a steady infusion of clevidipine without evidence of tachyphylaxis or drug accumulation

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VELOCITY: Efficacy Results – Change in BP (18 hour)VELOCITY: Efficacy Results – Change in BP (18 hour)

Time after start of infusion (hours)

% S

BP

Red

uctio

n fr

om B

asel

ine

(Mea

n ±

SE

)

0 3 6 9 12 15 18

0

-5

-10

-15

-20

-25

-30

Additional TitrationBP Adjustment

and Maintenance

30 min.Titration to ITR

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VELOCITY: Results – Long-term InfusionVELOCITY: Results – Long-term Infusion

92.3% of all patients were maintained on clevidipine monotherapy without the need for additional IV antihypertensive therapy

Clevidipine was well tolerated for a median duration of 21 hours (max 60 hours)

118 patients were eligible for transition to oral antihypertensive therapy

– 97.5% did so to a defined target BP within 6 hr of cessation of clevidipine infusion

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VELOCITY: Safety ResultsVELOCITY: Safety Results

2 patients (1.6%) fell below the lower ITR limit within first 3 min. of clevidipine infusion

– One patient had a narrower than specified ITR (205-195 mmHg), SBP was 15 mmHg below the lower limit

– One patient lower limit was 160 mmHg and SBP fell 4 mmHg below this

– Both patients continued clevidipine infusion beyond 18 hr without AEs

No hypotensive events related to clevidipine were reported throughout the study

– One patient was reported to have a hypotensive event not related to clevidipine 17 hours after infusion initiation

mITT population

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Clevidipine is formulated and administered in a lipid emulsion

Changes in serum triglyceride concentrations were assessed:

– Median percent change in serum triglyceride concentrations was zero

– Additional analyses were conducted to evaluate the relationship of triglycerides to total lipid dose exposure – No relationship was observed when triglyceride

concentrations at baseline and 6 hours post infusion were examined based on the total clevidipine dose received (Pearson’s correlation coefficient = -0.0269)

VELOCITY: Safety ResultsVELOCITY: Safety Results

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Conclusion:What We Learned From VELOCITYConclusion:What We Learned From VELOCITY

Clevidipine lowered BP to pre-specified target range in ~90% of patients within 30 min

Patients reached target BP without overshoot in a median 10.9 min

Clevidipine was easy to administer and well tolerated

– Peripheral venous administration

– BP monitoring via a cuff

– Non-weight based dosing regimen

Clevidipine was effective and well tolerated after prolonged infusion and maintained BP in patients with acute and severe hypertension