Clinical trial NCT01938547
Conditions: Pediatric Perioperative Blood Pressure Management
Keywords: perioperative blood pressure pediatrics pediatric surgery
Sponsor: Chiesi Farmaceutici S.p.A.
Start date: 2014-03-17; Completion date: 2024-02-20
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Evaluate the efficacy, safety, and dosing of clevidipine as an intravenous (IV) infusion for blood pressure (BP) management in paediatric participants in the perioperative setting.

Detailed description:
This was an open-label study to assess, in a stepwise approach across 4 age cohorts from oldest to youngest (birth to \<age 18), the efficacy and safety of clevidipine exposure for a minimum of 30 minutes and up to a maximum of 96 hours in pediatric participants undergoing a surgical procedure with anesthesia for greater than or equal to 1 hour and for whom parenteral IV infusion of antihypertensive therapy for the management of blood pressure was expected.

The reason for initiating clevidipine administration was to keep blood pressure within a pre-specified range during surgery.

After the study completion for Cohort 1 (adolescent patients 12 to less than 18 years), the PIONEER study was placed on partial clinical hold by the FDA; later, the study was terminated by the sponsor. Enrolment of the subsequent cohorts did not take place; results are presented for Cohort 1 only.

Arms: arm 1: An initial clevidipine IV infusion dose for the adolescent cohort has been specified per protocol. The initial dose for each of the subsequent age cohorts could be modified if necessary, based on the recommendation of the Data and Safety Monitoring Board (DSMB).

Following the initial dose, clevidipine will be up-titrated every 1.5 minutes, according to participant need, to achieve a systolic blood pressure (SBP) within the pre-specified SBP target range. Doses may be increased by less than doubling, and the time between dose adjustments may be lengthened, as the target blood pressure is approached. The infusion rate may be maintained for up to 96 hours, once the participant's SBP is within the target range, and titrated as necessary to maintain blood pressure within the range.
Interventions: intervention 1: clevidipine
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
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Open label study to assess the efficacy, safety and dosing of clevidipine in 
pediatric patients undergoing surgery (PIONEER study)  
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clevidipine 
 Clinical Study Protocol MDCO-CLV-12-01 
Confidential 
Page 3 
The Medicines Company MDCO-CLV-12-01: Version 3 
  Release date: 11 December 2013 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company:   The Medicines Company 
Name of Finished Product:      Cleviprex® (clevidipine) Injectable Emulsion 
Name of Active Ingredient:      clevidipine 
Title of Study:                            Open label study to assess the efficacy, safety 
and dosing of clevidipine in pediatric patients 
undergoing surgery  
Phase of Development:             IV  
Study Centers:                           2 centers  
Principal Investigator:             Joseph D. Tobias, MD 
Study Period: 
 
Estimated date first subject enrolled:        February 2014 
 
Estimated date last subject completed:     February 2016 
Objectives:  To evaluate the efficacy, safety and dosing of an intravenous (IV) 
infusion of clevidipine for blood pressure (BP) management in pediatric patients 
in the perioperative setting. 
Methodology: Open label study to assess, in a stepwise approach from oldest to 
youngest, the efficacy and safety of clevidipine exposure for a minimum of 30 
minutes and up to a maximum of 96 hours in pediatric patients undergoing a 
surgical procedure requiring anesthesia ≥1 hour, and for whom parenteral IV 
antihypertensive therapy for BP management is expected. 
Number of Patients: 80-100 planned; 80 evaluable for efficacy 
This study will evaluate the efficacy and safety of clevidipine in 80 pediatric 
patients presenting for surgery and anticipated to require BP management during 
the surgical procedure with parenteral IV antihypertensive therapy.  
 
Patients will be enrolled in a stepwise approach, starting with the adolescent 
cohort. An interim analysis of safety and dosing will be performed by the Data 
Safety Monitoring Board (DSMB) before initiation of each of the remaining 
cohorts.  
 Cohort 1: 20 adolescent patients (12 to less than 18 years). 
 Cohort 2: 20 children (2 to less than 12 years, including 10 patients in 
each age group 6 to less than 12 years and 2 to less than 6 years). 
 Cohort 3: 20 infants and toddlers (28 days to less than 24 months). 
 Cohort 4: 20 preterm and newborn infants (0 to less than 28 days). 


clevidipine 
 Clinical Study Protocol MDCO-CLV-12-01 
Confidential 
Page 4 
The Medicines Company MDCO-CLV-12-01: Version 3 
  Release date: 11 December 2013 
A DSMB will be set up to monitor the safety and dosing data on an ongoing basis 
for all cohorts. Following completion of the adolescent cohort, the DSMB will 
review the safety data and make safety recommendations to the Sponsor 
according to the DSMB Charter. The DSMB review of each completed cohort 
will be required before proceeding to the subsequent cohort to determine if it is 
appropriate to proceed with enrollment of subsequent cohorts and whether an 
adjustment in dosing scheme is required. 
An analysis to confirm appropriate sample size for desired precision will be 
conducted by the Sponsor following complete enrollment of each cohort. 
Diagnosis and Main Criteria for Selection: 
 
Patients will be eligible for inclusion if they satisfy the following criteria: 
 Less than 18 years of age 
 Written informed consent obtained before initiation of any study-related 
procedures 
 The enrolling physician determines that the patient will likely require a 
15% reduction in BP during the perioperative course 
 Intra-arterial line is available for blood pressure monitoring 
 Surgical procedure requiring at minimum of 1 hour of anesthesia, in 
which IV antihypertensive therapy to control BP for at least 30 minutes is 
anticipated 
Patients will be excluded if they present with any of the following exclusion 
criteria: 
 Administration of an IV or oral antihypertensive agent within 2 hours 
prior to study drug administration 
 Congenital heart disease described as single ventricle  
 Evidence of liver failure, severe liver disease, pulmonary disease (e.g., 
uncontrolled asthma), hyperlipidemia, lipoid nephrosis, lipid dysfunction 
or acute pancreatitis 
 Allergy to soya bean oil or egg lecithin 
 Known to be intolerant to calcium channel blockers 
 Hemophilia or blood coagulation disorders 
 Any serious medical condition which, in the opinion of the investigator, is 
likely to interfere with study procedures 
 Clinically significant abnormal physical findings at the screening 
evaluation 
 Any serious surgical or medical condition which, in the opinion of the 
investigator, is likely to interfere with study procedures or with the 
pharmacokinetics or pharmacodynamics of the study drug 


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clevidipine 
 Clinical Study Protocol MDCO-CLV-12-01 
Confidential 
Page 7 
The Medicines Company MDCO-CLV-12-01: Version 3 
  Release date: 11 December 2013 
implemented. The alternative agent should be chosen per the institutional 
practice. 
The use of an alternative IV antihypertensive agent is discouraged and should be 
limited to situations where it is medically necessary to maintain patient safety as 
determined by the principal investigator.  
If transition from clevidipine to an oral antihypertensive agent is required, at any 
time following administration of the oral antihypertensive agent, the clevidipine 
infusion may be down-titrated or terminated in order to achieve the desired blood 
pressure level. If BP rises to an undesirable level upon cessation of clevidipine 
infusion, additional therapy may be administered or clevidipine infusion may be 
restarted (at initial infusion rate) until successful transition to an oral therapy has 
been achieved. 
If treatment with an IV antihypertensive agent is still required after 96 hours of 
clevidipine therapy, the patient may be transitioned to an alternative IV 
antihypertensive agent according to the institutional standard of care. 
Rescue therapy with IV antihypertensive treatment will be determined by the 
principal investigator per the institutional treatment policy. If a patient is 
receiving rescue therapy with an IV antihypertensive treatment and transition to 
an oral antihypertensive agent is required, institutional practice must be followed. 
Reference Therapy, Dose and Mode of Administration, Batch Number(s):   
There will be no reference therapy in this trial. 
Efficacy Endpoints:  
The primary efficacy endpoints of this trial are: 
 
Median time and dose to attain the initial prespecified target SBP range 
(minimum of 20 mmHg and a maximum of 40 mmHg apart) during the 
first 30 minutes of clevidipine infusion 
 
Percentage of patients achieving the initial prespecified target SBP range 
during the first 30 minutes of clevidipine infusion 
Safety:   
Safety of a prolonged infusion of clevidipine (up to 96 hours) will be assessed 
according to clinical laboratory parameters. Adverse events and serious adverse 
events (SAEs) will be assessed from time of consent through 7 days following 
termination of study drug infusion. 
Pharmacology: 
 
Pharmacokinetic variables (half-life, area under the curve [AUC], volume 


clevidipine 
 Clinical Study Protocol MDCO-CLV-12-01 
Confidential 
Page 8 
The Medicines Company MDCO-CLV-12-01: Version 3 
  Release date: 11 December 2013 
of distribution, clearance) established by noncompartmental analysis or 
sparse population methodology 
 
 
Pharmacodynamic variables (relationship between change from baseline 
in SBP vs. blood concentration and infusion rate) 
The secondary efficacy endpoints of this trial are: 
 
The percentage of patients who reach the initial prespecified target SBP 
range without falling below the lower limit of the prespecified target range 
during the first 30 minutes of clevidipine infusion 
 
The percentage of patients in whom the SBP falls below the lower limit of 
the prespecified target range at any time during the first 30 minutes and at 
any time during the entire study drug treatment period 
 
Percent change in SBP from baseline at each time point during the first 30 
minutes of clevidipine infusion 
 
Percent change from baseline in SBP at each hour after the first 30 
minutes of clevidipine infusion up to the cessation of infusion 
 
Percent change from baseline in SBP over the first 12 hours post study 
drug termination 
 
The percentage of patients in whom the SBP is within target range at each 
hour after the first 30 minutes of clevidipine infusion 
 
Percent change from baseline in heart rate during the first 30 minutes of 
clevidipine infusion and the rest of the treatment period 
 
The percentage of patients who require rescue therapy (i.e., receive any 
alternative IV antihypertensive drug) at any time during study drug 
treatment period, or discontinuation due to adverse events  
 
Statistical Methods: 
The total sample size of 80 evaluable patients is primarily based on clinical 
judgment to provide adequate precision of the findings for this non-comparative 
study. For example, assuming that 90% of patients will achieve the initial target 
SBP range within the first 30 minutes of infusion, a sample size of 80 patients can 
provide a 95% confidence interval with a precision of ±6.6%. This precision will 
become ±7.8% if 85% of patients are assumed to achieve the initial target SBP 
range. The precision will be assessed at the end of each cohort and sample size 
for the next cohort may be adjusted. 


clevidipine 
 Clinical Study Protocol MDCO-CLV-12-01 
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Approximately 10-20 patients per pediatric age group are considered adequate to 
assess the PK/PD model, based on prior clinical experience in adults. Statistical 
analyses will be performed using the following patient populations: 
Safety population: all patients who are dosed with clevidipine. This will 
be the primary population used for the safety analyses. 
Intent-to-Treat (ITT) population: all patients who have received 
clevidipine therapy, and have baseline and at least one post-baseline SBP 
measurements. This will be the primary population used for the efficacy 
analyses. 
PK/PD population: all patients who are dosed with clevidipine and have 
at least one documented and evaluable blood concentration and/or SBP 
observation and documented dose records. Descriptive statistics and 
graphic display will be used to summarize the data collected in the case 
report form for overall and by cohort. Continuous variables will be 
summarized using mean, standard deviation, median, inter-quartile range, 
minimum and maximum. Categorical variables will be summarized using 
frequency and percentage. Time to event variables will be displayed using 
the Kaplan-Meier curve. The dose response relationship will be analyzed 
overall and by cohort.  P-values and/or two-tailed 95% confidence 
intervals will be provided whenever appropriate to demonstrate the 
strength of the findings.  


clevidipine 
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TABLE OF CONTENTS 
1. 
INTRODUCTION................................................................................................................... 16 
1.1. 
Background ............................................................................................................ 16 
1.2. 
Clevidipine (Cleviprex®) ........................................................................................ 18 
1.2.1. 
Preclinical Studies ................................................................................... 18 
1.2.2. 
Clinical Studies ........................................................................................ 19 
1.2.3. 
Known and Potential Risks and Benefits................................................. 21 
1.3. 
Study Rationale ...................................................................................................... 21 
1.4. 
Dose Rationale ....................................................................................................... 22 
1.5. 
Study Population ................................................................................................... 22 
2. 
TRIAL OBJECTIVES AND PURPOSE ................................................................................ 23 
2.1. 
Primary Objectives ................................................................................................ 23 
2.2. 
Secondary Objectives ........................................................................................... 23 
2.3. 
Exploratory Objectives .......................................................................................... 23 
3. 
TRIAL DESIGN ..................................................................................................................... 24 
3.1. 
Type/Design of Trial .............................................................................................. 24 
3.2. 
Schematic Diagram of Trial Design ..................................................................... 27 
3.3. 
Primary Endpoint(s) .............................................................................................. 28 
3.4. 
Secondary Endpoint(s) ......................................................................................... 28 
3.5. 
Exploratory Endpoint ............................................................................................ 29 
3.6. 
Data Safety Monitoring Board .............................................................................. 29 
3.7. 
Measures to Minimize/Avoid Bias ........................................................................ 29 
3.7.1. 
Unblinded Study ...................................................................................... 29 
4. 
SUBJECT POPULATION ..................................................................................................... 30 
4.1. 
Number of Patients ................................................................................................ 30 
4.2. 
Inclusion Criteria ................................................................................................... 30 
4.3. 
Exclusion Criteria .................................................................................................. 30 
4.4. 
Withdrawal Criteria ................................................................................................ 31 
4.4.1. 
Withdrawal from Study Medication .......................................................... 32 
4.4.2. 
Withdrawal from Trial ............................................................................... 32 
5. 
TREATMENT OF PATIENTS ............................................................................................... 33 
5.1. 
Study Medication ................................................................................................... 33 
5.1.1. 
Clevidipine ............................................................................................... 33 
5.1.2. 
Packaging and Labeling .......................................................................... 34 
5.1.3. 
Storage .................................................................................................... 34 
5.1.4. 
Accountability .......................................................................................... 34 


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5.2. 
Concomitant Medications ..................................................................................... 35 
5.2.1. 
Required Concomitant Medication(s) ...................................................... 35 
5.2.2. 
Prohibited Concomitant Medications ....................................................... 35 
5.2.3. 
Permitted Concomitant Medication(s) ..................................................... 35 
6. 
SCHEDULE AND SEQUENCE OF PROCEDURES ............................................................ 36 
6.1. 
Schedule of Events/Assessments ....................................................................... 38 
6.2. 
General Conduct of the Trial ................................................................................ 40 
6.3. 
Screening Period (Days -7 to 0) ............................................................................ 40 
6.4. 
Enrollment .............................................................................................................. 41 
6.5. 
Treatment Period ................................................................................................... 41 
6.5.1. 
Initial Dosing Phase, 0-1.5 minutes ......................................................... 41 
6.5.2. 
Dose Titration and Maintenance Phase, >1.5 minutes up to 96 hours ... 42 
6.5.3. 
Transition and Termination Phase, Transition to Oral to Study Drug 
Termination .............................................................................................. 45 
6.5.4. 
Follow-Up Period ..................................................................................... 46 
7. 
PROTOCOL ASSESSMENTS ............................................................................................. 48 
7.1. 
Assessment of Safety ........................................................................................... 48 
7.1.1. 
Adverse Events ....................................................................................... 48 
7.2. 
Assessment of Efficacy ........................................................................................ 48 
7.2.1. 
Blood Pressure ........................................................................................ 48 
7.2.1.1. 
Screening Period ................................................................. 48 
7.2.1.2. 
Screening Period immediately prior to study drug administration
 ............................................................................................. 48 
7.2.1.3. 
Initial Dosing Phase 0-1.5 minutes ...................................... 49 
7.2.1.4. 
Titration and Maintenance Phase 1.5–30 minutes and >30 
minutes up to 96 hours ........................................................ 49 
7.2.1.5. 
Transition and Termination Phase ....................................... 49 
7.2.1.6. 
Follow-up Phase 12 hours after first dose ........................... 49 
7.2.2. 
Concomitant Medication .......................................................................... 49 
7.3. 
Assessment of Pharmacodynamics .................................................................... 49 
7.4. 
Assessment of Pharmacokinetics ....................................................................... 49 
7.4.1. 
Blood Sample Collection ......................................................................... 49 
8. 
ADVERSE EVENTS ............................................................................................................. 51 
8.1. 
Definitions .............................................................................................................. 51 
8.1.1. 
Adverse Event ......................................................................................... 51 
8.1.1.1. 
AE severity ........................................................................... 51 
8.1.1.2. 
Study drug causality ............................................................. 51 
8.1.2. 
Serious Adverse Event ............................................................................ 52 
8.1.3. 
Additional Reporting Requirements ......................................................... 53 
8.1.4. 
Reporting Events of Pregnancy ............................................................... 53 
8.1.5. 
Complications of the Disease Under Study ............................................. 54 


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8.2. 
Procedure for NON-SERIOUS Adverse Event Recording .................................. 54 
8.3. 
Procedure for Serious Adverse Event Reporting ............................................... 54 
9. 
DATA COLLECTION ............................................................................................................ 55 
10. 
STATISTICAL PLAN ............................................................................................................ 56 
10.1. 
Sample Size ............................................................................................................ 56 
10.2. 
Definitions .............................................................................................................. 56 
10.2.1. 
Patient Study Population ......................................................................... 56 
10.2.1.1. 
Safety Population ................................................................. 56 
10.2.1.2. 
Intent-to-Treat (ITT) Population ........................................... 56 
10.2.1.3. 
Pharmacokinetics/Pharmacodynamics (PK/PD) Population56 
10.2.2. 
Observational Period ............................................................................... 57 
10.2.3. 
Statistical Periods .................................................................................... 57 
10.3. 
Statistical Analyses ............................................................................................... 57 
10.3.1. 
Demographic and Background Characteristics ....................................... 58 
10.3.2. 
Efficacy Analysis ...................................................................................... 58 
10.3.2.1. 
Primary Efficacy Endpoints .................................................. 58 
10.3.2.2. 
Secondary Efficacy Endpoints ............................................. 58 
10.3.3. 
Safety Analysis ........................................................................................ 59 
10.3.3.1. 
Adverse Events .................................................................... 59 
10.3.3.2. 
Laboratory Tests .................................................................. 60 
10.3.3.3. 
Vital Signs ............................................................................ 60 
10.3.3.4. 
Pharmacokinetic Parameters ............................................... 60 
10.4. 
Interim Analysis ..................................................................................................... 61 
10.5. 
Exploratory Analysis ............................................................................................. 61 
11. 
RECORDS RETENTION ...................................................................................................... 62 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................................... 63 
12.1. 
Monitoring .............................................................................................................. 63 
12.2. 
Auditing .................................................................................................................. 63 
12.3. 
Protocol Deviations ............................................................................................... 63 
13. 
ETHICS AND RESPONSIBILITY ......................................................................................... 65 
13.1. 
Informed Consent .................................................................................................. 65 
13.2. 
Institutional Review Board/Ethics Committee .................................................... 65 
14. 
CONFIDENTIALITY .............................................................................................................. 67 
15. 
INVESTIGATOR AGREEMENT ........................................................................................... 68 
16. 
REFERENCES...................................................................................................................... 69 
 


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 Clinical Study Protocol MDCO-CLV-12-01 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AHF 
acute heart failure 
ALT/SGPT
 alanine aminotransferase/ serum glutamic-pyruvic transaminase 
AST/SGPT       
aspartate aminotransferase/ serum glutamic oxaloacetic transaminase 
AUC 
area under curve 
AUCinf
area under curve of the blood concentration to infinity 
AUClast
area under curve of the blood concentration to the last measurable 
concentration 
BP
 blood pressure 
CH
 controlled hypotension 
Cmax
maximum observed blood concentration 
CL 
total clearance 
CLtot
total clearance 
CRF
case report form% 
CV
coefficient of variation 
DBP
diastolic blood pressure 
DCF
data clarification form 
DSMB
Data Safety Monitoring Board 
EC 
Ethics Committee 
eCRF
electronic case report form 
ECG 
electrocardiogram 
EDC
electronic data capture 
EMA
European Medicines Agency 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HDL 
high density lipoprotein 
HR 
heart rate 
ICH 
International Conference on Harmonization 


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 Clinical Study Protocol MDCO-CLV-12-01 
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Q 
quartile 
SAE 
serious adverse events 
SBP 
systolic blood pressure 
SD 
standard deviation 
SEM 
standard error of mean 
SNP 
sodium nitroprusside 
SVR 
systemic vascular resistance 
t1/2 
half-life 
TBPR 
target blood pressure range 
TEAE 
treatment emergent adverse event 
Tmax 
time to reach Cmaxλzterminal rate  
US 
United States 
VLDL 
very low density lipoprotein 
VSS 
volume distribution at a steady state 
Vz
volume of distribution based in the terminal phase 


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significantly related to increased complications. Basali et al3 reported that patients who 
develop intracranial hemorrhage after craniotomy were more likely to have been 
hypertensive in the intraoperative and early postoperative periods. Therefore, the rationale 
for the treatment of hypertension perioperatively is based on the potential to reduce the risk 
of perioperative mortality and morbidity from both short- and long-term adverse effects.  
Perioperative hypertension in the pediatric patient can be caused by renal failure or 
insufficiency, volume overload, or activation of the sympathetic nervous system. Patients 
with congenital heart disease and intracranial pathology may exhibit a higher likelihood of 
perioperative hypertension, and are more prone to have blood pressure problems with 
potentially more significant adverse outcomes. Once treatable and reversible causes of 
hypertension such as pain, hypercarbia, and hypoxemia are corrected, pharmacologic control 
of BP is indicated. This includes the use of intravenous antihypertensives that reverse the 
sympathetic system’s increase in systemic vascular resistance by producing vasodilation. 
Additionally, controlled hypotension (CH), a deliberate reduction in blood pressure to reduce 
bleeding, transfusion therapy and better visualization of the surgical site, may also be utilized 
during surgery in children. Commonly used agents for both BP control and deliberate 
hypotension in infants and children include sodium nitroprusside (SNP), labetalol, and 
calcium channel antagonists, including nicardipine (NIC). These various pharmacologic 
strategies manifest a number of clinical limitations.  
SNP dilates venous capacitance vessels and decreases preload, causing a decrease in cardiac 
output which predisposes patients to organ ischemia. It is frequently associated with 
tachyphylaxis, reflex tachycardia and, with renal insufficiency or renal failure especially with 
prolonged use, SNP may also cause cyanide toxicity. The potential for excessive hypotension 
and fluctuations in BP necessitate the use of invasive monitoring during administration. 
Labetalol is a mixed alpha and non-specific beta blocker. It has an onset of action of 
approximately 2 to 5 minutes, but also has a long duration of action; estimate from 2 to 4 
hours. Labetalol’s side effects include bradycardia, decreased ventricular function, 
bronchospasm and heart block. Nicardipine (NIC) is a calcium channel blocker with a long 
half-life that makes it difficult to titrate and its BP control action is difficult to reverse.  
The pathophysiology of acute perioperative hypertension and control required during surgery 
require that an antihypertensive agent be arterial-selective, have a rapid onset and offset of 
action, be easy to titrate and have a predictable effect on the reduction of BP [Varon, 20084]. 
Although these above mentioned agents possess some of these characteristics, none possess 
all of them.  
Clevidipine was specifically and intentionally developed to address the limitations of other 
available IV antihypertensive therapies. Clevidipine is a rapidly-acting, vascular-selective, L-
type calcium channel antagonist that lowers arterial blood pressure by reducing systemic 
vascular resistance. Its arterial selectivity allows for BP reduction with no adverse effects on 
heart rate or cardiac output. The quick offset of action is due to rapid metabolism by non-


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specific blood and tissue esterases. Efficacy and safety have been well-documented in the 
adult population setting.  
1.2. 
CLEVIDIPINE (CLEVIPREX®) 
Clevidipine is a rapidly-acting, vascular-selective, L-type calcium channel antagonist that 
lowers arterial blood pressure by reducing systemic vascular resistance. It exerts a selective 
vasodilating action on arteriolar resistance vessels, but has no effect on venous capacitance 
vessels. Due to its fast onset and offset of effect on blood pressure, clevidipine can be easily 
titrated, allowing for effective, ongoing BP management. 
1.2.1. 
Preclinical Studies 
Clevidipine is classified as a short-acting, arterial-selective calcium channel antagonist since 
its primary effect is via inhibition of the calcium current in L-type calcium channels. 
Clevidipine is fifty times less potent in inhibiting myocardial contractility than in causing 
vascular smooth muscle relaxation, thereby illustrating that clevidipine is a vascular-selective 
calcium antagonist. At very high concentrations in vitro, clevidipine is more potent in 
inhibiting myocardial contractility than in depressing the spontaneous rate of depolarization 
in the sinus node or in prolonging atrioventricular conduction. Experiments in anesthetized 
dogs show that clevidipine reduces mean arterial pressure (MAP) due to a reduction in SVR, 
and that it does not exert any negative effects on cardiac contractility or conduction in the 
doses tolerated. Clevidipine causes a reflexogenic increase in heart rate in conscious rats and 
dogs but does not affect heart rate in anesthetized animals.  
Clevidipine is rapidly hydrolyzed to its inactive metabolite in blood and extravascular tissues 
in the rat and dog. In experiments with rats, dogs and rabbits, clevidipine demonstrated a 
very short half-life, and reached steady-state blood concentrations within minutes after the 
start of infusion.  
The general pharmacological studies of clevidipine have illustrated that it has a 
natriuretic/diuretic effect when given in a dose that only marginally lowers BP. This effect is 
similar to that of other dihydropyridines. At doses well above the therapeutic level, 
clevidipine inhibits gastrointestinal transport, which is also a characteristic of other calcium 
antagonists. Clevidipine is devoid of direct effects within the autonomic and central nervous 
systems and it does not interfere with neuromuscular transmission or skeletal muscle 
function. Clevidipine has no adverse pharmacological effects on respiratory, liver, or 
endocrine function or on bleeding time. It does not change body temperature.  
In the animal toxicity studies, most findings could be attributed to the lipid content in the test 
formulation. The few effects related to exposure of clevidipine included small biochemical 
differences and organ weight deviations and a slight local irritative vascular effect. Most of 
these findings were related to the dose and/or duration of treatment and satisfactory safety 


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margins have been established. Study results indicate no clinically relevant risks of 
genotoxicity. 
Further details on the preclinical studies with clevidipine are provided in the Investigator’s 
Brochure [Clevidipine Investigator’s Brochure, 20131]. 
1.2.2. 
Clinical Studies 
The clinical development program was comprised of 22 completed clinical studies (4 Phase I, 
10 Phase II, and 8 Phase III studies) [Clevidipine Investigator’s Brochure, 20131]. These 
studies included over 2400 patients overall, of whom 1522 were clevidipine-treated healthy 
subjects or hypertensive patients including the following:  
Four Phase I studies were conducted in 99 healthy volunteers to provide pharmacokinetic 
(PK), pharmacodynamic (PD), and safety/tolerability data. One of these studies, a QT/QTc 
study in 46 healthy volunteers was performed to establish the cardiac electrocardiogram 
(ECG) safety of clevidipine, and to provide further data documenting the tolerability and 
safety of a high therapeutic dose maintained continuously for approximately 24 hours.  
Nine Phase II studies were conducted to obtain preliminary data on the effectiveness of 
clevidipine in 423 patients with hypertension treated in the setting of medical management (3 
studies, 95 patients) or cardiac surgery (6 studies, 337 patients). One of these studies (TMC-
CLV-06-01) was conducted in 61 medical patients with mild to moderate essential 
hypertension to investigate the PK/PD effects and safety of clevidipine during prolonged 
(≥72 hours) continuous infusion. Clinical safety and efficacy data were sufficient to permit 
the design of adequate and well-controlled Phase III studies.  
An additional Phase II study, SPRINT (TMC-CLV-08-02) was completed post FDA 
marketing approval. This was an open-label, single-arm study that evaluated three different 
bolus doses of clevidipine (0.125 mg, 0.25 mg and 0.5 mg), in a total of 30 patients with 
hypertension undergoing elective cardiopulmonary bypass surgery. The study showed that 
clevidipine administered as an IV bolus was effective at rapidly reducing SBP in this 
population of cardiac surgery patients, with evidence of tolerability and a safety profile 
consistent with previous experience in other clinical settings. 
Eight Phase III trials were conducted in a total of 1985 medical, surgical, neurocritical care 
and acute heart failure patients, 1078 of whom received clevidipine. All studies evaluated the 
overall benefit-risk relationship of clevidipine as follows:  
• High-risk surgical patients (N=1720) with perioperative hypertension associated with 
cardiac surgery were treated with clevidipine (N=866), placebo (N=100), or the active 
comparators nitroglycerin (NTG), sodium nitroprusside (SNP), or nicardipine (NIC) 
(total comparator patients N=754) [ESCAPE-1 (TMC-CLV-03-01) and ESCAPE-2 
(TMC-CLV-03-02); ECLIPSE-NTG (TMC-CLV-03-03), ECLIPSE-SNP (TMC-CLV-


clevidipine 
 Clinical Study Protocol MDCO-CLV-12-01 
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  Release date: 11 December 2013 
03-04), and ECLIPSE-NIC (TMC-CLV-03-05)], all of which were submitted as part of 
the FDA New Drug Application (NDA) submission. 
• High-risk medical patients with severe hypertension requiring BP lowering, most with 
evidence of end-organ dysfunction, presenting to the emergency department were 
treated with clevidipine (N=126) titrated to BP effect followed by at least 18 hours of 
continuous infusion in the VELOCITY trial (TMC-CLV-06-02).  
• High-risk intracranial hemorrhage neurocritical care patients presenting to either the 
emergency department or neuro intensive care unit (ICU) with severe hypertension 
(N=35), and a subset of the total patients with intracranial pressure monitoring (N=7), 
were treated with clevidipine titrated to BP effect in the ACCELERATE trial (TMC-
CLV-07-02). 
• High-risk acute heart failure (AHF) patients presenting to the emergency department 
with severe hypertension and dyspnea (N=85) were treated with clevidipine titrated to 
BP effect in the PRONTO trial (TMC-CLV-08-01). 
The clinical development program included mild-, moderate- and high-risk patient 
populations with respect to demographics, risk variables, and comorbidities. The duration of 
exposure to clevidipine is reflective of clinical practice in the management of patients with 
hypertensive urgencies/emergencies and perioperative hypertension. Patients enrolled in the 
program had high-risk features such as advanced age and comorbidities including myocardial 
ischemia due to coronary artery disease, heart failure, renal and hepatic dysfunction, 
peripheral vascular disease, chronic hypertension and diabetes.  
The PK characteristics of clevidipine and the relationship between PK and PD have been 
studied. The findings demonstrate consistency of PK and PD behavior that is independent of 
infusion duration. Clevidipine has a direct effect and the rapid clearance determines ease and 
predictability of titration to desired effect as well as facilitates transition to oral therapy. No 
specific precautions are necessary with respect to patients with renal or hepatic impairment 
due to the route of metabolism. 
The efficacy of clevidipine has been consistently established in all studies across all 
hypertensive patient populations. Rapid BP lowering effects were observed and a high 
success rate was achieved in titration to the desired BP targets. The appropriateness of the 
recommended dose range (2 mg/h up to 32 mg/h) is supported by the current prescribing 
information [Cleviprex Prescribing Information, December 08, 20118].  
Safety and tolerability has been examined in a large database of high-risk patients with 
multiple comorbidities and end-organ injuries. The safety of the starting dose was confirmed. 
The feasibility of safe use in the emergency room environment was established, in which 
clevidipine was administered by peripheral venous infusion with monitoring of effect by 
sphygmomanometer. No new issues were identified with respect to the incidence of 


clevidipine 
 Clinical Study Protocol MDCO-CLV-12-01 
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Page 21 
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important clinical outcomes and adverse events (AEs). Subgroup analyses demonstrated 
consistent findings with the overall population analyses.  
Evidence from the Phase III safety program in cardiac surgery patients with perioperative 
hypertension demonstrated an improvement in BP control achieved in patients managed with 
clevidipine compared to two agents commonly used in that setting (NTG and SNP). The 
additional post-hoc finding of an association between BP control and 30-day mortality 
suggests that a parenteral agent providing rapid and tight BP control may improve patient 
outcomes.  
Further details of the clinical studies with clevidipine are provided in the Investigator’s 
Brochure [Clevidipine Investigator’s Brochure, 20131]. 
1.2.3. 
Known and Potential Risks and Benefits 
The lipid formulation of clevidipine has been well tolerated in all clinical studies to date. 
However, if strict aseptic precautions are not followed in the preparation and administration 
of clevidipine, accidental microbial contamination of the vial may occur. Septicemia may 
occur due to microbial growth within the vial contents followed by IV administration. This 
potential risk is mitigated by adherence with the recommended dosing and administration 
guidance provided to all investigators involved in the study.  
Clevidipine contains approximately 0.2 g of lipid per mL (2.0 kcal/8.4 kJ). Lipid intake 
restrictions may be necessary for patients with significant disorders of lipid metabolism. For 
these patients, a reduction in the quantity of concurrently administered lipids may be 
necessary to compensate for the amount of lipid infused as part of the clevidipine 
formulation. Clevidipine is contraindicated in patients with defective lipid metabolism e.g., 
pathologic hyperlipemia, lipid nephrosis and acute pancreatitis if it is accompanied by 
hyperlipidemia. As part of monitoring of this clinical trial, blood chemistry for hepatic and 
pancreatic function will be performed to minimize these risks. 
The most common adverse drug reactions (>2%) for clevidipine observed in patients were 
headache, nausea and vomiting [Cleviprex Prescribing Information, December 08, 20118]. 
1.3. 
STUDY RATIONALE 
Three previously conducted small case series in the perioperative setting have demonstrated 
the effectiveness and safety of clevidipine in the pediatric population aged 11 months to less 
than 18 years of age. These case series included infants and children undergoing surgery for 
repair of congenital heart disease and adolescents requiring controlled hypotension to 
minimize bleeding during spinal surgery. No significant adverse events during treatment 
were observed [Tobias et al6].  
Given these favorable preliminary benefits and considering the limitations of other available 
IV antihypertensive, this study will sequentially determine the dosing including PK/PD, 


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clevidipine 
 Clinical Study Protocol MDCO-CLV-12-01 
Confidential 
Page 23 
The Medicines Company MDCO-CLV-12-01: Version 3 
  Release date: 11 December 2013 
2. 
TRIAL OBJECTIVES AND PURPOSE 
2.1. 
PRIMARY OBJECTIVES  
To evaluate the dosing, efficacy and safety of an intravenous (IV) infusion of clevidipine for 
blood pressure (BP) management in pediatric patients in the perioperative setting. 
This will be accomplished by assessment of the median time and dose to attain a prespecified 
target SBP range during the first 30 minutes of clevidipine infusion, the percentage of 
patients achieving the prespecified range during the first 30 minutes of clevidipine infusion, 
as well as the pharmacokinetic variables established by sparse population methodology and 
pharmacodynamic variables. Safety will be assessed according to clinical laboratory 
parameters. Adverse events and serious adverse events (SAEs) will be assessed from time of 
consent through 7 days following termination of the study drug infusion. 
2.2. 
SECONDARY OBJECTIVES 
To evaluate additional efficacy, safety and dosing parameters associated with IV infusion of 
clevidipine for BP management in pediatric patients in the perioperative setting. 
Additional assessments will include the percentage change in SBP from baseline at each time 
point during the first 30 minutes following initiation of clevidipine infusion.  
Evaluation of efficacy after the initial 30 minute infusion period will include the percent 
change from baseline in SBP at each hour after the first 30 minutes of clevidipine infusion up 
to the cessation of infusion and the percentage of patients in whom the SBP is within target 
range at each hour after the first 30 minutes of clevidipine infusion.  
Safety data will include: 
• 
The percentage of patients who reach the initial prespecified target SBP range without 
falling below the lower limit of the prespecified target range during the first 30 
minutes of clevidipine infusion 
• 
The percentage of patients in whom the SBP falls below the lower limit of the 
prespecified target range at any time during the first 30 minutes and at any time 
during the entire study drug treatment period 
• 
The percent change from baseline in heart rate during the first 30 minutes of 
clevidipine infusion and during the rest of the treatment period; and  
• 
The percentage of patients who require rescue therapy at any time during study drug 
treatment period 
2.3. 
EXPLORATORY OBJECTIVES 
Efficacy will be evaluated in the subgroups of patients with and without pre-existing 
hypertension. Additional analyses may be performed for efficacy and/or safety when 
applicable. 


clevidipine 
 Clinical Study Protocol MDCO-CLV-12-01 
Confidential 
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3. 
TRIAL DESIGN 
3.1. 
TYPE/DESIGN OF TRIAL 
This study is a Phase IV open-label trial in pediatric patients undergoing elective surgery 
requiring anesthesia ≥1 hour and for whom parenteral IV antihypertensive therapy for BP 
management is expected for at least 30 minutes. Approximately 80-100 patients are planned 
to be enrolled in a stepwise process at 2 centers within 24 months from initiation of the study. 
Patients will be screened between 0 and 7 days before their scheduled surgical procedure. 
Written informed consent by parent or legal guardian and verbal assent by the patient as per 
institutional policy must be provided prior to initiating any study related procedures. All 
eligible patients meeting all inclusion and none of the exclusion criteria will be enrolled to 
receive clevidipine.  
This study will evaluate the dosing, efficacy and safety of clevidipine in 80 pediatric patients 
presenting for surgery and anticipated to require BP management with parenteral IV 
antihypertensive therapy during the surgical procedure.  
Patients will be enrolled in a stepwise approach, starting with the adolescent cohort. An 
interim analysis of safety and dosing of the adolescent cohort will be performed before the 
initiation of remaining cohorts.  
• 
Cohort 1: 20 adolescent patients (12 to less than 18 years). 
• 
Cohort 2: 20 children (2 to less than 12 years, including 10 patients in each age group 
6 to less than 12 years and 2 to less than 6 years). 
• 
Cohort 3: 20 infants and toddlers (28 days to less than 24 months). 
• 
Cohort 4: 20 preterm and newborn infants (0 to less than 28 days). 
A Data Safety Monitoring Board (DSMB) will be set up to monitor the safety and dosing on 
an ongoing basis for all cohorts. Following completion of the adolescent cohort, the DSMB 
will review the safety data and make any safety recommendations according to the DSMB 
Charter to the Sponsor prior to enrolling the remaining cohorts in a sequential order. The 
DSMB review of each completed cohort will be required before proceeding to the subsequent 
cohort to determine if it is appropriate to proceed with enrollment of subsequent cohorts and 
whether an adjustment in dosing scheme is required.  
It is anticipated that there will be 10-20 enrolled patients per pediatric age group whose 
PK/PD parameters will be measured during the first 24-hour period. Up to 10 blood samples 
within the infusion window of 24 hours are planned for PK analysis, with samples taken prior 
to and shortly after infusion start, at least 4-5 samples taken during the infusion period, and 4 
samples taken shortly following termination of infusion.  
Multiple, timed BP measurements are required to be taken prior to and following PK sample 
collection. Accurate and well-timed BP readings will also be necessary to capture the 


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clevidipine 
 Clinical Study Protocol MDCO-CLV-12-01 
Confidential 
Page 26 
The Medicines Company MDCO-CLV-12-01: Version 3 
  Release date: 11 December 2013 
After the first 30-minute treatment period, it may be necessary to alter the desired SBP target 
range over the course of the remaining treatment period. Any changes in the target range will 
be captured in the eCRF.  
Patients who receive alternative intravenous rescue therapy after the first 30 minutes of 
clevidipine may continue in the study. If transition from clevidipine to an oral 
antihypertensive agent is required, the clevidipine infusion may be down-titrated or 
terminated as appropriate to maintain the desired blood pressure. If the BP rises to an 
undesirable level upon cessation of clevidipine infusion, additional therapy may be 
administered or clevidipine infusion may be restarted (and continue until successful 
transition to an oral therapy has been achieved). For patients who receive prolonged 
clevidipine infusions and are not transitioned to other antihypertensive therapies should be 
monitored for the possibility of rebound hypertension for at least 8 hours after the infusion is 
stopped [Cleviprex Prescribing Information, December 08, 20118].  
If treatment with an IV antihypertensive agent is still required after 96 hours of clevidipine 
therapy, the patient will be transitioned to an alternative IV antihypertensive agent according 
to the institutional standard of care. Rescue therapy with IV antihypertensive treatment 
according to the standard of care will be determined by the investigator.  
A DSMB will be set up to monitor the safety and dosing on an ongoing basis for all cohorts.  
The DSMB will review the safety and dosing data from each cohort and make safety and 
dosing recommendations to the Sponsor according to the DSMB Charter prior to enrolling 
the remaining cohorts in sequential order. DSMB review of each completed cohort will be 
required before proceeding to the subsequent cohort. 
In addition, an analysis to assess adequate precision of the efficacy findings will be 
performed at the end of each cohort to ensure that sample size for the following cohort is 
sufficient.  
 
 


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3.3. 
PRIMARY ENDPOINT(S) 
The primary endpoint(s) of this trial are:  
• Median time and dose to attain the initial prespecified target SBP range (minimum of 
20 mmHg and a maximum of 40 mmHg apart) during the first 30 minutes of 
clevidipine infusion 
• Percentage of patients achieving the initial prespecified target SBP range during the 
first 30 minutes of clevidipine infusion 
• Pharmacokinetic variables (half-life, area under the curve [AUC], volume of 
distribution, clearance) established by sparse population methodology 
• Pharmacodynamic variables (relationship between change from baseline in SBP vs. 
blood concentration and infusion rate) 
• Safety of a prolonged infusion of clevidipine (up to 96 hours) assessed according to 
clinical laboratory parameters, adverse events and serious adverse events (SAEs) will 
be assessed from time of consent through 7 days following termination of study drug 
infusion 
3.4. 
SECONDARY ENDPOINT(S)  
The secondary endpoints of this trial are: 
 The percentage of patients who reach the initial prespecified target SBP range without 
falling below the lower limit of the prespecified target range during the first 30 
minutes of clevidipine infusion 
 The percentage of patients in whom the SBP falls below the lower limit of the 
prespecified target range at any time during the first 30 minutes and at any time 
during the entire study drug treatment period 
 Percentage change in SBP from baseline at each time point during the 30 minutes of 
clevidipine infusion 
 Percent change from baseline in SBP at each hour after the first 30 minutes of 
clevidipine infusion up to the cessation of infusion 
 The percentage of patients in whom the SBP is within target range at each hour after 
the first 30 minute of clevidipine infusion 
 Percent change from baseline in heart rate during the first 30 minutes of clevidipine 
infusion and the rest of the treatment period 
 Percentage of patients who require rescue therapy (i.e., receive any alternative IV 
antihypertensive drug) at any time during study drug treatment period, or 
discontinuation due to adverse events 


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 
Percent change from baseline in SBP over the first 12 hours post study drug 
termination 
3.5. 
EXPLORATORY ENDPOINT  
Subgroup analysis of efficacy in patients with and without pre-existing hypertension. 
Additional analyses may be performed for efficacy and/or safety when applicable. 
3.6. 
DATA SAFETY MONITORING BOARD 
The safety information in clinical studies has demonstrated the safety of clevidipine in adults. 
A DSMB will monitor the safety and dosing on an ongoing basis for all patients. Following 
completion of each cohort, the DSMB will review the data and make safety 
recommendations according to the DSMB Charter to the Sponsor prior to enrolling the 
remaining cohorts in sequential order. DSMB review of each completed cohort will be 
required before proceeding to the subsequent cohort. The Sponsor will monitor the starting 
dose and titration schedule for each cohort. Details regarding data evaluation and process will 
be provided in the DSMB Charter. 
3.7. 
MEASURES TO MINIMIZE/AVOID BIAS 
3.7.1. 
Unblinded Study  
This is an open label, single arm study. The primary endpoints are based on assessment of 
SBP and laboratory blood samples, which are measurements not likely to be subject to 
interpretation bias.  


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4. 
SUBJECT POPULATION 
4.1. 
NUMBER OF PATIENTS  
Approximately 80 pediatric patients scheduled for a surgical procedure who receive a 
minimum of 1 hour of anesthesia and are anticipated to require antihypertensive therapy to 
control BP will be studied at 2 centers located in the United States. It is anticipated that 80-
100 patients (up to 20% overage) may need to be enrolled to achieve this goal. 
4.2. 
INCLUSION CRITERIA 
Patients may be included in the study if they meet all of the following criteria: 
1. Patient must be less than 18 years 
2. Written informed consent  obtained before initiation of any study-related procedures 
3. The enrolling physician determines that patient will likely require a 15% reduction in 
BP during the perioperative course 
4. Intra-arterial line available for blood pressure monitoring 
5. Surgical procedure requiring at minimum 1 hour of anesthesia, in which IV 
antihypertensive therapy to control BP for at least 30 minutes is anticipated 
4.3. 
EXCLUSION CRITERIA 
Patients will be excluded if they present with any of the following exclusion criteria: 
1. Administration of an IV or oral antihypertensive agent within 2 hours prior to study 
drug administration 
2. Congenital heart disease described as single ventricle  
3. Evidence of liver failure, severe liver disease, pulmonary disease (e.g., uncontrolled 
asthma), hyperlipidemia, lipoid nephrosis, lipid dysfunction or acute pancreatitis 
4. Allergy to soya bean oil or egg lecithin 
5. Known to be intolerant to calcium channel blockers 
6. Hemophilia or blood coagulation disorders 
7. Any serious medical condition which, in the opinion of the investigator, is likely to 
interfere with study procedures  
8. Clinically significant abnormal physical findings at the screening evaluation 
9. Any serious surgical or medical condition which, in the opinion of the investigator, is 
likely to interfere with study procedures or with the pharmacokinetics or 
pharmacodynamics of the study drug 
10. Patient is terminally ill (death likely to occur within 48 hours) 


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11. Use of methylphenidate, calcium channel blockers, aripiprazole and other atypical 
anti-psychotics and antihypertensive used for BP control within 2 hours prior to study 
drug initiation 
12. Positive serum or urine pregnancy test for any female of childbearing potential 
13. Participation in other clinical research studies involving the evaluation of other 
investigational drugs or devices within 30 days of enrollment 
14. Patients who, for any reason, are deemed by the investigator to be inappropriate for 
this study  
15. Patient is a relative of the investigator or his/her deputy, research assistant, 
pharmacist, study coordinator, other staff directly involved in the conduct of the study 
Patients excluded for any of the above reasons may be re-screened for participation at any 
time if the exclusion characteristic has changed. 
4.4. 
WITHDRAWAL CRITERIA 
All patients or parent or legal guardian have the right to withdraw the patient at any point 
during treatment without prejudice. The investigator can discontinue any patient at any time 
if medically necessary. It will be documented whether or not each patient completed the 
clinical study. If, for any patient, study treatment or observations were discontinued, the 
reason will be recorded and the Sponsor should be notified promptly. Reasons for which a 
patient may discontinue participation in a clinical study are considered to constitute one of 
the following: 
 Adverse event(AE) 
 Death 
 Patient or parent or legal guardian withdrew consent 
 Physician decision 
 Lost to follow-up 
 Protocol violation  
 Administrative problems  
It is imperative to obtain complete follow-up data for all patients whether or not they receive 
their assigned treatment or have discontinued study drug. Every attempt should be made to 
collect follow-up information except for those patients who specifically withdraw consent to 
release of such information. All procedures and laboratory specimens or tests requested for 
evaluation following administration of the study drug should be carried out when possible, 
whether or not a patient continues to receive treatment according the protocol. Patients will 
not be replaced in this trial. 


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4.4.1. 
Withdrawal from Study Medication 
 
The following data will be collected within 1 hour (+ 30 minutes) after the end of study drug 
infusion, provided the patient or parent or legal guardian did not withdraw the right for the 
Sponsor to use the patient’s data: 
• Physical examination 
• Vital signs 
• Serum chemistry including serum creatinine, triglycerides, lipase, total cholesterol, 
HDL, LDL, VLDL, ALT/SGPT, AST/SGOT, total bilirubin, lactate dehydrogenase, 
blood urea nitrogen, sodium, potassium, calcium, and magnesium  
• AEs / SAEs  
• Concomitant medications including oral and/or IV antihypertensive administration  
• PK blood sample 
In addition, any PK samples collected will be analyzed. The patient should continue to be 
followed through the follow-up phase of the study. 
4.4.2. 
Withdrawal from Trial 
 
If a study patient or parent or legal guardian withdraws informed consent or assent for the 
trial or is withdrawn from the trial by the investigator for any reason after termination of drug 
prior to discharge, an attempt should be made to collect the following safety information: 
 Physical examination 
 AEs/ SAEs 
 Concomitant medications including oral and/or IV antihypertensive administration 
Patients who are withdrawn during study drug IV infusion (treatment phase) should follow 
Section 4.4.1 above. 


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5. 
TREATMENT OF PATIENTS 
5.1. 
STUDY MEDICATION 
Clevidipine is being studied for the management of BP in pediatric patients less than 18 years 
of age through preterm and newborn infants undergoing an elective surgery requiring ≥ 1 
hour of anesthesia. 
Clevidipine injectable emulsion (hereafter referred to as clevidipine emulsion) is a single use 
parenteral product that contains a phospholipid emulsion. Clevidipine emulsion may be 
administered via peripheral vein or by central venous infusion employing a volumetric pump. 
The vial containing clevidipine emulsion should be gently inverted several times before use 
to ensure uniformity of the emulsion prior to connecting to the IV tubing. The infusion must 
be administered via a single dedicated line separate from any other medications. However, 
strict aseptic technique should always be used when administering clevidipine emulsion to 
reduce the risk of nosocomial infection. Consistent with the clinical development program to 
date, once the stopper is punctured, a vial must be used within 12 hours and any unused 
portion, including that which is currently being infused, should be discarded.  
5.1.1. 
Clevidipine  
Clevidipine is a dihydropyridine L-type calcium channel blocker developed for the reduction 
of blood pressure (BP) when rapid and predictable control is desired.  
Clevidipine emulsion is intended for intravenous (IV) administration by infusion. Due to the 
rapidity with which clevidipine reduces BP, the dosage and rate of the clevidipine infusion is 
titrated to desired clinical effect.  
Clevidipine is metabolized by hydrolysis in blood and tissues by non-specific carboxyl 
esterases to an inactive compound, which in turn is further, metabolized (mainly by 
glucuronidation) and excreted via the kidneys (~70%). No intact clevidipine is excreted. 
Thus, the metabolic degradation of clevidipine differs from that of other dihydropyridines, 
which are mainly metabolized by the cytochrome P450 system in the liver. 
The high clearance and small volume of distribution result in very short half-lives for 
clevidipine. The half-lives of the two initial rapid phases that account for approximately 95% 
of the area under the curve (AUC) for blood concentration versus time after an IV bolus 
dose, ranged between 0.6 and 0.8 minutes and 2.2 and 2.3 minutes, respectively. The area 
under the terminal phase (half-life = 16–22 minutes) corresponded to between 3.3% and 
5.7% of the total AUC after an IV bolus.  
There is a linear relationship between dose rate and steady state blood concentration of 
clevidipine. The onset of effect is rapid after the start of a clevidipine infusion and the time 
required establishing steady state concentration and effect following an initial infusion or a 
change in administration rate is only 2 to 3 minutes. If the drug is discontinued, recovery of 
effect and return to baseline blood concentrations is rapid. In healthy volunteers, patients 


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with essential hypertension (with or without β-blockade) and post-cardiac surgery patients, 
more than a 50% recovery of effect (mean arterial pressure [MAP]) is achieved within 10 
minutes following termination of the infusion.  
Clevidipine reduces arterial BP dose-dependently by reduction of SVR. Clevidipine has no 
effect on central venous pressure. Stroke volume increases primarily as a result of afterload 
reduction with maintained cardiac preload. In post-cardiac surgical patients, a reflexogenic 
increase in heart rate (HR), typical of other antihypertensive therapies, has not been seen with 
clevidipine infusion. Cardiac output is maintained or improved.  
5.1.2. 
Packaging and Labeling  
The Medicines Company, Parsippany, NJ, USA will supply clevidipine emulsion to each 
investigative site packaged in boxes containing four single-use glass vials. Medication labels 
will comply with regulatory requirements. The storage conditions for the medication 
provided will be described on the medication label. 
5.1.3. 
Storage 
Clevidipine emulsion must be stored refrigerated in a secure enclosure at 2-8°C and should 
not be frozen, as specified in the Pharmacy Manual. Access should be strictly limited to the 
pharmacists and their designees or by investigators or designated study personnel if located 
outside of the pharmacy. Neither the pharmacists, investigators nor any designees may 
provide clevidipine to any subject not participating in this protocol and enrolled after full 
subject eligibility has been confirmed. Clevidipine emulsion will be stored in a secure cabinet 
in the Pharmacy or other hospital approved location under the appropriate conditions as 
specified in the Pharmacy Manual. 
5.1.4. 
Accountability 
The investigator or designee must maintain an inventory record of all vials of clevidipine 
emulsion received and all vials administered to assure the regulatory authorities and the 
Sponsor that the investigational drug labeled for use in the pediatric study will not be 
dispensed to any person who is not a patient under the terms and conditions set forth in this 
protocol. Drug accountability forms and/or specific instructions can be found in the 
Pharmacy Manual. 
The clevidipine emulsion supplied for use in this study is to be prescribed only by the 
principal investigator or designated sub-investigators and may not be used for any purpose 
other than that outlined in this protocol. 
During this study, all used (e.g., empty vials) and unused study drug containers will be kept 
until the study monitor has reviewed the drug accountability records. 
Upon study drug inventory and review of the accountability records by the monitor at the end 
of the study, unused clevidipine emulsion will be destroyed onsite based on their drug 


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destruction policy OR returned to the packaging and labeling facility for destruction. In the 
event that clevidipine emulsion needs to be returned for any other reason, the site will receive 
a written request listing the drug lot number(s) to be returned and the reason for the return 
request. 
5.2. 
CONCOMITANT MEDICATIONS 
5.2.1. 
Required Concomitant Medication(s) 
There are no required concomitant medications for this study. Concomitant medications, 
including anesthetic agents used as part of standard of care, will be recorded in the eCRF per 
the Schedule of Assessments (Section 6.1). 
 
5.2.2. 
Prohibited Concomitant Medications 
The following medications are prohibited and should not be administered to the patient 
within 2 hours prior to receiving treatment with clevidipine: 
1. Methylphenidate 
2. Aripiprazole and other atypical anti-psychotics  
3. Calcium channel blockers  
4. All other antihypertensive agents used for BP control 
This is a study of an IV antihypertensive agent in a pediatric surgical population. Use of non-
study drug medications and treatment procedures that affect the BP are discouraged during 
study drug administration, especially during the initial 30-minute period of study drug 
treatment. It is anticipated that an alternative antihypertensive agent(s) as rescue therapy will 
only be used if the study drug does not adequately lower BP. If a rescue therapy is used, it 
must be recorded in the eCRF, and the reason for such use must be documented. 
 
5.2.3. 
Permitted Concomitant Medication(s)  
1. Oral contraceptives will be permitted during the study for females of child-bearing 
potential 
2. Beta-adrenergic blockers used specifically for reflex tachycardia 
3. Ace inhibitors for volume overload 


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6. 
SCHEDULE AND SEQUENCE OF PROCEDURES 
The Schedule of Assessments (Section 6.1 and Table 1) summarizes the study tests and 
procedures by time point. This study is comprised of three consecutive periods: a screening 
period, a treatment period, and a follow up period. The maximum duration of a patient’s 
participation on study is approximately 18 days (screening up to 7 days, study drug 
administration up to 4 days and follow-up to 7 days). 
The screening period begins from the time patients are consented for elective surgery to 
immediately prior to administration of study drug. The screening period consists of obtaining 
informed consent, confirming patient eligibility and collecting baseline assessments. During 
this period, a medical history (including all medications taken) and a physical examination 
(including height, length and weight) will be performed. Laboratory assessments (Section 
6.3) including a pregnancy test for girls of childbearing potential will be performed. HR and 
BP measurements will be performed. With the exception of the pregnancy test, results of the 
laboratory tests are not required prior to administering study drug.  
Prior to study drug administration, HR and BP measurements will be recorded. These will 
serve as the baseline HR and BP. Once a patient is deemed eligible a prespecified SBP target 
range must be identified prior to initiation of study drug treatment and recorded in the 
patient’s medical record. The target range will later be entered into the eCRF. 
The study drug infusion will commence following: 
• Establishment of stable anesthetic condition (minimal change in anesthetic drug 
concentration and dose) 
• Observation of stable vital signs following skin incision 
The treatment period occurs from initiation of study drug up to 96 hours. This period is split 
into 3 phases for study drug administration. Initial dosing phase from 0 to 1.5 minutes; 
maintenance phase from > 1.5 to 30 minutes up to 96 hours and study drug transition phase 
defined as the transition and/or cessation of infusion.  
BP and HR will be measured and PK samples will be obtained throughout this period. 
Multiple, timed BP measurements are required to be taken prior to and following PK sample 
collection. Accurate and well-timed BP readings will also be necessary to capture the 
patient’s response to infusion rate adjustments during the first 30 minute period and through 
study drug termination.  To accommodate the frequency and precision required for this, 
physiologic blood pressure monitoring will be carried out using a peripheral arterial line, to 
allow for real-time heart rate and BP sampling while obtaining PK samples throughout the 
course of study drug titration and through the follow-up period. It is essential that the clock 
time of infusion pump devices, blood pressure monitors and clocks used to record the time of 
the PK sample be synchronized.  


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Serum chemistry (Sections 6.1 and 6.3) will be assessed. Concomitant medications, AEs and 
SAEs will be monitored throughout the study period and concludes on day 7 in the follow-up 
period. If appropriate, patients will be transitioned to oral therapy one hour prior to 
termination of clevidipine (Section 6.5.3). 
The follow-up period is divided into these time points following study drug termination: 1 
hour follow-up, 12 hour follow-up, 24 hour follow-up and 7 day follow-up. The 1 hour time 
point starts from discontinuation of study drug until 1 hour (+ 30 minutes) post study drug 
termination. During this period, concomitant medications, serum chemistry, BP, HR and PK 
samples (PK Samples 7, 8, 9, 10 – Table 1) will be obtained and AE and SAEs will continue 
to be monitored and recorded. During the 12 hour time point (+ 30 minutes) period BP, 
concomitant medications, AEs and SAEs will continue to be monitored and recorded. During 
the 24 hour (+ 30 minutes) time point period, concomitant medications, AE and SAEs will be 
monitored and recorded. The 7 day (+1 day) follow-up time point period occurs on day 7 (+1 
day) post study drug termination. The 7 days follow-up will occur by phone (if applicable) to 
monitor and record AE and SAEs.


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6.1. 
SCHEDULE OF EVENTS/ASSESSMENTS  
 
 
Study assessment 
 
Screening 
Period 
0 to -7 Days 
(prior to study 
drug initiation) 
Treatment Period 
Follow-up Period  
Post Study Drug Termination 
(up to 7 days after final dose) 
Treatment  
Phase 1  
Initial Dosing  
 0 -1.5 
minutes 
 
Treatment 
Phase 2 
 Titration & Maintenance 
Phase 
>1.5 to 30 minutes & >30 
minutes up to 96 hours 
Treatment  
Phase 3 
Transition & 
Termination 
Phase 
 
Follow-up 
1 Hour 
(+ 30 minutes) 
Follow-up 
12 Hour 
(+ 30 minutes) 
 
Follow-up 
24 Hour 
 (+ 30 minutes) 
 
Follow-up 
7 Day10 
(+ 1 day) 
Informed consent 
X1 
 
 
 
 
 
 
 
Medical history & Physical exam 
X2 
 
 
 
 
 
 
 
Height & Weight 
X2 
 
 
 
 
 
 
 
Prior Medications 
X2 
 
 
 
 
 
 
 
BP (SBP, DBP) /HR 
  X2, 3 
X3 
   X 4,5 
  X 4,5 
X6 
X6 
 
 
Pregnancy test 
X2 
 
 
 
 
 
 
 
Hematology (Section 6.3) 
X2 
 
 
 
 
 
 
 
Serum chemistry every 24 hours (Section 6.3) 
X2 
 
X 
 
X11 
 
 
 
SBP Target Range 
X2 
 
X9 
 
 
 
 
 
Enrollment via IVRS/IWRS 
X2 
 
 
 
 
 
 
 
Study drug administration 
 
X7 
X7 
X7 
 
 
 
 
PK sampling 
X3, 8 
   X3, 8 
X8 
X8 
X8 
 
 
 
Concomitant Medications 
 
        X 
                  X 
         X 
         X 
X 
X 
 
Oral Antihypertensive Administration 
 
 
 
         X 
 
 
 
 
AE and SAE reporting  
              X12 
 
1 Written informed consent from parent or legal guardian and verbal assent (as per institutional policy) before initiation of any study-related procedures.  
2 Assessment(s) must be performed prior to treatment to determine eligibility for enrollment into the study.  
3 BP (SBP, DBP) and HR are measured using an intra-arterial catheter with electronic transducer. PK Sample1 is to be taken up to 30 minutes prior to start of clevidipine infusion with BP and HR measured, immediately 
followed by PK Sample 1 collection.  Baseline BP and HR are recorded at 60 sec, 45 sec, 30 sec, and 0 sec prior to initiation of clevidipine. PK Sample 2 is taken at 1.5 minutes after the start of clevidipine infusion (before 
first dose titration) with BP and HR measured, immediately followed by PK Sample 2 collection.  The actual time of BP, HR and PK sample must be recorded using devices that are time synchronized. 
4  BP and HR will be recorded every 1.5 minutes (+ 30 second window where a PK sample is required) for a period of at least 30 minutes, every 10 minutes for the next hour, every 30 minutes for the next 2 hours and every 
1 hour until study drug is terminated (up to 96 hours). BP and HR will also be recorded immediately before each PK blood draw (Table 1) is obtained. 
5  If a dose adjustment is indicated, BP and HR should be recorded just prior to each study drug dose change as well as every 1.5 minutes for 15 minutes after the dose adjustment, then return to the BP assessment 
schedule just prior to the dose adjustment.  


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6  BP and HR will be recorded every 1 hour until study drug has been stopped for 12 hours post-study drug termination.  
7  Clevidipine administered as a continuous IV infusion. 
8  Blood samples for PK analysis will be obtained from an arterial line per the time intervals included in Table 1 below (1 before clevidipine infusion; 4-5 during clevidipine infusion; 4 post clevidipine infusion). NOTE: BP and 
HR will be recorded immediately  before each PK blood draw. The actual time of BP, HR and PK sample must be recorded using devices that are time synchronized.  
9  Beyond the first 30-minute treatment period, it may be necessary to alter the desired SBP target range over the course of the remaining treatment period. Any changes in the target range will be captured in the case report 
form (eCRF). 
10  The 7 day (+1 day) follow-up can occur by phone, if applicable. 
11.  Serum chemistry within 1 (+30 minutes) hour after study drug termination 
12.  AE and SAE reporting will be from time of consent through 7 days day) following termination of study drug infusion.  
 
 
Table 1: PK sampling times 
 
Sample 
Time point 
1 
Up to 30 minutes prior to start of clevidipine infusion 
2 
1.5 minutes post initiation of clevidipine infusion (before first dose titration) 
3 
1.5 minutes after first dose titration (must be performed before proceeding to second dose titration) 
4 
Once target SBP range is reached or 30 minutes after the initiation of clevidipine infusion, whichever 
comes first 
5 
(if applicable) 
If transition to an additional antihypertensive is desired and concurrent administration is needed, a 
sample should be taken right before beginning administration of the additional antihypertensive agent 
6 
Right before termination of the clevidipine infusion 
7 
0.5 minutes post termination of the clevidipine infusion 
8 
3 minutes post termination of the clevidipine infusion 
9 
15 minutes post termination of clevidipine infusion 
10 
 1  hour (+30 minutes) post final termination of the clevidipine infusion 


Clevidipine 
Clinical Study Protocol MDCO-CLV-12-01 
Confidential 
Page 40 
The Medicines Company MDCO-CLV-12-01: Version 3 
Release date 11 December 2013 
6.2. 
GENERAL CONDUCT OF THE TRIAL 
Written informed consent will be obtained for this study by the principal investigator or 
sub-investigator from all patients or parent or legal guardian, with verbal assent obtained 
from children as per Institutional Review Board’s (IRB’s) policy before the performance 
of any protocol-specific procedures. 
Multiple, timed BP measurements are required to be taken prior to PK sample collection. 
Accurate and well-timed BP readings will also be necessary to capture the patient’s 
response to infusion rate adjustments during the first 30 minute period and through study 
drug termination.  To accommodate the frequency and precision required for this, blood 
pressure monitoring will be carried out using a peripheral arterial line, to allow for real-
time heart rate and BP sampling while obtaining PK samples throughout the course of 
study drug titration and through the follow-up period. It is essential that the clock time of 
infusion pump devices, blood pressure monitors and clocks used to record the time of the 
PK sample be synchronized. 
6.3. 
SCREENING PERIOD (DAYS -7 TO 0) 
The approved informed consent form may be signed up to two weeks prior to schedule 
screening procedures.  
The following procedures will be performed within 0 to -7 days prior to enrollment:  
• Informed consent and verbal assent: Written informed consent will be obtained for 
this study by the principal investigator or  sub-investigator from all patients or 
parent or legal guardian, with verbal assent obtained from children as per IRB 
policy before the performance of any protocol-specific procedures are performed. 
• Medical history  
• Physical examination (including height/length and weight)  
• Prior medications  
• A pregnancy test for girls of childbearing potential only  
• Hematology including red blood cells, hemoglobin, hematocrit, white blood cells, 
and platelets 
• Serum chemistry including serum creatinine, triglycerides, lipase, total cholesterol, 
HDL, LDL, VLDL, ALT/SGPT, AST/SGOT, total bilirubin, lactate dehydrogenase, 
blood urea nitrogen, sodium, potassium, calcium, and magnesium  
 
 


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Clevidipine 
Clinical Study Protocol MDCO-CLV-12-01 
Confidential 
Page 43 
The Medicines Company MDCO-CLV-12-01: Version 3 
Release date 11 December 2013 
Clevidipine infusion may be administered continuously for up to a maximum duration of 
96 hours. Clevidipine may also be terminated at any time for safety reasons. If a dose 
adjustment is indicated, BP and HR should be recorded just prior to each study drug dose 
change as well as every 1.5 minutes for 15 minutes after the dose adjustment 
If the desired BP control effect is not attained using the maximum dose of clevidipine, 
rescue therapy with the use of an alternative IV antihypertensive agent should be 
implemented. Patients who receive rescue therapy along with clevidipine may continue in 
the study. The alternative agent should be chosen per the institutional practice. The use of 
an alternative IV antihypertensive agent is discouraged and should be limited to situations 
where it is medically necessary to maintain patient safety as determined by the principal 
investigator.   
If an additional/alternative IV antihypertensive agent is required, the clevidipine infusion 
may be down-titrated or terminated after initiation of the antihypertensive infusion in 
order to achieve the desired blood pressure level. If a patient is receiving rescue therapy 
with an IV antihypertensive treatment and transition to an oral antihypertensive agent is 
required, institutional practice must be followed. An alternative/additional IV 
antihypertensive agent that is administered as ‘rescue therapy’ will be recorded as rescue 
therapy in the eCRF. The following assessments will be performed during the titration 
and maintenance phase:  
1.5 Minutes – 30 Minutes Post Study Drug Initiation 
• PK Sample 3:  obtain 1.5 minutes after the first dose titration of study drug (taken in 
the order below) 
 BP and HR 
 PK Sample 3 (Table 1), taken immediately following BP and HR 
measurements 
• Then, every 1.5 minutes for the remaining first 30 minutes post-study drug 
initiation: 
 BP and HR 
• PK Sample 4:  obtain once target range is achieved, or at 30 minutes if target range 
is not achieved (taken in the order below): 
 BP and HR 
 PK Sample 4 (Table 1), taken immediately following BP and HR 
measurements 
 BP and HR, taken every 1.5 minutes for the remaining first 30 minutes post-
study drug initiation, as instructed above. 


Clevidipine 
Clinical Study Protocol MDCO-CLV-12-01 
Confidential 
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The Medicines Company MDCO-CLV-12-01: Version 3 
Release date 11 December 2013 
• PK Sample 5:  only taken if transition to an additional antihypertensive is desired 
and concurrent administration is needed prior to the end of the first 30 minutes 
(taken in the order below) 
 BP and HR 
 PK Sample 5 (as applicable): taken immediately after BP and HR and before 
beginning administration of an additional antihypertensive agent  
 BP and HR, taken every 1.5 minutes, as instructed above, for the remaining 
first 30 minutes post-study drug initiation if the PK Sample 5 is obtained prior 
to the end of the first 30 minute period. 
Note:  The actual time of the BP, HR and PK sample should be recorded.  The clocks 
used for these measurements should be synchronized (e.g., when the clock on the BP and 
HR devices reads 13:01, the clock used to record the PK sample should also read 13:01). 
30 Minutes (and up to 96 hours) Post-Study Drug Initiation 
 BP and HR 
- every 10 minutes for the next 1 hour  
- every 30 minutes for the next 2 hours  
- once every hour until study drug is terminated (up to 96 hours) 
- If a dose adjustment is indicated, BP and HR should be recorded just prior 
to each study drug dose change as well as every 1.5 minutes for 15 
minutes after the dose adjustment.  
 PK Sample 5:  only taken if transition to an additional antihypertensive is desired 
and concurrent administration at any time >30 minutes and up to 96 hours (taken 
in the order below) 
- BP and HR 
- PK Sample 5 (as applicable): taken immediately after BP and HR and 
before beginning administration of an additional antihypertensive agent  
- BP and HR, taken  as instructed above 
- BP and HR – to continue as instructed above 
 Serum chemistry (Section 6.3) every 24 hours (+ 1 hour) from initiation of study 
drug infusion (up to 96 hours) or at the termination of study drug infusion if study 
drug is administered for less than the 24 hours  
 Concomitant medications 
 AE(s) and SAE(s)  


Clevidipine 
Clinical Study Protocol MDCO-CLV-12-01 
Confidential 
Page 45 
The Medicines Company MDCO-CLV-12-01: Version 3 
Release date 11 December 2013 
Note:  The actual time of the BP, HR and PK sample should be recorded.  The clocks 
used for these measurements should be synchronized (e.g., when the clock on the BP and 
HR devices reads 13:01, the clock used to record the PK sample should also read 13:01). 
All assessments above (except PK) should be performed again if clevidipine is 
restarted for any reason. 
6.5.3. 
Transition and Termination Phase, Transition to Oral to 
Study Drug Termination  
For transition to oral therapy, approximately 1 hour prior to the anticipated cessation of 
clevidipine infusion, the oral antihypertensive agent may be administered. At any time 
following administration of the oral antihypertensive agent, the clevidipine continuous IV 
infusion may be down-titrated or terminated in order to achieve the desired blood 
pressure level.  
If treatment with an IV antihypertensive agent is still required after 96 hours of 
clevidipine therapy, the patient may be transitioned to an alternative IV antihypertensive 
agent according to the institutional standard of care. 
If an additional/alternative IV antihypertensive agent is required, the clevidipine infusion 
may be down-titrated or terminated after initiation of the antihypertensive infusion in 
order to achieve the desired blood pressure level. An alternative/additional IV 
antihypertensive agent that is administered as ‘rescue therapy’ will be recorded as rescue 
therapy in the eCRF.  
A PK sample will be taken just prior to discontinuation of study drug. Immediately 
before study drug termination, BP and HR will be measured, immediately followed by 
PK Sample 6, which will be taken from the indwelling arterial line within a 30 second 
window after BP and HR are obtained. 
The following assessments will be performed during transition phase:  
 BP and HR  
- at least every hour until study drug is terminated (up to 96 hours) 
 PK Sample 5:  only taken if transition to an additional antihypertensive is desired 
and concurrent administration at any time >30 minutes and up to 96 hours (taken 
in the order below) 
- BP and HR 
- PK Sample 5 (as applicable): taken immediately after BP and HR and 
before beginning administration of an additional antihypertensive agent  
- BP and HR, taken  as instructed above 


Clevidipine 
Clinical Study Protocol MDCO-CLV-12-01 
Confidential 
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The Medicines Company MDCO-CLV-12-01: Version 3 
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- PK Sample 6:  obtain immediately prior to study drug termination (taken in the 
order below) 
- BP and HR 
- PK Sample 6, taken immediately after BP and HR  
- BP and HR – to continue, as instructed above, every hour until study drug 
is terminated 
 Serum chemistry (Section 6.3) every 24 hours (+ 1 hour) during study drug 
administration (up to 96 hours).  
 Concomitant medications 
 AE(s) and SAE(s) 
Note:  The actual time of the BP, HR and PK sample should be recorded.  The clocks 
used for these measurements should be synchronized (e.g., when the clock on the BP and 
HR devices reads 13:01, the clock used to record the PK sample should also read 13:01). 
6.5.4. 
Follow-Up Period 
The follow-up period is divided into these time points following study drug termination: 
The 1 hour time point is from study drug termination to 1 hour (+ 30 minutes) post study 
drug termination. The 12 hour,  24 hour and 7 day time points occur from 12 hours (+ 30 
minutes), 24 hours (+ 30 minutes) and 7 days (+/- 1 day) post study drug termination, 
respectively. During this phase of the study, 4 PK samples will be taken: PK Sample 7 
taken 0.5 minutes post study drug termination, PK Sample 8 taken at 3 minutes post 
study drug termination, PK Sample 9 taken at 15 minutes post study drug termination and 
PK Sample 10 taken 1 hour post study drug initiation.  For all samples, BP and HR will 
be measured immediately followed by the PK blood draw, which will be taken from the 
indwelling arterial line within a 30 second window after BP and HR are obtained. 
The following assessments will be performed during the Follow-up Period:  
 BP and HR  
o measured at least every 15 min. until study drug has been stopped for 60 
min. then at least every hour until study drug has been stopped for 12 
hours post study drug termination  
 PK Samples 7, 8, 9, 10:  taken at 0.5 min. (PK Sample 7), 3 mins (PK Sample 8), 
15 min (PK Sample 9) and 1  hours (+ 30 minutes) (PK Sample 10) post study 
drug termination (taken in the order below) 
o BP and HR 
o PK Sample 


Clevidipine 
Clinical Study Protocol MDCO-CLV-12-01 
Confidential 
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The Medicines Company MDCO-CLV-12-01: Version 3 
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o BP and HR – to continue at least every 15 min. until study drug has been 
stopped for 60 min. then at least every hour until study drug has been 
stopped for 12 hours post study drug termination, as instructed above  
 Serum chemistry (Section 6.3) within 1 hour (+ 30 minutes) of termination of 
study drug.  
 Concomitant medications through 24 hours post study drug termination (update if 
ongoing medications through day 7) 
 AEs and SAEs through 24 hours post study drug termination (update if ongoing 
AEs through day 7 [+1 day]) 
Note:  The actual time of the BP, HR and PK sample should be recorded.  The clocks 
used for these measurements should be synchronized (e.g., when the clock on the BP and 
HR devices reads 13:01, the clock used to record the PK sample should also read 13:01). 
Participation in the study is complete after day 7 follow-up visit is completed; all ongoing 
SAEs have been followed to resolution. 


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Clinical Study Protocol MDCO-CLV-12-01 
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7. 
PROTOCOL ASSESSMENTS 
7.1. 
ASSESSMENT OF SAFETY  
7.1.1. 
Adverse Events 
All patients with adverse events (AEs) will be carefully monitored for AE by the 
investigator during the entire study. All AEs and SAE information and the treatment 
provided during the study must be documented in source and will be captured in the 
electronic Case Report Form (eCRF). 
All AEs and SAEs will be assessed and documented from time of consent through 7 days 
post study drug termination. 
Those events that are serious in nature must be reported to The Medicines Company in an 
expedited manner (Section 8 for definitions and reporting requirements). 
Patients experiencing adverse events should be followed clinically until their health has 
returned to baseline status or until all parameters have returned to normal or have 
otherwise been explained. It is expected that the investigator will provide or arrange 
appropriate supportive care for the patient if necessary. 
The AEs will be assessed and reported as detailed in Section 8. The investigator is 
responsible for evaluation and documentation of each AE or SAE occurring during the 
study. The investigator will inform the Sponsor about all AEs, independent of their 
relationship with the study medication. AEs being reported by the patient as well as 
laboratory findings outside normal ranges (e.g., serum chemistry, hematology, urinalysis) 
or other examination results deviating from normal values (e.g., blood pressure, pulse, 
12-lead ECG, etc.), which are considered as clinically relevant by the investigator, must 
be reported to the principal investigator.  
7.2. 
ASSESSMENT OF EFFICACY  
7.2.1. 
Blood Pressure 
7.2.1.1. 
Screening Period 
Screening period is 0-7 days prior to surgery and BP (SBP, diastolic blood pressure  
[DBP]) measured using an intra-arterial catheter with electronic transducer. BP and other 
hemodynamic measurements will be obtained as specified in this protocol. 
7.2.1.2. 
Screening Period immediately prior to study drug 
administration 
BP (SBP, DBP) will be recorded at 60 sec, 45 sec, 30 sec, and 0 sec prior to study drug 
initiation. These BP measurements (SBP, DBP) will serve as the basis for determining 
target SBP range before the start of study drug. 


Clevidipine 
Clinical Study Protocol MDCO-CLV-12-01 
Confidential 
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The Medicines Company MDCO-CLV-12-01: Version 3 
Release date 11 December 2013 
7.2.1.3. 
Initial Dosing Phase 0-1.5 minutes 
BP will be measured at 1.5 minutes post initiation of study drug and prior to the PK 
sample draw. 
7.2.1.4. 
Titration and Maintenance Phase 1.5–30 minutes 
and >30 minutes up to 96 hours 
BP will be measured every 1.5 minutes for a period of 30 minutes and prior to each PK 
sample draw.  
BP will be measured every 10 minutes for the next 1 hour, then every 30 minutes for the 
next 2 hours, at least every 1 hour until the study drug is terminated (up to 96 hours) and 
prior to each PK sample draw. 
If a dose adjustment is indicated, BP and HR should be recorded just prior to each study 
drug dose change as well as every 1.5 minutes for 15 minutes after the dose adjustment.  
7.2.1.5. 
Transition and Termination Phase 
BP will be measured every 1 hour until study drug is terminated (96 hour maximum 
duration of study drug). 
7.2.1.6. 
Follow-up Phase 12 hours after first dose 
BP will be measured at least every 15 minutes until study drug has been stopped for 60 
mins, and then at least every hour until study drug has been stopped for 12 hours. 
7.2.2. 
Concomitant Medication 
The objective of monitoring concomitant medications to control BP is to determine the 
efficacy of clevidipine as monotherapy. 
7.3. 
ASSESSMENT OF PHARMACODYNAMICS  
BP will be measured at the time points specified in Section 7.2.1. Pharmacodynamic 
variables (the changes from baseline in SBP and its relationship with blood concentration 
of clevidipine and infusion rate) will be assessed. 
7.4. 
ASSESSMENT OF PHARMACOKINETICS  
7.4.1. 
Blood Sample Collection 
Blood samples for determination of the blood concentrations of clevidipine and its 
inactive carboxylic acid metabolite M1 (H152/81) will be obtained from an intra-arterial 
catheter distant from the drug administration site, within 30 minutes before initiating 
clevidipine infusion; at 1.5 min post initiation of infusion before dose titration; right 
before the 2nd dose titration; once target BP is reached or at 30 minutes after the initial 
start of clevidipine infusion, whichever comes first; right before transitioning to another 
antihypertensive agent (if applicable); and at a time point just before the infusion 


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8. 
ADVERSE EVENTS  
8.1. 
DEFINITIONS 
8.1.1. 
Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or 
clinical investigation subject administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom or 
disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
Planned hospital admissions and/or surgical operations for an illness or disease that 
existed before the drug was given or the subject was randomized in a clinical study are 
not to be considered AEs. 
Patients experiencing adverse events should be followed clinically until their health has 
returned to baseline status or until all parameters have returned to normal or have 
otherwise been explained. It is expected that the investigator will provide or arrange 
appropriate supportive care for the subject if necessary. 
8.1.1.1. 
AE severity 
The severity of an AE and the relationship to study drug will be assessed by the 
investigator. The investigator should ensure that any subject experiencing an AE receives 
appropriate medical support until the event resolves. 
Adverse events (AE) will be graded on a 3-point scale and reported as indicated on the 
case report form. The intensity of an AE is defined as follows: 
1 = Mild:  Discomfort noticed, but no disruption to daily activity. 
2 = Moderate:  Discomfort sufficient to reduce or affect normal daily activity. 
3 = Severe:  Inability to work or perform normal daily activity. 
8.1.1.2. 
Study drug causality 
The relationship of an AE to study treatment will be assessed with consideration to the 
following criteria: 
 Temporal relationship to the initiation of study medication 
 Response of the event to withdrawal of study medication 
 AE profile of concomitant therapies 
 Clinical circumstances during which the AE occurred 
 Patient’s clinical condition and medical history  


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Categorization* of causality will be designated by the investigator as stated below: 
1. Unrelated - A clinical event, including laboratory test abnormality, reported as an 
adverse reaction, which lacks a reasonable time sequence between study drug 
administration and the occurrence of the event(s) or for which medical history, 
concomitant medications or other drugs provide a more likely explanation. 
Response to withdrawal of the study drug should not support a relationship 
between the study drug and the event. 
2. Unlikely related - A clinical event, including laboratory test abnormality, with a 
temporal relationship to study drug administration which makes a causal 
relationship improbable, and in which other drugs, chemicals or underlying 
disease provide plausible explanations. 
3. Possibly related - A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the study drug, which may possibly 
be attributed to concurrent disease or other drugs or chemicals, and which follows 
a clinically reasonable response on withdrawal (de-challenge). Information on 
study drug withdrawal may be lacking or unclear. Re-challenge information is not 
required to fulfill this definition. 
4. Definitely related - A clinical event, including laboratory test abnormality, 
occurring in a plausible time relationship to study drug administration, and which 
cannot be explained by concurrent disease or other drugs or chemicals. The 
response to withdrawal of the study drug (de-challenge) should be clinically 
plausible. The event must be clinically definitive using a satisfactory re-challenge 
procedure if deemed necessary. 
* For the purposes of regulatory reporting, categories ‘3’ and ‘4’ will be considered 
“related.” 
8.1.2. 
Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
 Results in death, 
 Is life-threatening, i.e., the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred (it does not include an 
event that, had it occurred in a more severe form, might have caused death), 
 Results in a significant, persistent or permanent change, impairment, damage or 
disruption in the subject's body function/structure, physical activities and/or 
quality of life, 
 Requires in-subject hospitalization or prolongs hospitalization, 


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 Is a congenital anomaly/birth defect, or 
 Is another medically significant event that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above (e.g., allergic 
bronchospasm requiring intensive treatment in an emergency department or 
home, blood dyscrasias or convulsions that do not result in hospitalization, or 
the development of drug dependency or drug abuse). 
A distinction should be drawn between serious and severe AEs. Severity is an estimate or 
measure of the intensity of an AE, while the criteria for serious AEs are indications of 
adverse subject outcomes for regulatory reporting purposes. A severe AE need not 
necessarily be considered serious and a serious AE need not be considered severe. For 
example, nausea that persists for several hours may be considered severe nausea, but not 
an SAE. On the other hand, a myocardial infarction that may be considered minor could 
also be an SAE if it prolonged hospitalization. 
When death occurs, the cause of death must be reported as an SAE. “Fatal” will be 
reported as the outcome for these events. 
8.1.3. 
Additional Reporting Requirements 
Occurrences of events of overdose, drug misuse and drug abuse are considered 
“important medical events” that should also be reported within 24 hours using 
appropriate reporting form. These events should be reported regardless of their 
association with other adverse events or serious adverse events. 
• 
Abuse of a medicinal product: Persistent or sporadic, intentional excessive use of 
medicinal products which is accompanied by harmful physical or psychological 
effects [DIR 2001/83/EC Art 1(16)]. 
• 
Misuse: Intentional and inappropriate use of a medicinal product not in 
accordance with the prescribed or authorized dose, route of administration, and/or 
the indication(s) or not within the legal status of its supply (e.g., without 
prescription for medicinal products subject to medical prescription). 
• 
Overdose: Administration of a quantity of a medicinal product given per 
administration or per day which is above the maximum recommended dose 
according to the reference safety information for the investigational product or 
comparator as applicable. This also takes into account cumulative effects due to 
overdose.  
8.1.4. 
Reporting Events of Pregnancy 
Occurrences of pregnancy in a study subject or study subject’s partner should also be 
reported within 24 hours using the Pregnancy Reporting Form. In cases where a 


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pregnancy occurs with a Serious Adverse Event, the SAE Report Form should be used to 
report the SAE and the Pregnancy Reporting Form should be used to report the 
pregnancy. When a pregnancy occurs without any intercurrent SAE, the Pregnancy 
Reporting Form may be submitted alone. The pregnancy must be followed through to 
conclusion. Any pregnancy discovered from the time of consent to follow-up need to be 
reported. 
8.1.5. 
Complications of the Disease Under Study 
Certain symptoms are considered typical outcomes of pediatric surgery and thus are 
expected side effects in pediatric surgery. Clinical events that are considered standard 
post-operative occurrences will be reported as AEs if they are considered untoward or 
unfavorable. In cases where the event is not considered as untoward or unfavorable it 
must be recorded as such in the source document. Consistency in reporting adverse 
events from all participating sites will be ensured through appropriate training and 
monitoring and investigators will be required to report all untoward or unfavorable events 
as adverse events based on their clinical judgment. 
8.2. 
PROCEDURE FOR NON-SERIOUS ADVERSE EVENT RECORDING 
All non-serious AEs that occur from the time of signing informed consent through 7 days 
post study drug termination must be recorded on the source documents and eCRF 
provided by the Sponsor, regardless of causal relationship to study drug. 
8.3. 
PROCEDURE FOR SERIOUS ADVERSE EVENT REPORTING 
All SAEs that occur from consent up to 7 days following study drug termination must be 
reported to The Medicines Company (MDCO) within 24 hours of awareness of the event 
using the provided study specific SAE Report Form. The completion and processing of 
the SAE Report Form (paper or electronic) should be per the instructions in the provided 
SAE Report Form completion guidelines.  In addition to completing the SAE Report 
Form, each SAE must be entered on the appropriate page of the CRF.   
The investigator must assess the causality for each SAE. 
MDCO will contact the investigator, if necessary, to clarify any of the event information. 
The investigator should provide any follow-up information for the event to MDCO as 
soon as it becomes available. 
If the investigator is notified of a SAE that occurs post-study period, that he or she wishes 
to report to the Sponsor (e.g., an event suspected to be causally related to study drug), the 
event should be reported through the process described above.  
Where appropriate, if required by local regulations or procedures, the investigator should 
report these events to the Institutional Review Board (IRB)/Ethics Committee (EC) 
and/or national regulatory authority. 


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9. 
DATA COLLECTION 
An electronic data capture (EDC) system will be used for this trial. All users will be 
trained on the technical features of the EDC as well as the content of the electronic case 
report form (eCRF) by qualified personnel prior to gaining access to the EDC. A 
UserID/Password will be granted after training. This ID is not to be shared amongst the 
study staff. All users must have a unique account to enter or review data. The eCRF 
should be filled out by the site within 5 days after completion of the 24 hour assessment. 
It is not expected that the eCRF will serve as source for any data collected in the trial. If 
there is a reason for a site to do so, it must be approved by the Sponsor and documented 
in the site files. 
Prior to the database being locked, the investigator or designee will review, approve and 
electronically sign/date each completed eCRF. This signature serves as attestation of the 
Investigator’s responsibility for ensuring that all data entered into the eCRF are complete, 
accurate and authentic. After the end of the trial, a copy of the data will be provided to 
the site. This copy will contain the final data, an audit trail of activity on the data, and any 
queries and answers that were posted for data clarification. 


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10. 
STATISTICAL PLAN 
This study is a Phase IV, open-label trial in pediatric patients undergoing an elective 
surgery requiring anesthesia ≥ 1 hour and for whom parenteral IV antihypertensive 
therapy for BP management is expected. Approximately 80-100 patients of 4 cohorts are 
planned to be enrolled at 2 centers from initiation of the project to ensure 80 patients for 
efficacy evaluation. The primary objective of this study is to evaluate the efficacy, safety 
and dosing of an IV infusion of clevidipine for BP management in pediatric patients in 
the perioperative setting. 
A separate Statistical Analysis Plan document will provide more detailed specifications 
in data analysis and presentation. 
10.1. 
SAMPLE SIZE 
The total sample size of 80 (20 per cohort) evaluable patients is considered primarily 
based on clinical judgment to provide adequate precisions of the findings for this non-
comparative study. For example, assuming that 90% of patients will achieve the initial 
target SBP range within the first 30 minutes of infusion, a sample size of 80 patients can 
provide a 95% confidence interval with a precision of ±6.6%. This precision will become 
±7.8% if 85% of patients are assumed to achieve the initial target SBP range. The 
precision will be assessed at the end of each cohort and sample size for the next cohort 
may be adjusted.  
10.2. 
 DEFINITIONS 
10.2.1. 
Patient Study Population 
The following populations will be used for data analyses and/or presentation. 
10.2.1.1. Safety Population  
All patients who received any dose of clevidipine. This will be the primary population 
used for the safety analyses. 
10.2.1.2. Intent-to-Treat (ITT) Population 
All patients who have received clevidipine therapy and have baseline and at least one 
post-baseline SBP measurements. This will be the primary population used for the 
efficacy analyses. 
10.2.1.3. Pharmacokinetics/Pharmacodynamics 
(PK/PD) Population 
All patients who are dosed with clevidipine and have at least one documented and 
evaluable blood concentration and/or SBP observation and documented dose records. 
This will be the primary population for PK/PD analyses.  


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10.2.2. 
Observational Period 
The observational period for the study will be from the initiation of the study medication 
to 7 days following termination of the study drug. Adverse events and SAEs are to be 
reported from time of signing informed consent up to 7 days following termination of the 
study drug infusion. Any event occurring after the defined observational period, even if 
collected in the eCRF, will not be included in the planned statistical analysis. However, 
all data, including that reported before and after the defined observational period, will be 
included in the data listings. 
10.2.3. 
 Statistical Periods 
The study will occur in three consecutive periods: a screening period, a treatment period, 
and a follow-up period. The Screening Period is 0 to 7 days prior to the initiation of study 
drug (IV clevidipine treatment).  
The Treatment Period occurs from initiation of study drug administration up to 96 hours. 
This period can be split into 3 phases for study drug administration. Initial dosing phase 
from 0 to 1.5 minutes; titration and maintenance phase from >1.5 to 30 minutes and >30 
minutes to 96 hours; transition and termination phase from end of study drug infusion to 
12 hour follow-up.  
The Follow-up Period is divided into 4 time points. The 1 hour time point (+ 30 minutes) 
is from discontinuation of study drug until 1 hour post study drug termination. The 12 
hour time point (+ 30 minutes) is from study drug termination through12 hours post study 
drug termination. The 24 hour time point (+ 30 minutes) occurs from 12 hours post study 
drug termination until 24 hours post study drug termination. The 7 day time point (+ 1 
day) is the final time point in the follow-up period, which occurs from 24 hours post 
study drug termination through day 7. 
10.3. 
STATISTICAL ANALYSES 
All study data will be summarized using descriptive statistics, graphs, and/or data 
listings. Descriptive statistics for continuous variables will include but not limited to 
number of patients (n), mean, standard deviation (SD), median, quartiles (Q1 and Q3), 
minimum (min) and maximum (max) values. Analysis of categorical variables will 
include frequency and percentage. Time to event variables will be analyzed using the 
Kaplan-Meier method.  
No confirmatory hypothesis is established in this study; therefore no formal statistical 
hypothesis testing will be performed. However, p- values and/or two-tailed 95% 
confidence intervals may be generated to demonstrate the strength of the findings 
whenever appropriate.  
Unless otherwise specified, missing data will not be imputed and will be excluded from 
the associated analysis. 


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Analyses will be presented for overall and by cohort. 
10.3.1. 
Demographic and Background Characteristics 
Patient demographic and background characteristics (including BP and HR recorded prior 
to the first dose of study drug) will be descriptively summarized. Separate analyses will 
be prepared for the safety, ITT, and PK/PD populations. 
10.3.2. 
Efficacy Analysis 
10.3.2.1. Primary Efficacy Endpoints 
The primary efficacy endpoints of this trial are: 
• Median time and dose to attain the initial prespecified target SBP range 
(minimum of 20 mmHg and a maximum of 40 mmHg apart) during the first 30 
minutes of clevidipine infusion 
• Percentage of patients achieving the initial prespecified target SBP range 
during the first 30 minutes of clevidipine infusion 
Median time is the median of the time in minutes between the initiation of study 
medication and time the patient first achieves the initial prespecified target SBP range 
(TBPR) during the first 30 minutes of clevidipine infusion. The median time will be 
summarized using the Kaplan-Meier method. Median time will be estimated with a two-
tailed 95% confidence interval. If patients do not reach TBPR within 30 minutes from the 
initial treatment with study medication, or another intravenous antihypertensive agent is 
administered, the patient will be considered censored at 30 minutes or the time when 
another intravenous antihypertensive agent is given, whichever comes first. 
The percentage of patients achieving TBPR will be calculated using the number of ITT 
patients achieving the endpoint divided by the total number of ITT patients, and 
multiplied by 100.  
Number and percent of patients achieving TBPR during the first 30 minutes along with 
the calculated 95% confidence interval will be presented.  
Analysis of the infusion rate, total dose infused, and total volume infused at the time of 
first achieving TBPR during the first 30 minutes will be summarized descriptively.  
10.3.2.2. Secondary Efficacy Endpoints 
The secondary efficacy endpoints are:  
• The percentage of patients who reach the initial prespecified target SBP range 
without falling below the lower limit of the prespecified target range during 
the first 30 minutes of clevidipine infusion 


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• The percentage of patients in whom the SBP falls below the lower limit of the 
pre specified target range at any time during the first 30 minutes and at any 
time during the entire study drug treatment period  
• The percentage of patients in whom the SBP is within target range at each 
hour after the first 30 minute of clevidipine infusion 
• The percentage of patients who require rescue therapy (i.e., receive any 
alternative IV antihypertensive drug) at any time during study drug treatment 
period or discontinuation due to adverse events. 
The percentage of patients reaching each endpoint above will be calculated for overall 
and within each cohort using the number of ITT patients achieving the endpoint divided 
by the number of total ITT patients, and multiplied by 100.  
Number and percent of patients achieving each endpoint during the first 30 minutes along 
with the calculated 95% confidence interval will be presented. 
• Percent change in SBP from baseline at each time point during the 30 
minutes of clevidipine infusion 
• Percent change from baseline in SBP at each hour after the first 30 minutes 
of clevidipine infusion up to the cessation of infusion 
• Percent change from baseline in SBP over the first 12 hours post study drug 
termination 
• Percent change from baseline in heart rate during the first 30 minutes of 
clevidipine infusion and the rest of the treatment period 
Percent change from baseline at each time point specified in above endpoints will be 
calculated for each ITT patient. 
Descriptive statistics will be presented for overall and by cohort. 
10.3.3. 
Safety Analysis 
Safety of a prolonged infusion of clevidipine (up to 96 hours) will be assessed according 
to clinical laboratory parameters. Adverse events and serious adverse events (SAEs) will 
be assessed through 7 days following the termination of the study drug infusion. 
10.3.3.1. Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA)  will be used for coding 
adverse events (AEs). An AE (classified as preferred term) occurring during the 
treatment period will be counted as a treatment emergent AE (TEAE) either if it is not 
present at baseline or if it is present at baseline but increased in severity during the 
treatment period. 


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The number and percent of patients reporting TEAEs for each preferred term will be 
tabulated by system-organ class, by system-organ class and severity, and by system-
organ class and relationship to study drug. If more than one event occurred with the same 
preferred term for the same patient, the patient will be counted only once for that 
preferred term using the most severe or related occurrence for the summary by severity, 
or relationship to study drug, respectively. 
Listings will be presented for patients with SAEs/AEs leading to a discontinuation or 
death. 
10.3.3.2. Laboratory Tests 
Laboratory values as well as changes and percent changes from baseline at each time 
point will be summarized. Analyses will also be performed for each laboratory parameter 
on incidence rates of potentially clinical significant (PCS) values for patients without 
PCS value at baseline. 
10.3.3.3. Vital Signs 
Change and percent change from baseline in vital signs will be summarized descriptively 
at each scheduled time point. 
10.3.3.4. Pharmacokinetic Parameters  
Blood concentration versus time data will be analyzed using non-compartmental analysis 
and/or Nonlinear Mixed-Effect Modeling (NONMEM). Following pharmacokinetic 
parameters will be estimated: 
• Maximum observed blood concentration (Cmax) 
• Time to reach Cmax (tmax) 
• Area under the curve of the blood concentration to the last measurable 
concentration (AUClast) 
• Area under the curve of the blood concentration to infinity (AUCinf) 
• Terminal rate constant (λz) and its associated half-life (t1/2) 
• Mean residence time (MRT) 
• Total clearance (CL).  
• Volume of distribution at steady state (Vss) 
• Volume of distribution based in the terminal phase (Vz) 
All concentration data will be presented descriptively at each time point. Descriptive 
statistics comprise N, mean, geometric mean, SD, standard error of mean (SEM), median, 
percent coefficient of variation (%CV), minimum and maximum will be presented for the 


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pharmacokinetic variables (half-life, area under the curve [AUC], volume of distribution, 
clearance, etc.) established by sparse population methodology. 
10.4. 
INTERIM ANALYSIS 
Following completion of the adolescent cohort, the DSMB will review the safety data and 
make safety recommendations to the Sponsor according to the DSMB Charter prior to 
enrolling the remaining cohorts in sequential order. DSMB review of each completed 
cohort will be required before proceeding to the subsequent cohort to determine if it is 
appropriate to proceed with enrollment of subsequent cohorts and whether an adjustment 
in dosing scheme is required. 
In addition, an analysis to assess adequate precision of the efficacy findings will be 
performed at the end of each cohort to ensure that sample size for the following cohort is 
sufficient.  
10.5. 
EXPLORATORY ANALYSIS 
Efficacy assessments in patients with and without pre-existing hypertension will be 
performed. Additional analyses may be performed for efficacy and/or safety when 
applicable. 
 


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11. 
RECORDS RETENTION 
FDA regulations require all investigators participating in clinical drug trials to maintain 
detailed clinical data for one of the following periods: 
• 
At least two years following the date on which a New Drug Application is 
approved by the FDA, or 
• 
Two years after the Sponsor notifies the investigator that no further application is 
to be filed with the FDA. 
Similarly, International Conference on Harmonisation (ICH) guidelines require that 
essential documents be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. 
To comply with these requirements, the investigator will not dispose of any records 
relevant to this study without either (1) written permission from the Sponsor or (2) 
providing an opportunity for the Sponsor to collect such records. The investigator shall 
take responsibility for maintaining adequate and accurate hard copy source documents of 
all observations and data generated during this study, including any data clarification 
forms (DCFs) required for the study. Such documentation is subject to inspection by the 
Sponsor or its agents, the FDA and/or other regulatory agencies. 


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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1. 
MONITORING 
The Sponsor has ethical, legal and scientific obligations to carefully follow this study in 
accordance with established research principles and applicable regulations. The 
investigator, as part of his responsibilities, is expected to cooperate with the Sponsor in 
ensuring that the study adheres to the protocol and GCP requirements. 
As part of a concerted effort to fulfill these obligations, the Sponsor's monitor will visit 
the center(s) during the study in accordance with the Monitoring Plan set forth for this 
trial. The investigator will permit the Sponsor to monitor the study as frequently as is 
deemed necessary and provide access to medical records/source documents to ensure that 
data are being recorded adequately, that data are verifiable and that protocol adherence is 
satisfactory. 
12.2. 
AUDITING 
The Sponsor may conduct audits at the study center(s). Audits will include, but not be 
limited to, drug supply, presence of required documents, the informed consent process, 
and comparison of eCRF with source documents. The investigator agrees to permit audits 
conducted at a reasonable time in a reasonable manner. 
Regulatory authorities worldwide may also inspect the investigator during or after the 
study. The investigator should contact the Sponsor immediately upon notification of a 
site audit, and must permit regulatory authority inspections. 
12.3. 
PROTOCOL DEVIATIONS 
This study will be conducted as described in this protocol, except for an emergency 
situation in which the protection, safety, and well-being of the subject requires immediate 
intervention, based on the judgment of the investigator (or a responsible, appropriately 
trained professional designated by the investigator). In the event of a significant deviation 
from the protocol due to an emergency, accident, or mistake, the investigator or designee 
must contact the Sponsor, or their agent, at the earliest possible time by telephone. This 
will allow an early joint decision regarding the subject’s continuation in the study. The 
investigator and the Sponsor will document this decision. The IRB/EC will be informed 
of all protocol changes by the investigator in accordance with the IRB/EC established 
procedure. No deviations from the protocol of any type will be made without complying 
with all the IRB/EC established procedures. 
The following will be classified as Major Protocol Deviations: 
• Treatment of a patient who did not meet all inclusion criteria 
• Treatment of a patient who met one or more exclusion criteria 


Clevidipine 
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• Any study procedure performed either prior to or without written informed consent 
obtained from a patient’s guardian or legally authorized representative and without 
verbal assent performed as per institutional policy  
• Any patient dosed at a rate higher than the protocol-defined starting rate 
• Patient does not receive study drug as monotherapy for first 30 minutes of treatment 
• PK sampling not obtained at their specified time points 


Clevidipine 
Clinical Study Protocol MDCO-CLV-12-01 
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13. 
ETHICS AND RESPONSIBILITY 
This study will be conducted in compliance with the protocol, the Sponsor’s standard 
operating procedures and/or guidelines, the United States Food and Drug Administration 
(FDA) regulations and local regulations, the International Conference on Harmonization 
(ICH) GCP guidelines, the Declaration of Helsinki and other local regulations, as 
applicable. 
13.1. 
INFORMED CONSENT 
Written informed consent will be obtained from all subjects’ parent or legal guardian, and 
whenever possible, verbal assent will be obtained as per IRB or EC guidelines before any 
study-related procedures (including any pre-treatment procedures) are performed. The 
investigator(s) has both ethical and legal responsibility to ensure that each subject’s 
parent or legal guardian, and the child where possible, are being considered for inclusion 
in this study is given a full explanation of the protocol. This shall be documented on a 
written informed consent form, which shall be approved by the same IRB or EC 
responsible for approval of this protocol. Each informed consent form shall include the 
elements required by ICH, Part E6, Section 4.8 and any applicable local regulations. The 
investigator agrees to obtain approval from the Sponsor of any written informed consent 
form used in the study, preferably prior to submission to the IRB or EC.  
Once the appropriate essential information has been provided to the subject and fully 
explained by the investigators (or a qualified designee) and it is felt that the subject 
understands the implications of participating, the subject’s guardian or legally authorized 
representative and the investigator (or designee) shall sign and date the IRB- or EC-
approved written informed consent form. The subject’s parent or legal guardian, and the 
subject whenever possible, shall be given a copy of the signed and dated informed 
consent form, and the original shall be filed appropriately, according to the institution. A 
second copy may be filed in the subject's medical record, if allowed by the institution. 
13.2. 
INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE 
This protocol, the written informed consent form and any materials presented to patients 
shall be submitted to the IRB or EC identified with this responsibility. Notification in 
writing of approval must come from the IRB or EC chairman or secretary, to the 
investigator, either as a letter or as a copy of the appropriate Section of the IRB or EC 
meeting minutes where this protocol and associated informed consent form were 
discussed. The investigator will not participate in the decision. If the investigator is an 
IRB or EC member, the written approval must indicate such non-participation in the 
voting session. The investigator will submit status reports to the IRB or EC as required by 
the governing body. The IRB or EC must be notified by the investigator in writing of the 
interruption and/or completion of the study; the investigator must promptly report to the 
IRB or EC all changes in research (protocol amendments) and will not make such 


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Clinical Study Protocol MDCO-CLV-12-01 
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changes without IRB or EC approval, except where necessary to eliminate apparent 
immediate hazards to human patients. In cases where it is necessary to eliminate 
immediate hazards to patients, the IRB or EC must then be notified of the change as per 
local requirements. The investigator is required to maintain an accurate and complete 
record of all written correspondence to and received from the IRB or EC and must agree 
to share all such documents and reports with the Sponsor. 


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Clinical Study Protocol MDCO-CLV-12-01 
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The Medicines Company MDCO-CLV-12-01: Version 3 
Release date 11 December 2013 
14. 
CONFIDENTIALITY 
All information generated in this study must be considered highly confidential and must 
not be disclosed to any persons not directly concerned with the study without written 
prior permission from the Sponsor. However, authorized regulatory officials and Sponsor 
personnel will be allowed full access to the records. All medications provided and patient 
bodily fluids and/or other materials collected shall be used solely in accordance with this 
protocol, unless otherwise agreed to in writing by the Sponsor. 
Only unique patient numbers in eCRF will identify patients. Their full names may, 
however, be made known to a product regulatory agency or other authorized official if 
necessary. 
With respect to the clinical trial data that is received from countries in the European 
Economic Area and Switzerland, The Sponsor has certified adherence to the United 
States- European Union and the US-Swiss Safe Harbor Principles. 
 


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Release date 11 December 2013 
15. 
INVESTIGATOR AGREEMENT 
I have read and understand the protocol (including the Investigator’s Brochure) and agree 
that it contains all the ethical, legal and scientific information necessary to conduct this 
study. I will personally conduct the study as described. 
I will provide copies of the protocol to all physicians, nurses and other professional 
personnel responsible to me who will participate in the study. I will discuss the protocol 
with them to assure myself that they are sufficiently informed regarding the 
investigational drug clevidipine, the concurrent medications, the efficacy and safety 
parameters and the conduct of the study in general. I am aware that this protocol must be 
approved by the Institutional Review Board (IRB) or Ethics Committee (EC) responsible 
for such matters in the Clinical Study Facility where clevidipine will be tested prior to 
commencement of this study. I agree to adhere strictly to the attached protocol. I 
understand that this IRB or EC approved protocol will be submitted to relevant regulatory 
authorities by the Sponsor, as appropriate. I agree that clinical data entered on case report 
forms by me and my staff will be utilized by the Sponsor in various ways such as for 
submission to governmental regulatory authorities and/or in combination with clinical 
data gathered from other research sites, whenever applicable. I agree to allow Sponsor 
monitors and auditors full access to all medical records/source documents at the research 
facility for patients screened or randomized in the study. 
I agree to provide all patients with informed consent forms, as required by government 
and ICH regulations. I further agree to report to the Sponsor any adverse experiences in 
accordance with the terms of this protocol, ICH guideline, Part E6, Section 4.11 and 
applicable local regulations. 
 
 
 
Principal Investigator (Signature) 
 
Date 
 
Principal Investigator (Printed Name) 
 
 
 
Institution Name 
 
 
 


Clevidipine 
Clinical Study Protocol MDCO-CLV-12-01 
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The Medicines Company MDCO-CLV-12-01: Version 3 
Release date 11 December 2013 
16. 
REFERENCES 
1. Clevidipine Investigator’s Brochure, Edition 11, 02 April 2013 
2. Charlson, M.E., Mackenzie, C.R., Gold, J.P., et al. The Preoperative and 
Intraoperative Hemodynamic Predictors of Postoperative Myocardial Infarction or 
Ischemia in Patients Undergoing Noncardiac Surgery.  Ann. Surg. 1989; 637-648. 
3. Basali, A., Mascha, E.J, Kalfas, I., et al. Relation between Perioperative Hypertension 
and Intracranial Hemorrhage after Craniotomy.  Anesthesiology 2000; 93: 48-54. 
4. Varon J, Marik PE. Perioperative hypertension management. Vasc Health Risk 
Manag 2008; 4: 615-27. 
5. Towe, E. and Tobias, J. D.  Preliminary Experience with Clevidipine in the Pediatric 
Population.  J Intensive Care Med 2010; 25: 349-352. 
6. Tobias, J.D., Schechter, W.S., Phillips, A.  Clevidipine for Perioperative Blood 
Pressure Control in Infants and Children Undergoing Cardiac Surgery for Congenital 
Heart Disease.  J Pediatr Pharmacol Ther 2011 Vol. 16; No. 1: 55-60. 
7. Tobias, J.D. and Hoernschemeyer, D.G.  Clevidipine for Controlled Hypotension 
During Spinal Surgery in Adolescents.  J Neurosurg Anesthesiol 2011 Vol 00; No 00: 
1-5.  
8. Cleviprex Prescribing Information, December 08, 2011 


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SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
Version 0.1 
May 20, 2014 
 
 
Protocol Number: MDCO-CLV-12-01 
Open label study to assess the efficacy, safety and dosing of clevidipine 
in pediatric patients undergoing surgery (PIONEER study)  
NCT01938547


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Clevidipine 
Statistical Analysis Plan MDCO-CLV-12-01 
Confidential 
Page 3 
 
The Medicines Company 
 
Version  0.1, May 20, 2014 
TABLE OF CONTENTS 
Table of Tables ................................................................................................................... 5 
Abbreviations ...................................................................................................................... 6 
1. 
Introduction ................................................................................................................ 8 
1.1. 
Trial Introduction ........................................................................................... 8 
2. 
Objectives ................................................................................................................ 12 
2.1. 
Primary Objective ........................................................................................ 12 
2.2. 
Secondary Objectives ................................................................................... 12 
2.3. 
Exploratory Objectives ................................................................................ 12 
3. 
Study Populations .................................................................................................... 13 
3.1. 
Safety Population ......................................................................................... 13 
3.2. 
Intent-to-Treat (ITT) PopulatioN ................................................................. 13 
3.3. 
Pharmacokinetics/Pharmacodynamics (PK/PD) Population ....................... 13 
4. 
General Statistical Methodology.............................................................................. 14 
5. 
Patient Disposition and Study Completion .............................................................. 15 
6. 
Demographics and Baseline Characteristics ............................................................ 16 
7. 
Protocol Deviation ................................................................................................... 17 
8. 
Extent of Study Drug Exposure ............................................................................... 18 
9. 
Prior and Concomitant Medication .......................................................................... 20 
10. Efficacy Analyses .................................................................................................... 21 
10.1. Primary Efficacy Analysis ........................................................................... 21 
10.2. Secondary Efficacy AnalysIs ....................................................................... 21 
10.3. Other Efficacy Analysis ............................................................................... 24 
11. Safety Analyses ........................................................................................................ 25 
11.1. Adverse Events ............................................................................................ 25 
11.2. Laboratory Parameters ................................................................................. 25 
12. Pharmacokinetic/Pharmacodynamic Analyses ........................................................ 28 
12.1. Primary PK Analysis.................................................................................... 28 


Clevidipine 
Statistical Analysis Plan MDCO-CLV-12-01 
Confidential 
Page 4 
 
The Medicines Company 
 
Version  0.1, May 20, 2014 
12.2. Additional PK Analysis ............................................................................... 28 
12.3. PK/PD Relationship ..................................................................................... 29 
13. Subgroup Analyses .................................................................................................. 30 
14. Other/Exploratory Analysis ..................................................................................... 31 
14.1. Surgical Procedure ....................................................................................... 31 
14.2. Target SBP Range ........................................................................................ 31 
15. Interim Analysis ....................................................................................................... 32 
16. Sample Size Considerations ..................................................................................... 33 
17. Computer Methods................................................................................................... 34 
18. Changes to Analyses Specified in The Protocol ...................................................... 35 
19. References ................................................................................................................ 36 
20. Appendix .................................................................................................................. 37 
20.1. Time Windows ............................................................................................. 37 
20.2. Laboratory Normalization ............................................................................ 37 
 


Clevidipine 
Statistical Analysis Plan MDCO-CLV-12-01 
Confidential 
Page 5 
 
The Medicines Company 
 
Version  0.1, May 20, 2014 
TABLE OF TABLES 
Table 1: 
Schedule of Events/Assessments .............................................................. 10 
Table 2: 
PK Sampling Times .................................................................................... 11 
Table 3: 
Criteria for Potentially Clinically Significant Abnormal Laboratory Tests .... 27 
 


Clevidipine 
Statistical Analysis Plan MDCO-CLV-12-01 
Confidential 
Page 6 
 
The Medicines Company 
 
Version  0.1, May 20, 2014 
ABBREVIATIONS 
AE 
adverse event 
ALT/SGPT 
alanine transaminase/serum glutamic-pyruvic transaminase 
AST/SGOT 
aspartate transaminase/ serum glutamic oxaloacetic transaminase 
AUC 
area under the curve 
AUCinf 
area under the curve of the blood concentration to infinity 
AUClast 
area under the curve of the blood concentration to the last 
measurable concentration 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CI 
confidence interval 
CL 
total clearance 
CSR 
clinical study report 
Cmax 
maximum peak plasma concentration 
DBP 
dystolic blood pressure 
dL 
deciliter 
DSMB 
Data Safety Monitoring Board 
eCRF 
electronic case report form 
GPV 
Global Pharmacovigilence 
h 
hour 
HDL 
high density lipoprotein 
HR 
heart rate 
ITT 
intent-to-treat 
IV 
intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
kg 
kilogram 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
LLN 
lower limit of the standard reference (normal) range 
MAP 
mean arterial pressure 
max 
maximum 


Clevidipine 
Statistical Analysis Plan MDCO-CLV-12-01 
Confidential 
Page 7 
 
The Medicines Company 
 
Version  0.1, May 20, 2014 
MDCO 
The Medicines Company 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
min 
minimum 
min 
minute 
mmHg 
millimeter(s) of mercury 
MRT 
mean residence time 
M1 
carboxylic acid metabolite 
NONMEM 
Nonlinear Mixed-Effect Modeling 
PCS 
potentially clinically significant 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
Q 
quartile 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
statistical analysis system 
SBP 
systolic blood pressure 
SD 
standard deviation 
sec 
seconds 
SEM 
standard error of mean 
t1/2  
half-life 
TBPR 
target blood pressure rate 
TEAE 
treatment emergent adverse event 
tmax 
time to reach maximum peak plasma concentration 
ULN 
upper limit of the standard reference (normal) range 
U/L 
units per liter 
VLDL 
very low density lipoprotein 
Vss 
volume of distribution at a steady state 
Vz 
volume of distribution based in the terminal phase 
WHO 
World Health Organization 
µg 
microgram 
λz 
terminal rate constant 


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Clevidipine 
Statistical Analysis Plan MDCO-CLV-12-01 
Confidential 
Page 9 
 
The Medicines Company 
 
Version  0.1, May 20, 2014 
lengthened to greater than 1.5 minutes. If the target SBP range is achieved at any of the 
titration doses, that rate may be maintained for up to 96 hours to maintain the BP, or 
titrated up or down as necessary to maintain SBP within the target range. Clevidipine 
infusion may be terminated at any time for safety reasons.  
During the initial 30 minutes of the treatment period, clevidipine should be administered 
continuously as monotherapy. The use of an alternative IV antihypertensive agent is 
discouraged and should be limited to situations where it is medically necessary to 
maintain patient safety. If the desired BP control effect is not attained using the 
maximum dose of clevidipine, rescue therapy with the use of an alternative IV 
antihypertensive agent should be implemented.  
After the first 30-minute treatment period, it may be necessary to alter the desired SBP 
target range over the course of the remaining treatment period. Any changes in the target 
range will be captured in the electronic case report form (eCRF).  
Patients who receive alternative intravenous rescue therapy in addition to clevidipine may 
continue in the study. If transition from clevidipine to an oral antihypertensive agent is 
required, the clevidipine infusion may be down-titrated or terminated as appropriate to 
maintain the desired blood pressure. If the BP rises to an undesirable level upon cessation 
of clevidipine infusion, additional therapy may be administered or clevidipine infusion 
may be restarted (and continue until successful transition to an oral therapy has been 
achieved). Patients who receive prolonged clevidipine infusions and are not transitioned 
to other antihypertensive therapies should be monitored for the possibility of rebound 
hypertension for at least 8 hours after the infusion is stopped [Cleviprex Prescribing 
Information, 2011].  
If treatment with an IV anti-hypertensive agent is still required after 96 hours of 
clevidipine therapy, the patient will be transitioned to an alternative IV antihypertensive 
agent according to the institutional standard of care. 
The schedule of events/assessments is shown in Table 1 and the pharmacokinetic (PK) 
sampling time is shown in Table 2. 


Clevidipine 
Statistical Analysis Plan MDCO-CLV-12-01 
Confidential 
 
Page 10 
The Medicines Company 
 Version 0.1, May 20, 2014 
Table 1: Schedule of Events/Assessments 
 
 
Study assessment 
 
Screening 
Period 
0 to -7 Days 
(prior to study 
drug initiation) 
Treatment Period 
Follow-up Period  
Post Study Drug Termination 
(up to 7 days after final dose) 
Treatment  
Phase 1  
Initial Dosing  
0 -1.5  
minutes 
 
Treatment 
Phase 2 
 Titration & Maintenance 
Phase 
>1.5 to 30 minutes & >30 
minutes up to 96 hours 
 
Treatment  
Phase 3 
Transition & 
Termination 
Phase 
 
Follow-up 
1 Hour 
(+ 30 minutes 
Follow-up 
12 Hour 
(+ 30 minutes) 
 
Follow-up 
24 Hour 
 (+ 30 minutes) 
 
Follow-up 
7- Day10 
(+ 1 day) 
Informed consent 
X1 
 
 
 
 
 
 
 
Medical history & Physical exam 
X2 
 
 
 
 
 
 
 
Height & Weight 
X2 
 
 
 
 
 
 
 
Prior Medications 
X2 
 
 
 
 
 
 
 
BP (SBP, DBP) /HR 
  X2,3 
X3 
   X 4,5 
X 4,5 
X6 
X6 
 
 
Pregnancy test 
X2 
 
 
 
 
 
 
 
Hematology (Protocol Section 6.3) 
X2 
 
 
 
 
 
 
 
Serum chemistry every 24 hours (Protocol 
Section 6.3) 
X2 
 
X 
 
X11 
 
 
 
SBP Target Range 
X2 
 
X9 
 
 
 
 
 
Enrollment via IVRS/IWRS 
X2 
 
 
 
 
 
 
 
Study drug administration 
 
X7 
X7 
X7 
 
 
 
 
PK sampling 
  X3,8 
X3,8 
X8 
X8 
X8 
 
 
 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
 
Oral Antihypertensive Administration 
 
 
 
X 
 
 
 
 
AE and SAE reporting  
 
 
X12 
 
1 Written informed consent from parent or legal guardian and verbal assent (as per institutional policy) before initiation of any study-related procedures.  
2 Assessment(s) must be performed prior to treatment to determine eligibility for enrollment into the study.  
3 BP (SBP, DBP) and hear rate (HR) are measured using an intra-arterial catheter with electronic transducer. PK Sample1 is to be taken up to 30 minutes prior to start of clevidipine infusion with BP and HR measured, 
immediately followed by PK Sample 1 collection.  Baseline BP and HR are recorded at 60 sec, 45 sec, 30 sec, and 0 sec prior to initiation of clevidipine. PK Sample 2 is taken at 1.5 minutes after the start of clevidipine 
infusion (before first dose titration) with BP and HR measured, immediately followed by PK Sample 2 collection.  The actual time of BP, HR and PK sample must be recorded using devices that are time synchronized. 


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4  BP and HR will be recorded every 1.5 minutes (+ 30 second window where a PK sample is required) for a period of at least 30 minutes, every 10 minutes for the next hour, every 30 minutes for the next 2 hours and every 
1 hour until study drug is terminated (up to 96 hours). BP and HR will also be recorded immediately before each PK blood draw (Table 2) is obtained. 
5  If a dose adjustment is indicated, BP and HR should be recorded just prior to each study drug dose change as well as every 1.5 minutes for 15 minutes after the dose adjustment, then return to the BP assessment 
schedule just prior to the dose adjustment.  
6  BP and HR will be recorded every 1 hour until study drug has been stopped for 12 hours post-study drug termination.  
7  Clevidipine administered as a continuous IV infusion. 
8  Blood samples for PK analysis will be obtained from an arterial line per the time intervals included in Table 2 below (1 before clevidipine infusion; 4-5 during clevidipine infusion; 4 post clevidipine infusion). NOTE: BP and 
HR will be recorded immediately before each PK blood draw. The actual time of BP, HR and PK sample must be recorded using devices that are time synchronized.  
9  Beyond the first 30-minute treatment period, it may be necessary to alter the desired SBP target range over the course of the remaining treatment period. Any changes in the target range will be captured in the case report 
form (eCRF). 
10  The 7 day (+1 day) follow-up can occur by phone, if applicable. 
11.  Serum chemistry within 1 (+30 minutes) hour after study drug termination 
12.  AE and SAE reporting will be from time of consent through 7 days day) following termination of study drug infusion.  
 
 
 
 
Table 2: PK Sampling Times 
Sample 
Time point 
1 
Up to 30 minutes prior to start of clevidipine infusion 
2 
1.5 minutes post initiation of clevidipine infusion (before first dose titration) 
3 
1.5 minutes after first dose titration (must be performed before proceeding to second dose titration) 
4 
Once target SBP range is reached or 30 minutes after the initiation of clevidipine infusion, whichever 
comes first 
5 
(if applicable) 
If transition to an additional antihypertensive is desired and concurrent administration is needed, a 
sample should be taken right before beginning administration of the additional antihypertensive agent 
6 
Right before the termination of the clevidipine infusion 
7 
0.5 minutes post termination of the clevidipine infusion 
8 
3 minutes post termination of the clevidipine infusion 
9 
15 minutes post termination of clevidipine infusion 
10 
 1hour (+30 minutes)  post final termination of the clevidipine infusion 


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2. 
OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
The primary objective of this study is to evaluate the dosing, efficacy and safety of an 
intravenous (IV) infusion of clevidipine for blood pressure (BP) management in pediatric 
patients in the perioperative setting. 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives of the study are to evaluate additional efficacy, safety and 
dosing parameters associated with IV infusion of clevidipine for BP management in 
pediatric patients in the perioperative setting. 
2.3. 
EXPLORATORY OBJECTIVES 
Efficacy will be evaluated in the subgroups of patients with and without pre-existing 
hypertension. Additional analyses may be performed for efficacy and/or safety when 
applicable.   
 


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3. 
STUDY POPULATIONS 
Three patient populations will be considered in the statistical analyses of this study. 
3.1. 
SAFETY POPULATION  
The safety population consists of all patients who are dosed with any study drug. This 
will be the primary population used for the safety analyses. 
3.2. 
INTENT-TO-TREAT (ITT) POPULATION 
The ITT population consists of all patients who are dosed with any study drug and have 
baseline and at least one post-baseline SBP measurement. This will be the primary 
population used for the efficacy analyses. 
3.3. 
PHARMACOKINETICS/PHARMACODYNAMICS (PK/PD) POPULATION 
The PK/PD population consists of all patients who are dosed with any study drug, have at 
least one documented and evaluable blood concentration and/or SBP observation and 
documented dose records. This will be the primary population for PK/PD analyses.  
 


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4. 
GENERAL STATISTICAL METHODOLOGY 
All statistical analyses and summary information will be generated according to this 
statistical analysis plan (SAP). Any deviations from this SAP will be documented in the 
clinical study report (CSR). 
Patient disposition, demographic and background characteristics will be presented for the 
safety, ITT and PK/PD populations. Unless otherwise specified, all efficacy analyses will 
be performed using the ITT population, all safety analyses will be performed using the 
safety population and all PK/PD analyses will be performed using the PK/PD population.  
Continuous variables will be summarized using descriptive statistics including the 
number of patients reflected in the calculation (n), mean, standard deviation (SD), 
median, interquartile range (Q1 and Q3), minimum (min), and maximum (max). 
Frequencies and percentages will be displayed for categorical variables.  
Because of the descriptive nature of this study, no formal statistical hypothesis testing 
will be performed. However, p-values and/or two-tailed 95% confidence intervals may be 
generated to demonstrate the strength of the findings whenever appropriate. 
All data will be summarized for overall and by age cohort. Data listings will be provided 
for all data collected in the eCRF. 
Unless otherwise specified for repeat pre-baseline assessments, the results from the final 
assessment made before or at the start of study medication will be used as baseline. If 
post-baseline assessments are repeated or unscheduled, the non-missing values from the 
first assessment will be used for generating summary statistics. 
Unless otherwise specified (eg, in Section 8), missing data will not be imputed and will 
be excluded from the associated analysis. 


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5. 
PATIENT DISPOSITION AND STUDY COMPLETION 
The number of patients included in each study population (i.e., safety, ITT and PK/PD) 
will be presented. The number and percentage of patients who completed and 
discontinued from the study, as recorded on the patient “End of Study” page of the eCRF, 
will be displayed for the three study populations. Reasons for discontinuation will be 
summarized descriptively. 
The number of patients included in each of three study populations for each study center 
will be tabulated. 
Listings of populations, discontinuation from the study along with the reason, will be 
provided by age cohort. 
 


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6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographics including sex, age, ethnicity, height, weight, and BMI, baseline 
characteristics including blood pressure and heart rate, relevant medical history, as well 
as relevant past surgical/interventional procedure will be summarized with descriptive 
statistics for all populations (safety, ITT and PK/PD). 
Listings of demographics, baseline characteristics, medical history and 
surgical/interventional procedures will be presented for each patient, including those who 
are enrolled but not treated with the study medication. 


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7. 
PROTOCOL DEVIATION 
Any protocol deviations that occur during the study will be recorded in the eCRF. The 
number and percentage of patients who had at least one protocol deviation will be 
summarized by violation type.  


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o On-drug infusion duration (h) (the summation of the durations of all 
the time segments when clevidipine was administered with an infusion 
rate of > 0 µg/kg/min ) 
o Total dose infused (mg) 
o Average infusion rate (µg/kg/min) (equals the total dose infused 
divided by on-drug infusion duration in minutes and baseline weight in 
kg) 
Missing infusion rates will be imputed by linear interpolation between two observed 
infusion rates when the associated infusion start and stop times are observed. No missing 
rates will be imputed by extrapolation. 


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9. 
PRIOR AND CONCOMITANT MEDICATION 
Prior and concomitant medications in addition to the study drug will be summarized 
descriptively using the safety and the ITT populations. Prior and concomitant 
medications will be coded using the World Health Organization (WHO) Drug Dictionary. 
 


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10. 
EFFICACY ANALYSES 
Unless otherwise specified, all efficacy analyses will be using the defined ITT 
population. 
10.1. 
PRIMARY EFFICACY ANALYSIS 
 The time to and percent of patients who attain the initial pre-specified SBP 
target range within the first 30 minutes of study drug initiation.  
The time to attain the initial pre-specified SBP target range is in minutes and is the 
duration between the initiation of study medication and the time a patient first achieves 
the initial pre-specified target SBP range (TBPR) during the first 30 minutes of 
clevidipine infusion. The time will be summarized using descriptive statistics and the 
Kaplan-Meier curve. The estimated median time with its two-tailed 95% confidence 
interval (CI) [Simon and Lee, 1982] will be presented. If a patient does not reach TBPR 
within 30 minutes from the initial treatment with study medication, or another 
antihypertensive agent is administered, the patient will be considered censored at 30 
minutes or the time when another antihypertensive agent is given, whichever comes first.  
The percentage of patients achieving the TBPR will be calculated using the number of 
ITT patients achieving TBPR divided by the number of ITT patients, and multiplied by 
100. Two-tailed 95% CIs will be computed for these percentages.  
 The dose to attain the initial pre-specified target SBP range (minimum of 20 
mmHg and a maximum of 40 mmHg apart) during the first 30 minutes of 
clevidipine infusion. 
The dose to attain the initial pre-specified target SBP consists of the infusion rate 
(µg/kg/min), total dose (mg) infused, and number of titrations made when TBPR is 
reached. 
The summary statistics on infusion rate, total dose infused, and number of titrations made 
when TBPR is reached will be presented. 
All the aforementioned analyses will be performed using the ITT population and also for 
data exploration using the safety population. 
10.2. 
SECONDARY EFFICACY ANALYSIS 
The secondary efficacy analysis will be performed on the following measures. 
All the secondary efficacy analyses will be performed using the ITT population and also 
for data exploration using the safety population. 


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10.2.1. 
The percentage of patients who reach the initial pre-specified target 
SBP range without falling below the lower limit of the pre-specified 
target range during the first 30 minutes of clevidipine infusion 
The percentage of patients reaching this endpoint will be calculated using the number of 
patients reaching the endpoint divided by total number of patients in the analysis 
population, and multiplied by 100. Two-tailed 95% CIs will be computed for these 
percentages. 
Number and percent of patients achieving the endpoint during first 30 minutes of 
clevidipine infusion along with the calculated 95% CI will be presented. 
10.2.2. 
The percentage of patients in whom the SBP falls below the lower limit 
of the pre-specified target range at any time during the first 30 minutes 
of treatment and at any time during the entire study drug treatment 
period 
Two analyses will be presented:  the percentage of patients in whom the SBP falls below 
the lower limit of the pre-specified target range at any time during the first 30 minutes of 
treatment period and below the lower limit of the target range at any time during the 
entire study drug treatment period. Both endpoints will be calculated using the number of 
patients achieving the endpoint divided by total number of patients in the analysis 
population, and multiplied by 100. Two-tailed 95% CIs will be computed for these 
percentages. 
Number and percent of patients achieving the endpoints along with the calculated 95% CI 
will be presented. 
10.2.3. 
The percentage of patients in whom the SBP is within target range at 
each hour after the first 30 minutes of clevidipine infusion 
The percentage of patients who stayed within target range at each hour after first 30 
minutes of clevidipine infusion will be calculated using the number of patients who 
reached the endpoint divided by total number of patients in the analysis population, and 
multiplied by 100. Two-tailed 95% CIs will be computed for these percentages. 
Time windows specified in Section 20.1.1 will be applied if the hemodynamic assessment 
is missing at a specific timepoint. 
Number and percent of patients achieving the endpoint at each hour after first 30 minutes 
of clevidipine infusion along with the calculated 95% CI will be presented. 


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10.2.4. 
The percentage of patients who require rescue therapy (i.e. receive any 
alternative IV antihypertensive drug) at any time during study drug 
treatment period or discontinuation due to adverse events 
The percentage of patients achieving this endpoint will be calculated using the number of 
patients achieving the endpoint divided by total number of patients, and multiplied by 
100. Two-tailed 95% CIs will be computed for these percentages. 
Number and percent of patients achieving the endpoints along with the calculated 95% CI 
will be presented. 
10.2.5. 
Percent change in SBP from baseline at each time point during the 30 
minutes of clevidipine infusion, at each hour after the first 30 minutes of 
clevidipine infusion up to the cessation of infusion, and over the first 12 
hours post study drug termination 
Blood pressure will be measured every 1.5 minutes for the first 30 minutes of infusion, 
every 10 minutes in the next hour, every 30 minutes for the next 2 hours then every hour 
until the study drug is terminated or maximum 96 hours from initiation of study drug is 
reached, whichever is earlier. Blood pressure will also be measured just prior to each PK 
blood draw and each dose adjustment, as well as every 1.5 minutes for 15 minutes after 
the dose adjustment. After termination of the clevidipine infusion, blood pressure will be 
taken every 15 minutes for the first hour, then every hour for a maximum of 12 hours.  
Descriptive statistics on changes and percent changes from baseline in SBP will be 
summarized at each specified timepoint. A graph will be presented on percent change in 
SBP during the first 30 minutes after initiation of study medication by age cohort. 
Individual patient graphs will present SBP across all timepoints along with the study drug 
dose levels in mg/h.  
10.2.6. 
Percent change from baseline in heart rate during the first 30 minutes of 
clevidipine infusion and the rest of the treatment period 
Heart rate (HR) will be measured every 1.5 minutes for the first 30 minutes of study drug 
infusion, every 10 minutes in the next hour, every 30 minutes for the next 2 hours then 
every hour until the study drug is terminated or maximum 96 hours from initiation of 
study drug is reached whichever is earlier. 
Descriptive statistics on changes and percent changes from baseline in HR will be 
summarized at each specified timepoint within 30 minutes of clevidipine infusion. A 
graph will be made of percent change in HR during the first 30 minutes after initiation of 
study medication by age cohort. 


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10.3. 
OTHER EFFICACY ANALYSIS 
The following endpoint will be summarized and presented: 
 Percent change from baseline in diastolic blood pressure (DBP) over time  
 Percent change from baseline in mean arterial pressure (MAP) over time 
 


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11. 
SAFETY ANALYSES 
Safety of a prolonged infusion of clevidipine up to 96 hours will be assessed according to 
adverse events (AE)/serious adverse events (SAE) up to 7 (+ 1) days following study 
treatment termination, and clinical laboratory parameters. 
Unless otherwise specified, all safety analyses will use the defined safety population. 
11.1. 
ADVERSE EVENTS 
The Medical Dictionary for Regulatory Activities (MedDRA) will be used for coding 
AEs. An AE (classified as preferred term) occurring after initiation of study drug will be 
counted as a treatment emergent AE (TEAE) either if it is not present at baseline or if it is 
present at baseline but increased in severity after initiation of study drug. If more than 
one AE with the same preferred term was reported pre-baseline, then the report with the 
greatest intensity is used as the benchmark for comparison to post-baseline reports of 
events with that preferred term. 
The number (percentage) of patients reporting TEAEs for each preferred term will be 
tabulated by system-organ class, by system-organ class and severity, and by system-
organ class and relationship to study drug. If more than one event occurred with the same 
preferred term for the same patient, the patient will be counted only once for that 
preferred term using the most severe or related occurrence for the summary by severity, 
or relationship to study drug, respectively. An individual patient will be counted only 
once for any specific preferred term regardless of the number of times that preferred term 
occurred for that patient. 
The incidence of SAEs and AEs leading to discontinuation of study drug will be 
summarized separately by system-organ class, preferred term for the safety population. 
Listings will be presented for patients with SAEs/AEs leading to a discontinuation or 
death.  
11.2. 
LABORATORY PARAMETERS 
Serum chemistry including serum creatinine, triglycerides, lipase, total cholesterol, high 
density lipoprotein (HDL), low density lipoprotein (LDL), very low density lipoprotein 
(VLDL), alanine transaminase/serum glutamic-pyruvic transaminase (ALT/SGPT), 
aspartate transaminase/ serum glutamic oxaloacetic transaminase (AST/SGOT), total 
bilirubin, lactate dehydrogenase, blood urea nitrogen, sodium, potassium, calcium, and 
magnesium will be assessed at screening and then every 24 hours (+/- 1 hour) during 
study drug administration up to 96 hours (or at the termination of study drug infusion if 
less than the 24 hour timepoint). A blood sample will also be drawn 4 hours (+/- 30 
minutes) after termination of study drug infusion. 


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Hematology including red blood cells, hemoglobin, hematocrit, white blood cells, and 
platelets will be collected only at screening. 
11.2.1. 
Laboratory normalization 
Because values of laboratory parameters in this study are provided from different local 
laboratories with different units and normal ranges, all numerical laboratory values will 
be converted to the conventional units and normalized to a standard set of 
reference/normal ranges [Chuang-Stein, 1992 and 2001]. The normalization process will 
be performed for each of the laboratory parameters. The method was adapted by a scale 
model described in Karvanen [2003] for values outside the normal local range and in the 
case of only one-sided defined standardized normal ranges. Details of the standardization 
process are described in the Appendix (Section 20.2). Normalized laboratory values will 
be used for the analyses of summary statistics, including relative and percent changes 
from baseline, described in Section 11.2.2. 
11.2.2. 
Laboratory analysis 
Descriptive statistics for the values of serum chemistry as well as relative and percent 
changes from baseline will be summarized by time point: baseline (screening), every 24 
hours during study drug administration (or at the termination of study drug infusion if 
less than the 24 hours timepoint), and at 4 hours after termination of study drug infusion. 
Values for each hematology parameter will be presented only at screening. 
Values of laboratory tests are considered potentially clinically significant (PCS) if they 
meet the PCS criteria listed in Table 3. The number (percentage) of patients with post-
baseline PCS values who do not have PCS values at baseline will be analyzed for the 
safety population. For calculation of the percentages, the denominator is based on the 
number of patients with non-PCS baseline values and at least one post-baseline 
assessment for the laboratory parameter being analyzed. The numerator is based on 
patients from the denominator who had at least one post-baseline PCS value for the 
laboratory parameter being analyzed. A supportive listing of patients with all PCS values 
will be provided including the patient number, age, gender, treatment time. Both raw and 
standardized pre-baseline, baseline, and post-baseline values and normal ranges will be in 
the listing, along with the standardized abnormality flag. 


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Table 3: Criteria for Potentially Clinically Significant Abnormal Laboratory 
Tests 
Parameter 
Low Limit 
High Limit 
Serum Chemistry 
Serum Creatinine, mg/dL 
_ 
2 mg/dL 
Triglycerides, mg/dL 
_ 
300 mg/dL 
Lipase, U/L 
_ 
3 × ULN 
Total Cholesterol, mg/dL  
_ 
300 mg/dL 
HDL, mg/dL 
_ 
≤20 mg/dL 
LDL, mg/dL 
_ 
200 mg/dL 
VLDL, mg/dL 
_ 
≥100 mg/dL 
Alanine Transaminase (ALT/SGPT), U/L  
_ 
3 × ULN 
Aspartate Transaminase (AST/SGOT), U/L  
_ 
3 × ULN 
Total Bilirubin, mg/dL 
_ 
1.5 × ULN 
Lactate Dehydrogenase (LDH) 
_ 
3 × ULN 
Blood Urea Nitrogen (BUN), mg/dL 
_ 
1.5 × ULN 
Electrolytes 
Sodium, mg/L 
≤0.9 × LLN 
1.1 × ULN 
Potassium, mg/L 
≤0.9 × LLN 
1.1 × ULN 
Calcium, mg/dL 
≤0.9 × LLN 
1.1 × ULN 
Magnesium 
≤0.9 × LLN 
1.1 × ULN 
LLN: Lower limit of the standard reference (normal) range. 
ULN: Upper limit of the standard reference (normal) range. 


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12. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES 
12.1. 
PRIMARY PK ANALYSIS 
Blood concentration versus time data will be analyzed using non-compartmental analysis 
and/or Nonlinear Mixed-Effect Modeling (NONMEM). The following pharmacokinetic 
parameters will be estimated: 
• Maximum observed blood concentration (Cmax) 
• Time to reach Cmax (tmax) 
• Area under the curve of the blood concentration to the last measurable 
concentration (AUClast) 
• Area under the curve of the blood concentration to infinity (AUCinf) 
• Terminal rate constant (λz) and its associated half-life (t1/2) 
• Mean residence time (MRT) 
• Total clearance (CL).  
• Volume of distribution at steady state (Vss) 
• Volume of distribution based in the terminal phase (Vz) 
All concentration data will be presented descriptively at each time point. Descriptive 
statistics comprising N, mean, geometric mean, SD, standard error of mean (SEM), 
median, %CV, minimum and maximum will be presented for the pharmacokinetic 
variables (half-life, area under curve [AUC], volume of distribution, clearance, etc.) 
established by sparse population methodology. 
All PK and PD analyses will be using the defined PK/PD population. 
12.2. 
ADDITIONAL PK ANALYSIS 
The following additional PK analysis will be performed: 
 Blood concentration of clevidipine and its carboxylic acid metabolite (M1) over 
time 
Blood concentration of clevidipine and M1 will be plotted over time by cohort. PK 
modeling of blood concentration of clevidipine versus any or all of weight, height, body 
surface area, age, sex or ethnicity may be explored when appropriate. 
 Relationship between dose and blood concentration of clevidipine for overall and 
by cohort 
Blood concentration will be plotted over dose for overall and by cohort. Dose 
proportionality will be explored. PK modeling of blood concentration of clevidipine 
versus dose plus any or all of weight, height, body surface area, age, sex or ethnicity may 


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be performed to explore the potential effect of covariance on the dose-concentration 
relationship. 
 Relationship between first on-study blood concentration of clevidipine and body 
weight  
First on-study blood concentration of clevidipine will be plotted over body weight. This 
might be done by age, sex or ethnicity. 
We may also perform analysis to explore the following: 
 Potential effect of body weight, height, body surface area, age, sex, ethnicity or 
dose on total clearance (CL) 
 Potential effect of body weight, body surface area, age, sex ethnicity or dose on 
volume of distribution (Vss) 
12.3. 
PK/PD RELATIONSHIP 
The following analyses will be performed for PK/PD relationship: 
 Relationship between change and/or percent change from baseline in SBP and 
first on-study blood concentration of clevidipine for overall and by cohort  
Change and/or percent change from baseline in SBP will be plotted over first on-study 
blood concentration for overall and by cohort. Appropriate PK/PD modeling may be 
explored whenever necessary. 
 Relationship between dose and change or percent change from baseline in SBP 
for overall and by cohort 
Change and/or percent change from baseline in SBP will be plotted over dose for overall 
and by cohort. Appropriate PK/PD modeling may be explored whenever necessary.  
 Relationship between blood concentration of clevidipine and change or percent 
change from baseline in SBP will be explored for overall and by cohort 
Change and/or percent change from baseline in SBP will be plotted over blood 
concentration for overall and by cohort. Appropriate PK/PD modeling may be explored 
whenever necessary.  
 


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13. 
SUBGROUP ANALYSES 
Subgroup analysis in patients with and without pre-existing hypertension will be 
performed for efficacy and safety endpoints for the cohorts with reasonable number of 
patients in each subgroup to warrant feasible analysis. 
Pre-existing hypertension for children of 1 to 17 years old will be defined as the average 
of SBP or DBP that is ≥95th percentile for gender, age and height on at least 3 separate 
occasions on or before baseline according to the definition specified in ”The Fourth 
Report on the Treatment of High Blood Pressure in Children and Adolescents” [NIH 
Publication, 2005]. The pre-existing hypertension for neonates will be defined according 
to the definition specified in “Neonatal hypertension: diagnosis and management” [Flynn, 
2000]. 
 
 


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14. 
OTHER/EXPLORATORY ANALYSIS 
14.1. 
SURGICAL PROCEDURE  
Surgery related parameters will be analyzed in this study including: 
 
Type of surgery 
 
Pump used for cardiac surgery (yes or no) 
 
Duration of surgery (initial incision to last suture placed)  
 
Duration of time on pump for cardiac surgery 
Descriptive statistics for each of the above endpoints will be provided by treatment group 
whenever appropriate. Patient data listings will also be provided.  
14.2. 
TARGET SBP RANGE 
Prior to enrollment, the investigator predetermines a patient-specific SBP target range for 
the desired BP reduction. The pre-specified SBP target range cannot be changed for the 
first 30 minutes of treatment and the difference between upper and lower limits of the 
specified target SBP range should be no less than 20 mmHg and no more than 40 mmHg. 
After completing the initial 30 minutes of treatment the SBP target range can be changed 
as needed.  
Initial target SBP range, new target SBP range along with the SBP, HR values at the time 
the range change was initiated will be summarized for overall and by age cohort. 


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15. 
INTERIM ANALYSIS 
Following completion of each cohort, the DSMB will review both safety and dosing data 
provided by the Sponsor and make safety and dosing recommendations to the Sponsor 
according to the DSMB charter prior to enrolling the next cohort. DSMB review of each 
completed cohort will be required before proceeding to the next cohort to determine if it 
is appropriate to proceed with enrollment of subsequent cohorts and whether an 
adjustment in dosing scheme is required. 
In addition, the Sponsor will perform an analysis based on the number of patients 
reaching TBPR within first 30 minutes of study drug infusion to assess the precision of 
the efficacy findings at the end of each cohort to ensure that sample size for the following 
cohort is sufficient based on clinical judgement.  


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16. 
SAMPLE SIZE CONSIDERATIONS 
The total sample size of 80 evaluable patients is primarily based on clinical judgment to 
provide adequate precision of the findings for this non-comparative study. For example, 
assuming that 90% of patients will achieve the initial target SBP range within the first 30 
minutes of infusion, a sample size of 80 patients can provide a 95% confidence interval 
with a precision of ±6.6%. This precision will become ±7.8% if 85% of patients are 
assumed to achieve the initial target SBP range. The precision will be assessed at the end 
of each cohort and sample size for the next cohort may be adjusted. 
Approximately 10-20 patients per pediatric age group are considered adequate to assess 
the PK/PD model, based on prior clinical experience in adults. 
 
 
 
 
 


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17. 
COMPUTER METHODS 
Statistical analyses will be performed using Statistical Analysis System (SAS) (version 
9.0 or later version). 


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18. 
CHANGES TO ANALYSES SPECIFIED IN THE PROTOCOL 
In Protocol Section 10.3.3.3, it was stated to analyze vital signs at each collection time 
point. In this study, the only vital signs that are collected are SBP, DBP and HR which 
are already analyzed as individual efficacy endpoint hence there is no additional analysis 
on vital signs performed. 
 


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19. 
REFERENCES 
Chuang-Stein C. Summarizing laboratory data with different reference ranges in 
multicenter clinical trials. Drug Inf J.. 1992; 26:77-84. 
Chuang-Stein C. Some issues concerning the normalization of laboratory data based 
on reference ranges. Drug Inf J.. 2001; 35:153-156. 
Cleviprex US Prescribing Information. The Medicines Company. December 8, 2011.  
Clinical Study Protocol MDCO-CLV-12-01. Open label study to assess the efficacy, 
safety and dosing of clevidipine in pediatric patients undergoing surgery. Version 3, 
December 11, 2013. 
Data Safety Monitoring Board (DSMB) Charter, MDCO-CLV-12-01. Open label study to 
assess the efficacy, safety and dosing of clevidipine in pediatric patients undergoing 
surgery. March 25, 2014. 
Flynn JT. Neonatal hypertension: diagnosis and management. Pediatr Nephrol2000; 
14(4): 332-341. 
Karvanen J. The statistical basis of laboratory data normalization. Drug Inf J. 2003; 
37:101–107. 
National High Blood Pressure Education Program Working Group on High Blood 
Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and 
treatment of high blood pressure in children and adolescents. NIH Publication No. 05-
5267. Revised May 2005. 
Simon R, Lee YJ. Nonparametric confidence limits for survival probabilities and median 
survival time. Cancer Treatment Reports. 1982; 66:37-42. 
 


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20. 
APPENDIX 
20.1. 
TIME WINDOWS 
20.1.1. 
Visit windows for hemodynamic data (SBP, DBP and HR) 
Hemodynamic data (SBP, DBP and HR) will be presented at every 1.5 minutes within 30 
minutes of study drug infusion, at every 30 minutes for the next 3 hours, at every hour 
thereafter till the cessation of infusion and over 12 hours post study treatment. The time 
window is 30 seconds for 1.5 minutes presentation, 10 minutes for every 30 minutes 
presentation and 30 minutes for hourly presentation.   
20.1.2. 
Visit windows for laboratory parameters 
The following are the time windows (in hours) used for the summary tables of laboratory 
parameters during the study drug infusion. 
>0 to <36 for 24 
≥36 to <60 for 48 
≥60 to <84 for 72 
≥84 to <106 for 96 
The following are the windows used for the data measured post the cessation of study 
drug infusion. 
≥1 h post-infusion to ≤5 h post-infusion for 4 hours post-infusion 
For example, if there is no 48-h measurement, the data measured in the time window 
between 36 h and 60 h will be considered. The values measured closest to 48 h in the 
window will be considered as the 48-hrs. value. If two values are both equally close to 48 
h in the window, the one measured in the earlier time will be used for the analysis. The 
assessment at 48-h will be considered missing if there are no assessments in the time 
window from 36 h to 60 h. 
20.2. 
LABORATORY NORMALIZATION 
Because values of laboratory parameters are provided from different study centers with 
different local laboratories, and with inconsistent units and normal ranges, all numerical 
laboratory values will be converted to conventional units and normalized to a standard set 
of reference/normal ranges by a location-scale model as described by Chuang-Stein 
(1992 and 2001).  The method was adapted by a scale model described in Karvanen 
[2003] for values outside normal local range and in the case of only one-sided defined 
standardized normal ranges. 
The normalization process will be performed for each laboratory parameter. 


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For numerical laboratory values, the normalized values will be proportional to the 
ratio of the widths of reference ranges and aligned with the corresponding lower 
limits.  For example, let (LS, US) denote the standard reference range.  Let φ denote 
the laboratory value provided from Laboratory A, which is to be normalized.  The 
normalized value, φS, can be derived from the formula, 
φS  = LS  + β × (φ - LA), 
where (LA, UA) represents the reference range from Laboratory A and β denotes 
the ratio of the width from standard reference range over the width from 
Laboratory A (ie, β =  (US  – LS) / (UA - LA)). 
If one, say the lower, of the limits of a reference range is missing then the missing 
limit will be imputed according to the ratio of the limits from one of the closest 
reference ranges provided in this study.  For example, let LM denote the missing 
lower limits from Laboratory M.  Its corresponding higher limit, UM, is found to 
be closest to the upper limit, UC from Laboratory C among all the reference upper 
limits in the study.  Then, LM will be imputed by the formula, 
LM  = LC  × (UM  / UC), 
where LC  denotes the lower limit from Laboratory C.  For cases where only the 
upper local limits are missing (i.e., the lower ones are not missing), the same 
imputation process will be performed.  For cases where both limits of a local 
reference range are missing, the missing upper and lower limits will be imputed by 
the largest upper and lowest lower limit among all the observed local reference 
ranges, respectively. 
For laboratory parameters with one-sided standard reference ranges the scale 
normalization formula (see formula 21 in Karvanen, 2003) will be applied as 
follows: 
Let LS  and US  denote either side of the standard reference range.  
Let w, Lw  and Uw denote the value and either side of the local reference range.  
If only LS is available the normalized value will equal w * LS / Lw.  
If only US is available the normalized value will equal w * US / Uw. 
For values outside the local reference ranges, the same formula will be applied to 
avoid complications by negative normalized values using the notation above: 
If w is below Lw, then the normalized value will equal w * LS / Lw.  
If w is above Uw, then the normalized value will equal w * US / Uw.