Pharmacokinetic, Efficacy and Safety Study of Tapentadol Oral Solution in Children With Postoperative Pain

Postoperative Pain Clinical Trial

Official title:

Open-label Evaluation of the Pharmacokinetic Profile, Safety, and Efficacy of Tapentadol Oral Solution for the Treatment of Post-surgical Pain in Children and Adolescents Aged From 2 Years to Less Than 18 Years.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01729728
• Other study ID #: KF5503/68
• Secondary ID: 2013-002016-27
• Status: Completed
• Phase: Phase 2
• Start date: November 2012
• Est. completion date: February 2014

Study information

• Verified date: October 2019
• Source: Grünenthal GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To find out if a drug called tapentadol administered by mouth safely relieves pain in children. Look at the amount of tapentadol in the blood after a single oral dose.

Tapentadol oral solution for children is still being tested and is not yet registered. Tapentadol tablets are effective in treating both acute and chronic pain in adults. This trial will help to understand how tapentadol oral solution works in children.

Description:

The lower age limit for the clinical trial was initially set to 3 years of age in the protocol. The trial planned for the inclusion of participants in three age categories. Age 3 to less than 6 years (young children), age 6 to less than 12 years (older children) and age 12 to less than 18 years of age (adolescents). There was a request by the Paediatric Committee (PDCO) at the European Medicines Agency to include participants 2 years of age (very young children). The protocol amendment thus planned to combine the two youngest age groups into a single reporting group. The protocol amendment only planned that the very young children group would have separate analysis for the Faces Pain Scale Revised (FPS-R) Scale and for the presentation of the serum concentrations, because the pharmacokinetic sampling scheme used in the 2 year old participants was different from the young children group (aged 3 to less than 6 years).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 86
• Est. completion date: February 2014
• Est. primary completion date: February 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 17 Years

Eligibility

Inclusion Criteria:

• A maximum body weight of 85.0 kg.

• A minimum body weight of 10 kg for participants aged 2 years to less than 3 years old.

• If female and post-menarchal, or 12 years or older, the subject has a negative urine pregnancy test within 24 hours before surgery.

• Having completed either dental surgery or tonsillectomy with or without adenoidectomy surgery (age group: 6 to less than 18 years of age).

• Having completed ear, nose, or throat surgery (including but not limited to tonsillectomy (age group: 2 to less than 3 years of age).

• Participant aged 6 to less than 18 years has a post-operative pain intensity score greater than or equal to 4 on the Color Analog Scale (CAS) as a result of the surgical procedure or the participant has a pain level that the usual standard of care following the surgical procedure (which reliably produces moderate to severe pain) requires opioid treatment.

• Participant aged 2 years to less than 6 years has a pain level following a surgical procedure that reliably produces moderate to severe pain, for which the usual standard of care requires opioid treatment.

• Participant is alert, orientated, and able to follow commands and complete the post-operative required procedures.

Exclusion Criteria:

• History of brain injury.

• Clinically relevant abnormal ECG.

• Clinically unstable vital signs and/or a saturation of oxygen saturation (SpO2) less than 93%. During surgery SpO2 may decrease <93%.

• Clinically relevant abnormal values for clinical chemistry, hematology, or urinalysis at enrollment.

• Body temperature above 38.5°C within 48 hours prior to dosing.

• Positive drugs of abuse test result.

Related Conditions & MeSH terms

• Acute Pain
• Pain, Postoperative
• Postoperative Pain

Intervention

Drug:
• Tapentadol
Tapentadol oral solution single dose (1mg/kg body weight)

Locations

Country	Name	City	State
United States	Jean Brown Research	Salt Lake City	Utah

Sponsors (2)

Lead Sponsor	Collaborator
Grünenthal GmbH	Janssen Research & Development, LLC

Country where clinical trial is conducted

United States, 

References & Publications (1)

Muse D, Tarau E, Lefeber C, Sohns M, Brett M, Goldberg J, Rosenburg R. Pharmacokinetics, safety, and efficacy of tapentadol oral solution for treating moderate to severe pain in pediatric patients. J Pain Res. 2019 May 31;12:1777-1790. doi: 10.2147/JPR.S1 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pharmacokinetic Profile of Serum Concentrations of Tapentadol After a Single Dose of Tapentadol Oral Solution in Adolescents (Age 12 to Less Than 18 Years).	Mean and Standard Deviation of Serum Concentrations of Tapentadol. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 0.2 ng/mL.	up to 15 hours
Primary	Pharmacokinetic Profile of Serum Concentrations of Tapentadol-O-glucuronide After a Single Dose of Tapentadol Oral Solution in Adolescents (Age 12 to Less Than 18 Years).	Mean and Standard Deviation of Serum Concentrations of Tapentadol-O-glucuronide. Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Tapentadol-O-glucuronide concentrations were measured in participants. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 10 ng/mL.	up to 15 hours
Primary	Pharmacokinetic Profile of Serum Concentrations of Tapentadol After a Single Dose of Tapentadol Oral Solution in Older Children (Age 6 to Less Than 12 Years).	Mean and Standard Deviation of Serum Concentrations of Tapentadol. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 0.2 ng/mL.	up to 15 hours
Primary	Pharmacokinetic Profile of Serum Concentrations of Tapentadol-O-glucuronide After a Single Dose of Tapentadol Oral Solution in Older Children (Age 6 to Less Than 12 Years).	Mean and Standard Deviation of Serum Concentrations of Tapentadol-O-glucuronide. Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Tapentadol-O-glucuronide concentrations were measured in participants. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 10 ng/mL.	up to 15 hours
Primary	Pharmacokinetic Profile of Serum Concentrations of Tapentadol After a Single Dose of Tapentadol Oral Solution in Younger Children (Age 3 to Less Than 6 Years).	Mean and Standard Deviation of Serum Concentrations of Tapentadol. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 0.2 ng/mL.	up to 15 hours
Primary	Pharmacokinetic Profile of Serum Concentrations of Tapentadol-O-glucuronide After a Single Dose of Tapentadol Oral Solution in Younger Children (Age 3 to Less Than 6 Years).	Mean and Standard Deviation of Serum Concentrations of Tapentadol-O-glucuronide. Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Tapentadol-O-glucuronide concentrations were measured in participants. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 10 ng/mL.	up to 15 hours
Primary	Pharmacokinetic Profile of Serum Concentrations of Tapentadol After a Single Dose of Tapentadol Oral Solution in Very Young Children (Age 2 to Less Than 3 Years).	Mean and Standard Deviation of Serum Concentrations of Tapentadol. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 0.2 ng/mL.	up to 15 hours
Primary	Pharmacokinetic Profile of Serum Concentrations of Tapentadol-O-glucuronide After a Single Dose of Tapentadol Oral Solution in Very Young Children (Age 2 to Less Than 3 Years).	Mean and Standard Deviation of Serum Concentrations of Tapentadol-O-glucuronide. Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Tapentadol-O-glucuronide concentrations were measured in participants. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 10 ng/mL.	up to 15 hours
Primary	Non-Compartmental Pharmacokinetic (PK) Parameter of Tapentadol Area Under the Concentration-Time Curve (AUC 0-15) After a Single Dose of Tapentadol in Adolescent Participants (Age 12 to Less Than 18 Years).	Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in participants 12 years to less than 18 years of age.; Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours.; The Area Under the Curve (AUC) from dose to 15 hours (AUC 0-15) is a summary measure of data from each pharmacokinetic blood sample taken over the 15 hour time period.; The area is that below the line fitted to the data points.	up to 15 hours
Primary	Non-Compartmental Pharmacokinetic (PK) Parameter: Cmax (Maximum Concentration) of Tapentadol After a Single Dose of Tapentadol in Adolescents (Age 12 to Less Than 18 Years).	Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in participants 12 years to less than 18 years of age.; Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours. The concentration of tapentadol (active drug) is assessed during absorption and distribution.; The maximum concentration is derived from the Area Under the Curve, from dose to 15 hours (AUC 0-15). It is the highest amount of active drug observed in the blood sample	up to 15 hours
Primary	Non-Compartmental Pharmacokinetic (PK) Parameter: Time to Maximum Concentration (Tmax) of Tapentadol After a Single Dose of Tapentadol in Adolescents (Age 12 to Less Than 18 Years).	Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in participants 12 years to less than 18 years of age.; The time to maximum concentration is derived from the area under the curve from dose to 15 hours (AUC 0-15). The Tmax is the time after dosing at which the maximum concentration of the tapentadol (active drug) occurs.; Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours.	up to 15 hours
Primary	Non-Compartmental Pharmacokinetic (PK) Parameter of Tapentadol-O-glucuronide Area Under the Concentration-Time Curve (AUC 0-15) After a Single Dose of Tapentadol in Adolescents (Age 12 to Less Than 18 Years).	Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in participants 12 years to less than 18 years of age.; Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours. The concentration of tapentadol (active drug) is assessed during absorption and distribution.; The maximum concentration is derived from the Area Under the Curve, from dose to 15 hours (AUC 0-15). It is the highest amount of active drug observed in the blood sample.	up to 15 hours
Primary	Non-Compartmental Pharmacokinetic (PK) Parameter: Cmax (Maximum Concentration) of Tapentadol-O-glucuronide After a Single Dose of Tapentadol in Adolescents (Age 12 to Less Than 18 Years).	Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours. The concentration of tapentadol-O-glucuronide (metabolite) is assessed to study absorption and distribution.; The maximum concentration is derived from the Area Under the Curve, from dose to 15 hours (AUC 0-15). It is the highest amount of metabolite observed in the blood sample.	up to 15 hours
Primary	Non-Compartmental Pharmacokinetic (PK) Parameter: Time to Maximum Concentration (Tmax) of Tapentadol-O-glucuronide After a Single Dose of Tapentadol in Adolescents (Age 12 to Less Than 18).	Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in participants 12 years to less than 18 years of age. The time to maximum concentration is derived from the area under the curve from dose to 15 hours (AUC 0-15). The Tmax is the time after dosing at which the maximum concentration of the tapentadol-O-glucuronide (metabolite) occurs. Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours.	up to 15 hours
Secondary	Pain Intensity Assessments Using the Visual Analog Scale (VAS) in Adolescents (Age 12 to Less Than 18 Years).	At predefined times after investigational medicinal product administration, participants were asked to rate their pain on a 100 mm line (visual analog scale - VAS) by marking a point on the line in response to: "My pain at this time is". The mark was scored between "no pain" and " pain as bad as it could be". The distance was then measured by a clinician and reported.; A value of 0 indicates "no pain". A value of 100 indicates "pain as bad as it could be".	Baseline; 15 hours
Secondary	Pain Intensity Assessments Using the McGrath Color Analog Scale in Adolescent Participants and Older Children (Age 6 to Less Than 18 Years).	Pain intensity assessments were with a 0 (no pain) to 10 (worst pain) scored McGrath color analog scale (CAS) in participants aged 6 years to less than 18 years, i.e. in Adolescents and Older Children. Participants were presented with the CAS and instructed to place the sliding bar on the color that best represented their pain intensity level at the time of assessment. The CAS is a pocket size tool used to measure the self-reported pain intensity of the older participants. The CAS consists of a 145 mm long triangular shaped strip of plastic, varying in width and hue from 1 mm wide and light pink hue at the bottom (and text no pain), to 3 mm wide and deep red hue at the top (most pain). This instrument includes 2 sides. One side shows the color pain intensity scale as described and the other shows a graduated scale, which provides a specific numeric value for the participant-reported level of pain.	Baseline; 15 hours post-dose
Secondary	Pain Intensity Assessments Using the Faces Pain Scale (Revised) in Children Age 3 to Less Than 12 Years.	This assessment tool was used in 3 to less than 12 year old participants, i.e. Older Children and Young Children.; The Faces Pain Scale (Revised) [FPS-R] score as allocated to a selected face by the participant. There are 6 faces and the participant is asked to indicate on a face to express how much it hurts.; The numeric value 0 (no pain) to 10 (very much pain) is read off the reverse side of the scale by the clinician.	Baseline; 15 hours post-dose
Secondary	Pain Intensity Assessment Using the Face, Legs, Activity, Cry, Consolability Scale in Young and Very Young Children (Age 2 to Less Than 6 Years).	The Face Legs Activity Cry Consolability (FLACC) Scale was developed by the Department of Anesthesiology, University of Michigan Medical School and Health Systems. The FLACC Scale is a behavioral scale for scoring postoperative pain in children between the ages of two months and seven years or in persons unable to communicate. In this trial the scale was used in the young and very young children, i.e. in participants aged 2 to less than 6 years. This tool includes five categories of pain behaviors, including facial expression, leg movement, activity, cry, and consolability. The clinician observes the participant for 5 minutes or more and scores each category with a 0, 1 or 2. The scores are added together for a total score ranging from 0 (no pain) to 10 (worst pain). The higher the total score the higher the pain.	Baseline; 15 hours post-dose
Secondary	Sum of Pain Intensity Differences Over the 4 Hours After Dosing Derived From the Different Pain Scales and for All Age Groups	Different pain intensity assessment tools were used in the different age groups. Therefore the sum of pain intensities were calculated and are reported for each age group based on the tool used.; Adolescents - Age 12 to Less Than 18 Years.; Older Children - Age 6 to Less Than 12 Years.; Young Children - Age 3 to Less Than 6 Years.; Very Young Children - Age 2 to Less Than 3 Years.; CAS (McGrath color analog scale) [Theoretical Range: -40 to + 40],; VAS (100 mm Visual Analog Scale) [Theoretical Range: -400 to + 400],; FPS-R (6-point Faces Pain Scale - Revised) [Theoretical Range: -40 to + 40],; FLACC (Face, Legs, Activity, Cry, and Consolability score) [Theoretical Range: -40 to + 40].; A mean score of zero indicates that there was no pain intensity change over the 4 hours.; The positive values indicate that in the group as a whole the sum of all pain intensity values over the first 4 hours lead to a reduction in pain in the time period.	Baseline; 4 hours post-dose
Secondary	Respiratory Rate Assessments	Respiratory rate assessments were performed at pre-defined times during the 15 hour period following investigational medicinal product intake.; Pre-surgery data for these participants is also given from the enrollment Visit (Visit 1).	Enrollment Visit; 15 hours post-dose
Secondary	Oxygen Saturation Assessments	Oxygen saturation assessments were performed at pre-defined times during the 15 hour period following investigational medicinal product intake.; Oxygen saturation was assessed using pulse oximetry. The uppermost value is 100%.; Pre-surgery data for these participants is also given from the enrollment Visit (Visit 1).	Enrollment Visit; 15 hours post-dose
Secondary	Systolic and Diastolic Blood Pressure Assessments	Systolic and Diastolic blood pressure assessments were performed at pre-defined times during the 15 hour period following investigational medicinal product intake.; Pre-surgery data for these participants is also given from the enrollment Visit (Visit 1).	Enrollment Visit; 15 hours post-dose
Secondary	Change From Enrollment in 12-lead Electrocardiogram Parameters	12-lead electrocardiograms (ECG) were part of the planned safety assessments. 12-lead Electrocardiograms were performed prior at the enrollment visit after informed consent and at the discharge visit. The discharge visit was as per standard of care.; The changes in ECG parameters are reported. Negative mean values indicate that the millisecond intervals decreased from the enrollment to the discharge visit. Positive mean values indicate that the millisecond intervals increased from the enrollment to the discharge visit. The Letters P,Q,R,S and T refer to specific medically defined points on an ECG tracing and correspond to specific heart activities.	Enrollment (pre-surgery); Discharge Visit
Secondary	Change From Enrollment in 12-lead Electrocardiogram Heart Rate Parameter	12-lead Electrocardiograms (ECG) were part of the planned safety assessments. 12-lead Electrocardiograms were performed prior at the enrollment visit after informed consent and at the discharge visit. The discharge visit was as per standard of care.; The changes in heart rate (beats per minute) parameters are reported per treatment group between the visits.; A positive value indicates that the heart rate was higher at discharge than at enrollment.	Enrollment; Discharge Visit
Secondary	Treatment Emergent Adverse Events by Intensity	The intensity of all treatment emergent adverse events (TEAEs) were scored by the investigator. Treatment emergent adverse events were those adverse events documented from the time of investigational medicinal product (IMP), study drug, up to 48 hours post dosing.; The clinical "intensity" of an adverse event was classified as: Mild: Signs and symptoms that can be easily tolerated. Symptoms can be ignored and disappear when the subject is distracted.; Moderate: Symptoms cause discomfort but are tolerable; they cannot be ignored and affect concentration.; Severe: Symptoms which affect usual daily activity.; For adverse events where the intensity changes over time, the maximum intensity observed was documented.	Baseline; 48 hours post dosing
Secondary	Intake of Additional Analgesic Medication During the Trial	Number of participants with intakes of supplemental analgesic medication between investigational medicinal product (IMP) intake and Site Discharge grouped according to preparation taken (non-opioid/opioid).	Baseline; 15 hours post dosing
Secondary	Hematology Safety Laboratory Assessments: Hemoglobin Concentration	The hemoglobin test is a commonly ordered blood test and was done as part of a complete blood count (CBC). It is routinely done before and after surgery to check for anemia, the presence of chronic kidney disease or other chronic medical problems. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit; Visit 2 and Discharge Visit
Secondary	Hematology Safety Laboratory Assessments: Hematocrit	Hematocrit is a blood test that measures the percentage of the volume of whole blood that is made up of red blood cells (RBC). This measurement depends on the number of red blood cells and the size of red blood cells. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit; Visit 2 and Discharge Visit
Secondary	Hematology Safety Laboratory Assessments: Erythrocyte Mean Corpuscular Volume (Mean Corpuscular Volume)	Erythrocyte Mean Corpuscular volume is a measurement of the average size of Red Blood Cells (RBC). It is also referred to as Mean Corpuscular Volume. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit; Visit 2 and Discharge Visit
Secondary	Hematology Safety Laboratory Assessments: Platelet Count	Platelets are cell fragments that are vital for normal blood clotting. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit; Visit 2 and Discharge Visit
Secondary	Hematology Safety Laboratory Assessments: Leukocyte Concentration	Leukocytes are also called white blood cells (WBC). These were measured to assess immune function. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit; Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Blood Glucose Concentration	A blood glucose test measures the amount of a sugar called glucose in blood. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit; Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Blood Sodium Concentration	Sodium is required by the body for the body to function properly. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit; Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Blood Potassium Concentration	Potassium is a mineral that the body needs to work normally. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit; Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Blood Calcium Concentration	All cells need calcium in order to function. In the study there were 3 planned safety blood draws for routine blood tests. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit; Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Blood Chloride Concentration	Chloride with other electrolytes help keep the proper balance of body fluids and maintain the body's acid-base balance. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care	Enrollment Visit; Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Blood Phosphate Concentration	Phosphate is needed by the body. This test was done to see how much phosphate is in the blood. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit; Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Blood Urea Nitrogen (BUN) Concentration	This test is to measure the amount of urea nitrogen in the blood. It was used to test liver and kidney function. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit; Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Creatinine Concentration	Creatinine is removed from the body entirely by the kidneys. If kidney function is not normal, creatinine level increases in the blood. In the study there were 3 planned safety blood draws for routine blood tests. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit; Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Aspartate Aminotransferase (AST) Enzyme Activity	AST is considered to be one of the two most important tests to detect liver injury. During liver damage the enzyme is released into the blood. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit; Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Triglycerides Concentration	Triglycerides are a group of fat. Triglycerides were measured as part of metabolic and cardiac assessments. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit; Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Serum Albumin Concentration	Albumin is a protein made by the liver. Albumin prevents fluid leaking into the tissues. Albumin also transports many small molecules. Serum albumin was measured in the clear liquid portion of the blood called serum. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit; Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Urate in the Blood	Uric acid (urate is the salt) is a chemical created when the body breaks down substances called purines. Most urate dissolves in blood and travels to the kidneys. From there, it passes out in the urine. The test is used to determine kidney function. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit; Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Calculated Glomerular Filtration Rate	Glomerular filtration rate (GFR) was done to check how well the kidneys are working. It estimates how much blood passes through the glomeruli in the kidney each minute. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit; Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Urine Specific Gravity	This test was used to test for the water balance and urine concentration. A urine sample was tested right away. A dipstick with a color-sensitive pad was used. The color the dipstick changes and the specific gravity of the urine was read off the color chart. In the study there were 2 planned safety urine collections. At Visit 1 in the enrollment period, after consent and assent obtained. The second sample was obtained at Visit 3 prior to discharge from the hospital. The discharge visit was as per standard of care.	Enrollment Visit and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Urine pH (Acid, Alkalinity) Test	A urine sample was tested right away. A dipstick made with a color-sensitive pad was used. The color indicated the acidity of the urine. In the study there were 2 planned safety urine collections. At Visit 1 in the enrollment period, after consent and assent obtained. The second sample was obtained at Visit 3 prior to discharge from the hospital. The discharge visit was as per standard of care.	Enrollment Visit and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Liver Function Test - Alanine Aminotransferase (ALT) Enzyme Activity	This test was done in combination with other tests (such as AST, ALP, and bilirubin) to diagnose and monitor the liver function. In the study there were 3 planned safety blood draws for routine blood tests. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit, Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Liver Function Test - Gamma-Glutamyl Transferase (GGT) Enzyme Activity	The gamma-glutamyl transferase (GGT) test was used in combination with the alkaline phosphatase (ALP) test. Both ALP and GGT can be elevated in bile duct or liver complications. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit, Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Liver Function Test - Bilirubin Concentration	Old red blood cells are replaced by new blood cells every day. Bilirubin is made by the body when the old blood cells are removed. The concentration of bilirubin in the blood measures liver function. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit, Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Liver Function Test - Lactate Dehydrogenase (LDH) Enzyme Activity	Lactate Dehydrogenase (LDH) was used to check for tissue damage. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit, Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Blood Protein Concentration	The test was done to verify kidney and liver function. It is done in combination with the albumin test. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit, Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Creatine Kinase (CK) Enzyme Activity	The creatine kinase (CK) test was used to detect inflammation of muscles. The test was done in combination with other tests. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit, Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Alkaline Phosphatase (ALP) Enzyme Activity	The Alkaline Phosphatase activity was used to detect bone or hepatobiliary disease. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to study drug administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit, Visit 2 and Discharge Visit
Secondary	Biochemistry Safety Laboratory Parameters: Triacylglycerol Lipase (TL) Enzyme Activity	A triacylglycerol lipase test was done to check for pancreatic function. In the study there were 3 planned safety blood draws for routine blood tests. In the study there were 3 planned safety blood draws for routine blood tests: at Visit 1 (during the enrollment period, including surgery), at Visit 2 (prior to investigational medicinal product administration) and at Visit 3 (prior to discharge from the hospital). The discharge visit was as per standard of care.	Enrollment Visit, Visit 2 and Discharge Visit