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

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".

Time frame: Baseline; 15 hours

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.

Time frame: Baseline; 15 hours post-dose

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.

Time frame: Baseline; 15 hours post-dose

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.

Time frame: Baseline; 15 hours post-dose

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.

Time frame: Baseline; 4 hours post-dose

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).

Time frame: Enrollment Visit; 15 hours post-dose

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).

Time frame: Enrollment Visit; 15 hours post-dose

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).

Time frame: Enrollment Visit; 15 hours post-dose

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.

Time frame: Enrollment (pre-surgery); Discharge Visit

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.

Time frame: Enrollment; Discharge Visit

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.

Time frame: Baseline; 48 hours post dosing

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).

Time frame: Baseline; 15 hours post dosing

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.

Time frame: Enrollment Visit; Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit; Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit; Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit; Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit; Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit; Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit; Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit; Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit; Visit 2 and Discharge Visit

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

Time frame: Enrollment Visit; Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit; Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit; Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit; Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit; Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit; Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit; Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit; Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit; Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit and Discharge Visit

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.

Time frame: Enrollment Visit and Discharge Visit

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.

Time frame: Enrollment Visit, Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit, Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit, Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit, Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit, Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit, Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit, Visit 2 and Discharge Visit

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.

Time frame: Enrollment Visit, Visit 2 and Discharge Visit