A Study to Look at Tapentadol Tablets in Children and Ado... | NCT02151682

NCT02151682

ID	Type	Description	Link
2012-004360-22	EudraCT Number
U1111-1154-4572	Other Identifier	WHO

Status Module

Sponsor/Collaborators Module

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Morphine prolonged-release (Part 1)	Active Comparator	10 milligram (mg) or 30 mg tablets were taken orally twice daily. Starting doses varied from 10 to 40 mg morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	Drug: Morphine prolonged release
Tapentadol prolonged-release (Part 1)	Experimental	25 mg or 100 mg tablets were taken orally twice daily. Starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	Drug: Tapentadol prolonged release
Tapentadol in Part 2 after Tapentadol or Morphine in Part 1	Experimental	Participants on tapentadol PR in Part 1 of the study continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants who were randomized to morphine PR in Part 1 of the study were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.	Drug: Tapentadol prolonged release
Observation Period after Tapentadol in Part 1	No Intervention	Participants who completed tapentadol PR in Part 1 of the study or discontinued tapentadol treatment early in Part 1 could continue directly in the observation period in Part 2 for up to 12 months (with standard-of-care treatment if needed).

Name	Type	Description	Arm Group Labels	Other Names
Tapentadol prolonged release	Drug		Tapentadol in Part 2 after Tapentadol or Morphine in Part 1 Tapentadol prolonged-release (Part 1)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants Classified as Responder (Part 1)	The proportion of participants classified as responders was assessed and compared between the treatment groups. A participant was defined as responder if both of the following criteria were met: Completion of the 14-day Treatment Period (Part 1). One of the following calculated from the scheduled pain assessments ("pain right now") documented during the last 3 days of the Treatment Period: Average pain less than 50 on a visual analog scale (VAS, range 0 [no pain] to 100 [pain as bad as it could be]) for participants aged 12 years to less than 18 years; or less than 5 on the Faces Pain Scale-revised (FPS-R, range 0 [no pain] and 10 [very much pain]) for participants aged 6 years to less than 12 years. Average reduction from baseline of pain greater than or equal to 20 on a VAS for participants aged 12 years to less than 18 years; or greater than or equal to 2 on the FPS-R for participants aged 6 years to less than 12 years.	From Day 1 up to Day 14 (End of Part 1)

Secondary Outcomes

Measure	Description	Time Frame
Extent of Constipation (Part 1)	Constipation was assessed using the modified constipation assessment scale (mCAS). This is an 8-item questionnaire where the observer has scored constipation on a nominal scale (no Problem [score 0], some problem [score 1] or severe Problem [score 2]). The response to an item could also be scored as "unable to assess". The Total Score can vary from 0-16; the higher the Total Score the higher the extent of constipation. A positive change from Day 1 to Day 14 indicates a worsening, a negative change an improvement.

Other Outcomes

Measure	Description	Time Frame
Change in Pain Intensity in the Open-label, Active-controlled Treatment Period (Part 1)	Pain intensity was assessed by scoring "Pain right now" twice daily up to Day 14 by every participant using the Visual Analog Scale (VAS) as well as the Faces Pain Scale-Revised (FPS-R) in an electronic diary. Pain intensity was first documented using the VAS and directly thereafter the FPS-R. If required, pain intensity diary entry could be assisted by the legal guardian or a health care provider. The VAS is scored from 0, equivalent to "no pain", to 100, equivalent to "pain as bad as it could be". The FPS-R is a validated self-reported 6-point scale with 0 representing "no pain" and 10 representing "very much pain". Facial representations were used to indicate how much the pain hurts. The "pain right now" scores at baseline (last evaluation before starting IMP) and the mean of last 6 assessments collected up to the time point of last IMP intake in Part 1 (i.e., Day 14 or the day of early discontinuation) were used for the calculation of the change in pain intensity from baseline.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Part 1 - Randomized to open-label, active comparator controlled treatment

Participants were eligible for the study at enrollment if all the following applied:

Informed consent (if applicable assent) obtained.
Male or female participant at least 6 years of age at the Enrollment Visit and less than 18 years of age on Day 14.
Participant has an underlying long-term pain condition (e.g., cancer, chronic disease, planned or performed surgery) that is, according to the judgment of the investigator, expected to require a twice-daily prolonged release opioid treatment until at least the end of the 14-day Treatment Period.
Participant can swallow tablets of appropriate size.
Participant is able to participate in the study as planned and willing to comply with the requirements of the protocol including refraining from drinking beverages containing alcohol and recreational intake of drugs while on study medication.

Participants had to satisfy the following criteria before allocation to treatment:

Less than 18 years of age.
No opioid intake or last calculated morphine equivalent dose of less than 3.5 mg/kg per day.
Participant has a body weight of at least 17.5 kg.
If a female of childbearing potential (post menarchal and not surgically incapable of childbearing) and sexually active, must practice an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double barrier method, contraceptive patch) before allocation to study medication until the end of intake of study medication.
If a female and post menarchal or older than 12 years, has a negative urine pregnancy test on the day before or on the day of allocation to study medication.

Part 2

Inclusion criteria for the Tapentadol Open-label extension period:

Participant has completed the 14-day Treatment Period.
Participant is still in need of prolonged release opioid treatment.
Participant does not meet any of the compulsory discontinuation criteria.

Exclusion Criteria:

Participants were not eligible for the study if any of the following applied.

The following was checked at enrollment:

Has been previously enrolled in this study or a previous study with tapentadol.
Has a clinically relevant history of hypersensitivity, allergy, or contraindication to morphine or tapentadol or any ingredient, including galactose intolerance (see investigator's brochure for tapentadol prolonged-release [PR] and summary of product characteristics for morphine PR), or naloxone.
History or current condition of any one of the following:
- Seizure disorder or epilepsy.
- Serotonin syndrome.
- Traumatic or hypoxic brain injury, brain contusion, stroke, transient ischemic attack, intracranial hematoma, posttraumatic amnesia, brain neoplasm, or episode(s) of more than 24 hours duration of unconsciousness.
History or current condition of any one of the following:
- Moderate to severe renal or hepatic impairment.
- Abnormal pulmonary function or clinically relevant respiratory disease (e.g., acute or severe bronchial asthma, hypercapnia)
- Complex regional pain syndrome.
- A pain indication with a strong psycho-somatic component that, in the judgment of the investigator, is unlikely to respond to opioids.
History of alcohol or drug abuse in the investigator's judgment, based on history and physical examination. Drugs of abuse detected in urine screen unless explained by allowed concomitant medication
Participant has:
- A clinically relevant abnormal electrocardiogram.
- Signs of pre-excitation syndrome.
- Brugada's syndrome.
- QT or corrected QT (QTcF, Fridericia) interval greater than 470 ms.
Any surgery scheduled during the first 14 days of the study that is expected to require post-surgical intensive care unit (ICU) treatment, or that requires post-surgical parenteral pain-treatment, or may, affect the safety of the participant.
Participant is not able to understand and comply with the protocol as appropriate for the age of the participant or participant is cognitively impaired in the investigator's judgment such that they cannot comply with the protocol.
Participant, parent or the legal representative is an employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, or family member of the employees or the investigator.

The following was checked at the enrollment and the allocation visits:

Has a concomitant disease or disorder (e.g., endocrine, metabolic, neurological, psychiatric, infection) that in the opinion of the investigator may affect or compromise participant safety during the study participation.
Pancreatic/biliary tract disease (e.g., pancreatitis) or paralytic ileus.
Intake of forbidden concomitant medication/use of forbidden therapies (see synopsis section Concomitant medications/therapies).
Female participant is breastfeeding a child.

The following was checked at the allocation to treatment visit:

Has received a drug or used a medical device not approved for human use within 30 days prior to visit.
Based on data from the local laboratory, one or more of:
- Total serum bilirubin greater than 2.0 mg/dL.
- Serum albumin less than 2.8 g/dL.
- Aspartate transaminase or alanine transaminase greater than 5 times upper limit of normal.
Based on data from the local laboratory, creatinine clearance less than 30 mL/min per 1.73 m2 (calculated according to a formula that is appropriate for the respective age group).

Contacts/Locations Module

Name	Affiliation	Role
Director Clinical Trials	Grünenthal GmbH	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
BE001		Leuven		3000	Belgium
BG005

References Module

No data available

No data is available for this block.

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Morphine Prolonged-release (Part 1)	10 milligram (mg) or 30 mg tablets were taken orally twice daily. Starting doses varied from 10 to 40 mg morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jul 27, 2017	Aug 23, 2018

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

Masking Info

FG00024 subjects
FG00145 subjects
FG0020 subjectsGroup not defined for Part 1.
FG0030 subjectsGroup not defined for Part 1.
FG0040 subjectsGroup not defined for Part 1.
FG0050 subjectsGroup not defined for Part 1.

Arm/Group Information

ID	Title	Description
BG000	Morphine Prolonged-release (Part 1)	The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.
BG001	Tapentadol Prolonged-release (Part 1)	The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	OG00019 OG00132

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Farrington-Manning test	Non-inferiority of tapentadol prolonged-release versus morphine prolonged-release has been demonstrated.	0.0790	The p-value is based on Farrington-Manning variance estimator using a pre-specified non-inferiority margin of -0.2. A 1-sided alpha of 0.1 was used. A p-value <0.1 represents non-inferiority.	Risk Difference (RD)	-0.06			2-Sided	80	-0.19	0.06			A confidence interval for the risk difference (RD) completely above the pre-specified non-inferiority margin of -0.2 represents non-inferiority of tapentadol prolonged-release versus morphine prolonged-release.

Secondary

Extent of Constipation (Part 1)

Constipation was assessed using the modified constipation assessment scale (mCAS). This is an 8-item questionnaire where the observer has scored constipation on a nominal scale (no Problem [score 0], some problem [score 1] or severe Problem [score 2]). The response to an item could also be scored as "unable to assess".

The Total Score can vary from 0-16; the higher the Total Score the higher the extent of constipation. A positive change from Day 1 to Day 14 indicates a worsening, a negative change an improvement.

Safety Set

Posted

Mean

Standard Deviation

score on a scale

From Day 1 to Day 14 (End of Part 1)

ID	Title	Description
OG000	Morphine Prolonged-release (Part 1)	The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.
OG001	Tapentadol Prolonged-release (Part 1)	The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.

Secondary

Tolerability Over the Complete Trial Period

Tolerability was assessed by the number of participants with exactly 1 to more than 5 treatment emergent adverse events (TEAE) by treatment group during the different trial periods, on a participant level.

In addition, tolerability was assessed by the number of participants with TEAEs which were considered by the investigator to be at least possibly related to the treatment the participant received.

Safety Set

Posted

Number

participants

Part 1: Day 1 (Start of Part 1) to Day 14; Part 2: Day 15 to Day 379 (End of Part 2)

ID	Title	Description
OG000	Morphine Prolonged-release (Part 1)	The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.
OG001	Tapentadol Prolonged-release (Part 1)	The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.

Other Pre-specified

Change in Pain Intensity in the Open-label, Active-controlled Treatment Period (Part 1)

Pain intensity was assessed by scoring "Pain right now" twice daily up to Day 14 by every participant using the Visual Analog Scale (VAS) as well as the Faces Pain Scale-Revised (FPS-R) in an electronic diary. Pain intensity was first documented using the VAS and directly thereafter the FPS-R. If required, pain intensity diary entry could be assisted by the legal guardian or a health care provider.

The VAS is scored from 0, equivalent to "no pain", to 100, equivalent to "pain as bad as it could be".

The FPS-R is a validated self-reported 6-point scale with 0 representing "no pain" and 10 representing "very much pain". Facial representations were used to indicate how much the pain hurts.

The "pain right now" scores at baseline (last evaluation before starting IMP) and the mean of last 6 assessments collected up to the time point of last IMP intake in Part 1 (i.e., Day 14 or the day of early discontinuation) were used for the calculation of the change in pain intensity from baseline.

Full Analysis Set

Posted

Mean

Standard Deviation

units on a scale

From Baseline up to Day 14 (End of Part 1) or early discontinuation

ID	Title	Description
OG000	Morphine Prolonged-release (Part 1)	The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.

Other Pre-specified

Change in Pain Intensity in the Tapentadol Open-label Extension Period (Part 2)

Pain intensity was assessed by scoring "Pain right now" using the Visual Analog Scale (VAS) as well as the Faces Pain Scale-Revised (FPS-R) at each visit. The pain intensity was first documented using the VAS and directly thereafter the FPS-R. If required, pain intensity assessments could be assisted by the legal guardian or a health care provider.

The VAS is scored from 0, equivalent to "no pain", to 100, equivalent to "pain as bad as it could be". The FPS-R is a validated self-reported 6-point scale with 0 representing "no pain" and 10 representing "very much pain". Facial representations were used to indicate how much the pain hurts.

The "pain right now" score at the tapentadol baseline (last evaluation before or at Day 15) and at the last assessment for those subjects who completed the 12 months treatment of Part 2 were used for the calculation of the change in pain intensity from the tapentadol baseline.

Full Analysis Set; data from 9 subjects who completed the visit 12 months after start of Part 2 were analyzed.

Posted

Mean

Standard Deviation

units on a scale

From Day 15 to Day 379 (End of Part 2)

ID	Title	Description
OG000	Tapentadol Prolonged-release (Part 2)	36 participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.

Other Pre-specified

Use of Rescue Medication in the Open-Label, Active-controlled Treatment Period (Part 1)

Due to an overall low intake of rescue medication, it was not appropriate to present the number of doses of oral morphine solution used at different dose levels of investigational medicinal product (IMP) but the average daily dose (milligrams per kilogram body weight) for the treatment period and a modified average daily dose. Average daily dose and modified average daily dose were both calculated based on drug accountability.

For the modified average daily doses, implausible values were excluded from the analysis, i.e., the amount of rescue medication that was lost due to a broken bottle was excluded from the analysis and negative amounts of rescue medication intakes due to measurement inaccuracies for bottle weights were considered as no intake.

Full Analysis Set

Posted

Mean

Standard Deviation

milligrams per kilogram per day

From Day 1 up to Day 14 (End of Part 1)

ID	Title	Description
OG000	Morphine Prolonged-release (Part 1)	The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.
OG001	Tapentadol Prolonged-release (Part 1)

Other Pre-specified

Serum Concentrations of Tapentadol (Part 1)

Tapentadol serum concentrations were measured in participants in the tapentadol treatment arm (Part 1).

All participants who had quantifiable serum concentrations during the Treatment Period were included in the descriptive pharmacokinetic analysis. Data from participants who vomited within 6 hours of administration of IMP during the Treatment Period were carefully assessed to decide if the data should be included in the pharmacokinetic analysis.

Pharmacokinetic Analysis Set

Posted

Mean

Standard Deviation

nanograms per milliliter

From Day 1 to Day 14 (End of Part 1)

ID	Title	Description
OG000	Tapentadol Prolonged-release (All Participants)	The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.
OG001	Tapentadol Prolonged-release (6 Years to Less Than 12 Years)	The treatment group comprised 12 participants aged 6 years to less than 12 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.

Other Pre-specified

Serum Concentrations of Tapentadol-O-glucuronide (Part 1)

Tapentadol-O-glucuronide is a metabolite of tapentadol. The body transforms tapentadol into its metabolites so that it can be more easily/quickly removed from the body. Tapentadol-O-glucuronide serum concentrations were measured in participants who received tapentadol PR in Part 1.

All participants who had quantifiable serum concentrations were included in the descriptive pharmacokinetic analysis. Data from participants who vomited within 6 hours of administration of IMP during Part 1 were carefully assessed to decide if they should be included in the pharmacokinetic analysis.

Pharmacokinetic Analysis Set

Posted

Mean

Standard Deviation

nanograms per milliliter

From Day 1 to Day 14 (End of Part1)

ID	Title	Description
OG000	Tapentadol Prolonged-release (All Participants)	The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.
OG001	Tapentadol Prolonged-release (6 Years to Less Than 12 Years)	The treatment group comprised 12 participants aged 6 years to less than 12 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.

Other Pre-specified

Palatability of Study Medication (Part 1, Day 8)

Palatability was determined in Part 1 by asking the participant "How does the medication taste". The participant was requested to give a score on a 5-point hedonic faces rating scale in combination with a verbal rating. The response can range from really bad to really good.

Full Analysis Set

Posted

Count of Participants

Participants

Day 8 (Part 1)

ID	Title	Description
OG000	Morphine Prolonged-release (Part 1)	The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.
OG001	Tapentadol Prolonged-release (Part 1)	The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.

Other Pre-specified

Palatability of Study Medication (Part 1, Day 14)

Full Analysis Set

Posted

Count of Participants

Participants

Day 14 (Part 1)

ID	Title	Description
OG000	Morphine Prolonged-release (Part 1)	The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.
OG001	Tapentadol Prolonged-release (Part 1)	The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.

Other Pre-specified

Acceptability of Study Medication (Part 1, Day 8)

Acceptability of the study medication was determined in Part 1 by asking the participant "Swallowing the medication is...". The participant was requested to give a score on a 5-point hedonic faces rating scale in combination with a verbal rating. The response can range from really difficult to really easy.

Full Analysis Set

Posted

Count of Participants

Participants

Day 8 (Part 1)

ID	Title	Description
OG000	Morphine Prolonged-release (Part 1)	The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.
OG001	Tapentadol Prolonged-release (Part 1)	The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.

Other Pre-specified

Acceptability of Study Medication (Part 1, Day 14)

Full Analysis Set

Posted

Count of Participants

Participants

Day 14 (End of Part 1)

ID	Title	Description
OG000	Morphine Prolonged-release (Part 1)	The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.
OG001	Tapentadol Prolonged-release (Part 1)	The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.

Other Pre-specified

Extent of Constipation (Part 2)

Constipation was assessed using the modified constipation assessment scale (mCAS). This is an 8-item questionnaire where the observer has scored constipation on a nominal scale (no problem [score 0], some problem [score 1] or severe problem [score 2]). The response to an item could also be scored as "unable to assess".

The Total Score can vary from 0-16; the higher the Total Score the higher the extent of constipation. A positive change from baseline to last assessment indicates a worsening, a negative change an improvement.

Safety Set

Posted

Mean

Standard Deviation

units on a scale

From baseline (Day 15 or switch) to last assessment (up to Day 379 of Part 2)

ID	Title	Description
OG000	Tapentadol in Part 2 After Tapentadol or Morphine in Part 1	Participants on tapentadol PR in Part 1 of the study continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants who were randomized to morphine PR in Part 1 of the study were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower.The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily. Tapentadol prolonged release
OG001	Observation Period After Tapentadol in Part 1	Participants who completed tapentadol PR in Part 1 of the study or discontinued tapentadol treatment early in Part 1 could continue directly in the observation period in Part 2 for up to 12 months (with standard-of-care treatment if needed).

Other Pre-specified

Change From Baseline in Subjective Opiate Withdrawal Scale (SOWS)

Opiate withdrawal symptoms were assessed using the Subjective Opiate Withdrawal Scale (SOWS) questionnaire. The SOWS is designed to reflect common motoric, autonomic, musculoskeletal, and psychic signs and symptoms of opiate withdrawal. Each participant was requested to rate the first 15 items of the 16-item questionnaire for 7 days after last IMP intake. Participants rated the intensity of specific signs and symptoms on a scale of 0 (not at all) to 4 (extremely). The minimum overall score is 0, the maximum score is 64.

SOWS Total Score at baseline (i.e., for Part 1 = Day 14-17, for Part 2 = Day 352-380, or the day after an early termination visit (Part 1/2)), and changes from baseline 2-7 days after last intake of IMP in Part 1 (= up to Day 23) and in Part 2 (= up to Day 386) are presented.

Safety Set

Posted

Mean

Standard Deviation

units on a scale

From Day 1 to Day 386 (End of Part 2 + 7 days)

ID	Title	Description
OG000	Morphine Prolonged-release (Part 1)	The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.
OG001	Tapentadol Prolonged-release (Part 1)

Other Pre-specified

Time to Discontinuation (Lack of Efficacy) in Part 1

The time to discontinuation from IMP due to lack of efficacy was planned to be analyzed for both treatment arms (tapentadol PR and morphine PR) in Part 1 of the trial. However, no participant was reported with early discontinuation from IMP due to lack of efficacy. Consequently, no time to discontinuation can be reported.

Not Posted

From first day in Part 1 (Day 1) to last day in Part 1

Participants

Other Pre-specified

Time to Discontinuation (Lack of Efficacy) in Part 2

The time to discontinuation from IMP due to lack of efficacy was analyzed for tapentadol PR treatment in Part 2 of the trial.

Safety Set; 3 participants with early discontinuation from IMP due to lack of efficacy

Posted

Mean

Full Range

weeks

From first day in Part 2 (Day 15) to last day in Part 2 (Day 379)

ID	Title	Description
OG000	Tapentadol Prolonged-release (Part 2)	36 participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.

Units	Counts
Participants	OG000

Other Pre-specified

Time to Discontinuation (Treatment Emergent Adverse Events) in Part 1

The time to discontinuation from IMP due to treatment emergent adverse events (TEAEs) was analyzed for both treatment arms (tapentadol PR and morphine PR) in Part 1 of the study.

Note that no participant discontinued due to a TEAE in the morphine PR arm, and 2 participants in the tapentadol PR arm.

Posted

Mean

Full Range

days

From first day in Part 1 (Day 1) to last day in Part 1 (Day 14)

ID	Title	Description
OG000	Morphine Prolonged-release (Part 1)	The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.
OG001	Tapentadol Prolonged-release (Part 1)	The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.

Other Pre-specified

Time to Discontinuation (Treatment Emergent Adverse Events) in Part 2

The time to discontinuation from IMP due to treatment emergent adverse events (TEAEs) was analyzed for tapentadol PR treatment in Part 2 of the study.

Safety Set; 3 participants discontinued due to treatment emergent adverse events.

Posted

Mean

Full Range

weeks

From first day in Part 2 (Day 15) to last day in Part 2 (Day 379)

ID	Title	Description
OG000	Tapentadol Prolonged-release (Part 2)	36 participants who completed Part 1 of the trial (26 on tapentadol PR and 10 participants on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2. Participants on tapentadol PR in Part 1 continued on the current dose of tapentadol PR in Part 2 and if necessary could modify their tapentadol PR dosage. Participants on morphine PR in Part 1 were rotated to tapentadol PR in Part 2 with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg body weight tapentadol PR twice daily.

Units	Counts
Participants	OG000

Other Pre-specified

Time to First Intake of Rescue Medication in the Open-label, Active-controlled Treatment Period (Part 1)

Morphine oral solution could be given during Part 1 as rescue medication in both treatment groups. The dose per rescue medication intake was 1/6 of the total daily dose of the scheduled tapentadol or morphine PR intakes. Rescue medication administration times and doses were recorded.

18 Participants in the morphine PR group and 27 participants in the tapentadol PR group had no documented intake of rescue medication between Day 1 and Day 14.

Summary statistics were calculated based on participants with any intake, i.e., those that took at least 1 dose of rescue medication. The mean (standard deviation) time (hours) to first dose of rescue medication following the first dose of the IMP (on Day 1) is presented.

Full Analysis Set

Posted

Mean

Standard Deviation

hours

From Day 1 up to Day 14 (End of Part 1)

ID	Title	Description
OG000	Morphine Prolonged-release (Part 1)	The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.
OG001	Tapentadol Prolonged-release (Part 1)

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Morphine Prolonged-release (Part 1)	The treatment group comprised 7 participants aged 6 years to less than 12 years and 17 participants aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on participant's weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 200 mg per day.	24	1	24	11	24
EG001	Tapentadol Prolonged-release (Part 1)	The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for participants weighing 55 kg and more was 500 mg per day.	45	3	45	26	45
EG002	Overall (Part 1)	Overall (Part 1) includes all participants with a 2-week treatment with tapentadol PR or morphine PR tablets. One participant who completed the tapentadol PR treatment in Part 1 died in the Observation Period (Part 2; standard-of-care treatment, no IMP) due to progression of Ewing's sarcoma, which started progressing in Part 1. A second participant died in the Observation Period after Tapentadol in Part 1 due to serious progression of osteosarcoma with fatal outcome. The progression started in the Observation Period.	69	4	69	37	69
EG003	Tapentadol Prolonged-release in Part 2	Tapentadol prolonged release in Part 2 comprises all participants who completed Part 1 (on tapentadol PR or morphine PR) and continued on or switched to an extended treatment with tapentadol PR for up to 12 months. No deaths were reported during treatment with tapentadol PR in Part 2. Following tapentadol PR treatment in Part 2, 1 participant died during the Observation Period (under standard-of-care treatment, no IMP) due to malignant neoplasm progression (sarcoma). The progression started in the Observation Period.	36	13	36	30	36

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Lymphopenia	Blood and lymphatic system disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG0031 events1 affected36 at risk
Sickle cell anaemia with crisis	Blood and lymphatic system disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0001 events1 affected24 at risk EG0010 events0 affected45 at risk EG0021 events1 affected69 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0001 events1 affected24 at risk EG0010 events0 affected45 at risk EG0021 events1 affected69 at risk EG003
Breakthrough pain	General disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Malaise	General disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Mucosal inflammation	General disorders	MedDRA 20.1	Systematic Assessment	EG0001 events1 affected24 at risk EG0010 events0 affected45 at risk EG0021 events1 affected69 at risk EG003
Pain	General disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Pyrexia	General disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Appendicitis	Infections and infestations	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Application site infection	Infections and infestations	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Clostridium difficile infection	Infections and infestations	MedDRA 20.1	Systematic Assessment	EG0001 events1 affected24 at risk EG0010 events0 affected45 at risk EG0021 events1 affected69 at risk EG003
Cystitis	Infections and infestations	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0011 events1 affected45 at risk EG0021 events1 affected69 at risk EG003
Herpes zoster	Infections and infestations	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Infection	Infections and infestations	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
White blood cell count decreased	Investigations	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Malignant neoplasm progression	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0011 events1 affected45 at risk EG0021 events1 affected69 at risk EG003
Movement disorder	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Neuralgia	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Somnolence	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Dissociation	Psychiatric disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Acute kidney injury	Renal and urinary disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0011 events1 affected45 at risk EG0021 events1 affected69 at risk EG003
Cutaneous lupus erythematosus	Skin and subcutaneous tissue disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Limb operation	Surgical and medical procedures	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Thrombophlebitis superficial	Vascular disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG0033 events3 affected36 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0017 events6 affected45 at risk EG0027 events6 affected69 at risk EG003
Abdominal pain upper	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0002 events2 affected24 at risk EG0010 events0 affected45 at risk EG0022 events2 affected69 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0004 events4 affected24 at risk EG0017 events7 affected45 at risk EG00211 events11 affected69 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0013 events3 affected45 at risk EG0024 events4 affected69 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0005 events4 affected24 at risk EG00110 events10 affected45 at risk EG00215 events14 affected69 at risk EG003
Toothache	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment	EG0009 events7 affected24 at risk EG0016 events6 affected45 at risk EG00216 events14 affected69 at risk EG003
Fatigue	General disorders	MedDRA 20.1	Systematic Assessment	EG0003 events3 affected24 at risk EG0012 events2 affected45 at risk EG0025 events5 affected69 at risk EG003
Pyrexia	General disorders	MedDRA 20.1	Systematic Assessment	EG0001 events1 affected24 at risk EG0015 events3 affected45 at risk EG0026 events4 affected69 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0013 events3 affected45 at risk EG0023 events3 affected69 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0012 events1 affected45 at risk EG0022 events1 affected69 at risk EG003
Dizziness	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0014 events4 affected45 at risk EG0024 events4 affected69 at risk EG003
Dysarthria	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0002 events2 affected24 at risk EG0010 events0 affected45 at risk EG0022 events2 affected69 at risk EG003
Headache	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0003 events3 affected24 at risk EG0019 events6 affected45 at risk EG00212 events9 affected69 at risk EG003
Paraesthesia	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Somnolence	Nervous system disorders	MedDRA 20.1	Systematic Assessment	EG0002 events2 affected24 at risk EG0010 events0 affected45 at risk EG0022 events2 affected69 at risk EG003
Nightmare	Psychiatric disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0011 events1 affected45 at risk EG0021 events1 affected69 at risk EG003
Sleep disorder	Psychiatric disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0010 events0 affected45 at risk EG0020 events0 affected69 at risk EG003
Dysuria	Renal and urinary disorders	MedDRA 20.1	Systematic Assessment	EG0002 events2 affected24 at risk EG0010 events0 affected45 at risk EG0022 events2 affected69 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0011 events1 affected45 at risk EG0021 events1 affected69 at risk EG003
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA 20.1	Systematic Assessment	EG0000 events0 affected24 at risk EG0011 events1 affected45 at risk EG0021 events1 affected69 at risk EG003
Pruritus	Skin and subcutaneous tissue disorders	MedDRA 20.1	Systematic Assessment	EG0003 events3 affected24 at risk EG0011 events1 affected45 at risk EG0024 events4 affected69 at risk EG003

ID	Term
D010146	Pain
D059350	Chronic Pain

ID	Term
D000077432	Tapentadol

Units	Counts
Participants	OG00024 OG00145

Units	Counts
Participants	OG00024 OG00145

Units	Counts
Participants	OG00024 OG00145

The treatment group comprised 12 participants aged 6 years to less than 12 years and 33 participants aged 12 years to less than 18 years. Participants starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on participant's weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group.

The highest dose defined for participants weighing 55 kg and more was 500 mg per day.

OG0011223.8± 511.27

OG0021700.3± 1363.41

Title	Measurements
	OG0001.8± 2.7 OG0010.4± 0.8 OG0020.4± 1.2 OG0030.8± 1.7

Title	Measurements
	OG000-0.7± 3.3 OG001-1.4± 2.1 OG002-1.6± 1.7 OG003-1.4± 2.7

No documented intake of rescue medication between Day 1 and Day 14.

ID	Term
D009461	Neurologic Manifestations
D012816	Signs and Symptoms
D013568	Pathological Conditions, Signs and Symptoms

ID	Term
D010636	Phenols
D001555	Benzene Derivatives
D006841	Hydrocarbons, Aromatic
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons
D009930	Organic Chemicals