Intravenous Tapentadol in Post-Bunionectomy Pain

• Sponsor: Grünenthal GmbH (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01435577
• Collaborator: (none)
• Enrollment: 177
• Location: 1
• Arms: 2
• Duration (Months): 5
• Patients Per Site Per Month: 35.2

Study Details

Study Description

Brief Summary

The purpose of this trial is to established the safety and efficacy of multiple dose treatment with tapentadol IV in an adult population with moderate to severe pain following bunionectomy.

Condition or Disease	Intervention/Treatment	Phase
Bunion; Pain	Drug: Tapentadol; Drug: Matching Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 177 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled Parallel Group, Multicenter Trial to Evaluate the Efficacy and Safety of Multiple Dose Administration of an Intravenous Formulation of Tapentadol in the Treatment of Acute Pain Following Bunionectomy.
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Feb 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tapentadol intravenous Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by Tapentadol alone.	Drug: Tapentadol; 30 mg per administration, maximum 12 administrations over 48 hours; Other Names: Palexia, Nucynta
Placebo Comparator: Matching placebo intravenous Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.	Drug: Matching Placebo; Maximum 12 administrations over 48 hours

Outcome Measures

Primary Outcome Measures

1. Sum of Pain Intensity Differences (SPID 24) [Baseline value; up to 24 hours after first study drug administration]

   Pain Intensity assessed at predefined time points (at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 20 and 24 hours after first drug administration) over a 24 hour period using an 11-point Numeric Rating Scale (NRS) where a score of zero indicates "no pain" and a score of ten indicates "pain as bad as you can imagine". Pain Intensity Differences at each predefined time point (calculated as post-baseline NRS values - baseline NRS values) were analyzed. Negative SPID24 values indicate a decrease in pain intensity and positive values indicate an increase in pain intensity since baseline.

Secondary Outcome Measures

1. Mean Pain Intensity Scores at Fixed Time Points [Baseline; up to 48 hours]

   The mean pain intensity at fixed time points in the trial for all participants is listed. The pain intensity was measured using the Pain Intensity (PI). Pain intensity was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine.

2. Pain Intensity Differences at Fixed Time Points [Starting at 15 minutes and up to 48 hours after first drug administration]

   Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between baseline pain intensity (prior to the first dose) and the pain intensity at the time. A negative number indicates a decrease in pain in the whole treatment group. The greater the negative pain intensity difference value the greater the pain relief in the treatment arm. A score of 0 indicates that there has been no change in pain in a treatment group. A positive value indicates an increase in pain in the treatment group.

3. Patient Global Impression of Change After 12 Hours of Treatment [Baseline value to 12 hours after first study drug administration]

   In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period. The participant verbally rated their impression of overall status with 1 of 7 possible responses (very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse).

4. Patients Global Impression of Change After 24 Hours of Treatment [Baseline value to 24 hours after study drug administration]

   In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period. The participant verbally rated their impression of overall status with 1 of 7 possible responses (very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse).

5. Patient Global Impression of Change After 48 Hours of Treatment [Baseline value to 48 hours after first study drug administration]

   In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period. The participant verbally rated their impression of overall status with 1 of 7 possible responses (very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse).

6. Sum of Pain Intensity Differences After 60 Minutes [Baseline value to 60 minutes after first study drug administration]

   Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between the PI after fixed times after first dose and the baseline PI (prior to the first dose). The Sum of Pain Intensity Differences over 60 minutes was calculated. If the value is negative then the baseline pain intensity was greater than the pain intensity measured after dosing.

7. Sum of Pain Intensity Differences After 4 Hours [Baseline value to 4 hours after first study drug intake]

   Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between the PI after fixed times after first dose and the baseline PI (prior to the first dose). The Sum of Pain Intensity Differences over 4 hours was calculated. If the values are negative (then the baseline pain intensity was greater than the pain intensity measured after dosing).

8. Sum of Pain Intensity Differences After 8 Hours [Baseline value to 8 hours after first study drug administration]

   Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between the PI after fixed times after first dose and the baseline PI (prior to the first dose). The Sum of Pain Intensity Differences over 8 hours was calculated. If the values are negative (then the baseline pain intensity was greater than the pain intensity measured after dosing).

9. Sum of Pain Intensity Differences After 12 Hours [Baseline value to 12 hours after first study drug administration]

   Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between the PI after fixed times after first dose and the baseline PI (prior to the first dose). The Sum of Pain Intensity Differences over 12 hours was calculated. If the values are negative (then the baseline pain intensity was greater than the pain intensity measured after dosing).

10. Sum of Pain Intensity Differences After 48 Hours [Baseline value to 48 hours after first study drug administration]

    Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between the PI after fixed times after first dose and the baseline PI (prior to the first dose). The Sum of Pain Intensity Differences over 60 minutes was calculated. If the values are negative (then the baseline pain intensity was greater than the pain intensity measured after dosing).

11. Number of Participants With 30% Response After 12 Hours, Based on Pain Intensity Scores [Baseline value to 12 hours after first study drug administration]

    Individual participant response. Number of participants that reported a 30% or more reduction in pain intensity from the administration of the first dose to 12 hours after the first study drug administration are counted as having a response if their pain intensity decreased by 30% from their baseline value.

12. Number of Participants With 30% Response After 24 Hours, Based on Pain Intensity Scores [Baseline value to 24 hours after first study drug administration]

    Individual participant response. Number of participants that reported a 30% or more reduction in pain intensity from the administration of the first dose to 24 hours after the first study drug administration are counted as having a response if their pain intensity decreased by 30% from their baseline value.

13. Number of Participants With 30% Response After 48 Hours, Based on Pain Intensity Scores [Baseline value to 48 hours after first study drug administration]

    Individual participants response. Number of participants that reported a 30% or more reduction in pain intensity from the administration of the first dose to 48 hours after the first study drug administration are counted as having a response if their pain intensity decreased by 30% from their baseline value.

14. Number of Participants With 50% Response After 12 Hours, Based on Pain Intensity Scores [Baseline value to 12 hours after first study drug administration]

    Individual participant response. Number of participants that reported a 50% or more reduction in pain intensity from the administration of the first dose to 12 hours after the first study drug administration are counted as having a response if their pain intensity decreased by 50% from their baseline value.

15. Number of Participants With 50% Response After 24 Hours, Based on Pain Intensity Scores [Baseline value to 24 hours after first study drug administration]

    Individual participant response. Number of participants that reported a 50% or more reduction in pain intensity from the administration of the first dose to 24 hours after the first study drug administration are counted as having a response if their pain intensity decreased by 50% from their baseline value.

16. Number of Participants With 50% Response After 48 Hours, Based on Pain Intensity Scores [Baseline value to 48 hours after first study drug administration]

    Individual participant response. Number of participants that reported a 50% or more reduction in pain intensity from the administration of the first dose to 48 hours after the first study drug administration are counted as having a response if their pain intensity decreased by 50% from their baseline value.

17. Time to First Rescue Medication [up to 48 hours]

    The median time to first rescue medication intake (600 mg ibuprofen) in hours.

18. Time to Perceptible Pain Relief [up to 48 hours]

    When the participant began to feel any pain-relieving effect after the administration of the first dose they were requested to stop the first stopwatch. The time was noted. This measured when the participant first felt any difference in the pain.

19. Time to Meaningful Pain Relief [up to 48 hours]

    The participant was instructed to stop the stopwatch when they had meaningful pain relief. That is, when the pain relief made a real difference, after the first drug administration.

20. Pharmacokinetic Concentrations of Tapentadol [15 minutes to 20 hours after first drug administration]

    Tapentadol concentrations were measured in participants in the tapentadol treatment arm. 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.

21. Pharmacokinetic Concentrations of Tapentadol-O-glucuronide [15 minutes to 20 hours after first drug administration]

    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 can be more easily or quickly removed from the body. Tapentadol-O-glucuronide concentrations were measured in participants in the tapentadol treatment arm. 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.

22. Mean Pain Intensity Scores at Relative Time- Tapentadol Randomized Participants [Baseline; for the first 6 administrations]

    The pain intensity at the relative time points are the pain intensity before and one hour after study drug administration. The pain intensity was measured using the Pain Intensity (PI). Pain intensity was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine.

23. Mean Pain Intensity Scores at Relative Time - Matching Placebo Randomized Participants [Baseline; for the first 6 administrations]

    The pain intensity at the relative time points are the pain intensity before and one hour after study drug administration. The pain intensity was measured using the Pain Intensity (PI). Pain intensity was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Scheduled to undergo primary unilateral first metatarsal bunionectomy

• Female patients must be postmenopausal, surgically sterile, or practicing an effective method of birth control if they are sexually active

• Qualifying pain intensity (within a maximum of 5 hours after the last surgical stitch) and Baseline pain intensity (last pain score measured within 10 minutes before dosing) 5 on an 11-point (0 to 10) pain intensity numerical rating scale (NRS).

Exclusion Criteria:

• History of malignancy within the past 2 years

• Current or history of alcohol or drug abuse.

• Clinically relevant pulmonary, gastrointestinal, endocrine, metabolic, neurological, psychiatric disorders (resulting in disorientation, memory impairment or inability to report accurately

• History of seizure disorder, epilepsy, or any condition that would put the subject at risk of seizures

• Severely impaired renal function

• Moderately or severely impaired hepatic function

• Contraindications, or a history of allergy or hypersensitivity, to tapentadol, ibuprofen, or excipients

• Use of prohibited concomitant medication, or not allowed use of restricted concomitant medication

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Jean Brown Research	Salt Lake City	Utah	United States	84124

Sponsors and Collaborators

• Grünenthal GmbH

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Grünenthal GmbH
• ClinicalTrials.gov Identifier: NCT01435577
• Other Study ID Numbers: 295054
• First Posted: Sep 16, 2011
• Last Update Posted: Oct 28, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by Grünenthal GmbH: Bunionectomy; Postsurgical Pain; Acute Pain
• Additional relevant MeSH terms: Bunion; Tapentadol

Study Results

Participant Flow

Recruitment Details	The recruitment period for this trial was from the 26 September 2011 and was completed on the 14 Feb 2012.
Pre-assignment Detail	177 participants signed informed consent. 132 participants underwent surgery. 131 participants reported a pain intensity that qualified them to enter the trial, i.e. one participant did not report sufficient pain to enter the trial. 129 participants were randomized to receive treatment.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by tapentadol alone. 64 Participants Randomized, 64 Participants in the Safety Set (SAF), 64 Participants in the Full Analysis Set (FAS). The FAS comprised all randomized subjects who were administered at least 1 dose and had a baseline pain assessment.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain. 65 Randomized participants, 65 Participants in the Safety Set (SAF), 65 Participants in the Full Analysis Set(FAS). The FAS comprised all randomized subjects who were administered at least 1 dose and had a baseline pain assessment.
Period Title: Overall Study
STARTED	64	65
COMPLETED	47	13
NOT COMPLETED	17	52

Baseline Characteristics

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous	Total
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by Tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.	Total of all reporting groups
Overall Participants	64	65	129
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.2 (12.61)	35.8 (12.41)	38.5 (12.75)
Sex: Female, Male (Count of Participants)
Female	57 89.1%	60 92.3%	117 90.7%
Male	7 10.9%	5 7.7%	12 9.3%
Region of Enrollment (participants) [Number]
United States	64 100%	65 100%	129 100%
Baseline pain intensity (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	7.2 (1.41)	7.3 (1.54)	7.2 (1.47)

Outcome Measures

1. Primary Outcome

Title	Sum of Pain Intensity Differences (SPID 24)
Description	Pain Intensity assessed at predefined time points (at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 20 and 24 hours after first drug administration) over a 24 hour period using an 11-point Numeric Rating Scale (NRS) where a score of zero indicates "no pain" and a score of ten indicates "pain as bad as you can imagine". Pain Intensity Differences at each predefined time point (calculated as post-baseline NRS values - baseline NRS values) were analyzed. Negative SPID24 values indicate a decrease in pain intensity and positive values indicate an increase in pain intensity since baseline.
Time Frame	Baseline value; up to 24 hours after first study drug administration

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): patients who took at least one dose of study medication, had a baseline value, and had at least one post-baseline measurement; Last Observation Carried Forward (LOCF) after dropout, and LOCF for 6 hours after each rescue medication intake.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	64	65
Least Squares Mean (95% Confidence Interval) [units on a scale]	-51.23	25.46

2. Secondary Outcome

Title	Mean Pain Intensity Scores at Fixed Time Points
Description	The mean pain intensity at fixed time points in the trial for all participants is listed. The pain intensity was measured using the Pain Intensity (PI). Pain intensity was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine.
Time Frame	Baseline; up to 48 hours

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS). Participants who took at least one dose of study medication, had a baseline value, and had at least one post-baseline measurement; Last Observation Carried Forward (LOCF) after dropout, and LOCF for 6 hours after each rescue medication intake.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by Tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	64	65
Baseline (before first study drug administration)	7.2 (1.41)	7.3 (1.54)
0.25 hours after first dose	3.7 (1.99)	7.1 (1.57)
0.5 hour after first dose	3.1 (1.77)	7.4 (1.63)
1 hour after first dose	3.6 (1.77)	7.8 (1.76)
2 hours after first dose	5.8 (2.03)	8.5 (1.5)
4 hours after first dose	6.1 (1.92)	8.6 (1.46)
6 hours after first dose	6.3 (2.25)	8.7 (1.47)
8 hours after first dose	6.5 (2.29)	8.6 (1.61)
12 hours after first dose	5.2 (2.7)	8.5 (1.67)
16 hours after first dose	3.8 (2.58)	8.2 (2.12)
20 hours after first dose	3.7 (2.52)	8.0 (2.24)
24 hours after first dose	4.1 (2.43)	8.1 (2.08)
36 hours after first dose	3.9 (2.49)	8.0 (2.39)
48 hours after first dose	4.3 (2.56)	8.1 (2.21)

3. Secondary Outcome

Title	Pain Intensity Differences at Fixed Time Points
Description	Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between baseline pain intensity (prior to the first dose) and the pain intensity at the time. A negative number indicates a decrease in pain in the whole treatment group. The greater the negative pain intensity difference value the greater the pain relief in the treatment arm. A score of 0 indicates that there has been no change in pain in a treatment group. A positive value indicates an increase in pain in the treatment group.
Time Frame	Starting at 15 minutes and up to 48 hours after first drug administration

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): Participants who took at least one dose of study medication, had a baseline value, and had at least one post-baseline measurement; Last Observation Carried Forward (LOCF) after dropout, and LOCF for 6 hours after each rescue medication intake.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	64	65
0.25 hours after first administration	-3.5 (2.22)	-0.2 (0.95)
0.5 hours after first administration	-4.1 (2.24)	0.1 (1.18)
1 hour after first administration	-3.5 (2.07)	0.5 (1.4)
2 hours after first administration	-1.3 (2.24)	1.2 (1.39)
4 hours after first dose administration	-1.0 (2.09)	1.4 (1.47)
6 hours after first dose administration	-0.9 (2.32)	1.4 (1.51)
8 hours after first dose administration	-0.7 (2.5)	1.3 (1.58)
12 hours after first dose administration	-2.0 (3.01)	1.2 (1.57)
16 hours after first dose administration	-3.4 (2.90)	0.9 (1.82)
20 hours after first dose administration	-3.5 (2.89)	0.7 (2.08)
24 hours after first dose administration	-3.1 (2.65)	0.9 (2.0)
36 hours after first dose administration	-3.2 (2.68)	0.8 (2.26)
48 hours after first dose administration	-2.9 (2.76)	0.8 (2.11)

4. Secondary Outcome

Title	Patient Global Impression of Change After 12 Hours of Treatment
Description	In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period. The participant verbally rated their impression of overall status with 1 of 7 possible responses (very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse).
Time Frame	Baseline value to 12 hours after first study drug administration

Outcome Measure Data

Analysis Population Description

Participants contributing data. Missing PGIC values were mainly due to participants discontinuing the trial before this time point.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by Tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	54	15
Very Much Improved	11 17.2%	0 0%
Much Improved	20 31.3%	1 1.5%
Minimally Improved	14 21.9%	9 13.8%
No Change	5 7.8%	4 6.2%
Minimally Worse	4 6.3%	1 1.5%
Much Worse	0 0%	0 0%
Very Much Worse	0 0%	0 0%

5. Secondary Outcome

Title	Patients Global Impression of Change After 24 Hours of Treatment
Description	In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period. The participant verbally rated their impression of overall status with 1 of 7 possible responses (very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse).
Time Frame	Baseline value to 24 hours after study drug administration

Outcome Measure Data

Analysis Population Description

Participants contributing data. Missing PGIC values were mainly due to participants discontinuing the trial before this time point.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by Tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	52	15
Very Much Improved	13 20.3%	0 0%
Much Improved	26 40.6%	5 7.7%
Minimally Improved	11 17.2%	6 9.2%
No Change	1 1.6%	2 3.1%
Minimally Worse	1 1.6%	2 3.1%

6. Secondary Outcome

Title	Patient Global Impression of Change After 48 Hours of Treatment
Description	In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period. The participant verbally rated their impression of overall status with 1 of 7 possible responses (very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse).
Time Frame	Baseline value to 48 hours after first study drug administration

Outcome Measure Data

Analysis Population Description

Participants contributing data. Missing PGIC values were mainly due to participants discontinuing the trial before this time point.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by Tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	47	13
Very Much Improved	19 29.7%	2 3.1%
Much Improved	24 37.5%	8 12.3%
Minimally Improved	4 6.3%	2 3.1%
No Change	0 0%	1 1.5%
Minimally Worse	0 0%	0 0%
Much Worse	0 0%	0 0%
Very Much Worse	0 0%	0 0%

7. Secondary Outcome

Title	Sum of Pain Intensity Differences After 60 Minutes
Description	Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between the PI after fixed times after first dose and the baseline PI (prior to the first dose). The Sum of Pain Intensity Differences over 60 minutes was calculated. If the value is negative then the baseline pain intensity was greater than the pain intensity measured after dosing.
Time Frame	Baseline value to 60 minutes after first study drug administration

Outcome Measure Data

Analysis Population Description

Full analysis set.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	64	65
Mean (95% Confidence Interval) [units on a scale]	-3.65	0.26

8. Secondary Outcome

Title	Sum of Pain Intensity Differences After 4 Hours
Description	Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between the PI after fixed times after first dose and the baseline PI (prior to the first dose). The Sum of Pain Intensity Differences over 4 hours was calculated. If the values are negative (then the baseline pain intensity was greater than the pain intensity measured after dosing).
Time Frame	Baseline value to 4 hours after first study drug intake

Outcome Measure Data

Analysis Population Description

Full analysis set. Primary imputation method was analyzed: Last Observation Carried Forward (LOCF) after dropout, and LOCF for 6 h after each rescue medication intake.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by Tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	64	65
Mean (95% Confidence Interval) [units on a scale]	-6.76	4.22

9. Secondary Outcome

Title	Sum of Pain Intensity Differences After 8 Hours
Description	Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between the PI after fixed times after first dose and the baseline PI (prior to the first dose). The Sum of Pain Intensity Differences over 8 hours was calculated. If the values are negative (then the baseline pain intensity was greater than the pain intensity measured after dosing).
Time Frame	Baseline value to 8 hours after first study drug administration

Outcome Measure Data

Analysis Population Description

Full Analysis Set.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	64	65
Mean (95% Confidence Interval) [units on a scale]	-9.9	9.74

10. Secondary Outcome

Title	Sum of Pain Intensity Differences After 12 Hours
Description	Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between the PI after fixed times after first dose and the baseline PI (prior to the first dose). The Sum of Pain Intensity Differences over 12 hours was calculated. If the values are negative (then the baseline pain intensity was greater than the pain intensity measured after dosing).
Time Frame	Baseline value to 12 hours after first study drug administration

Outcome Measure Data

Analysis Population Description

Full Analysis Set.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	64	65
Mean (95% Confidence Interval) [units on a scale]	-14.98	14.82

11. Secondary Outcome

Title	Sum of Pain Intensity Differences After 48 Hours
Description	Pain Intensity (PI) was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine. Pain Intensity Difference (PID) was the difference between the PI after fixed times after first dose and the baseline PI (prior to the first dose). The Sum of Pain Intensity Differences over 60 minutes was calculated. If the values are negative (then the baseline pain intensity was greater than the pain intensity measured after dosing).
Time Frame	Baseline value to 48 hours after first study drug administration

Outcome Measure Data

Analysis Population Description

Full Analysis Set.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	64	65
Mean (95% Confidence Interval) [units on a scale]	-122.93	45.86

12. Secondary Outcome

Title	Number of Participants With 30% Response After 12 Hours, Based on Pain Intensity Scores
Description	Individual participant response. Number of participants that reported a 30% or more reduction in pain intensity from the administration of the first dose to 12 hours after the first study drug administration are counted as having a response if their pain intensity decreased by 30% from their baseline value.
Time Frame	Baseline value to 12 hours after first study drug administration

Outcome Measure Data

Analysis Population Description

Full analysis set.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	64	65
Number [participants]	27 42.2%	1 1.5%

13. Secondary Outcome

Title	Number of Participants With 30% Response After 24 Hours, Based on Pain Intensity Scores
Description	Individual participant response. Number of participants that reported a 30% or more reduction in pain intensity from the administration of the first dose to 24 hours after the first study drug administration are counted as having a response if their pain intensity decreased by 30% from their baseline value.
Time Frame	Baseline value to 24 hours after first study drug administration

Outcome Measure Data

Analysis Population Description

Full analysis set.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	64	65
Number [participants]	31 48.4%	4 6.2%

14. Secondary Outcome

Title	Number of Participants With 30% Response After 48 Hours, Based on Pain Intensity Scores
Description	Individual participants response. Number of participants that reported a 30% or more reduction in pain intensity from the administration of the first dose to 48 hours after the first study drug administration are counted as having a response if their pain intensity decreased by 30% from their baseline value.
Time Frame	Baseline value to 48 hours after first study drug administration

Outcome Measure Data

Analysis Population Description

Full analysis set.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	64	65
Number [participants]	8 12.5%	1 1.5%

15. Secondary Outcome

Title	Number of Participants With 50% Response After 12 Hours, Based on Pain Intensity Scores
Description	Individual participant response. Number of participants that reported a 50% or more reduction in pain intensity from the administration of the first dose to 12 hours after the first study drug administration are counted as having a response if their pain intensity decreased by 50% from their baseline value.
Time Frame	Baseline value to 12 hours after first study drug administration

Outcome Measure Data

Analysis Population Description

Full analysis set.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	64	65
Number [participants]	18 28.1%	1 1.5%

16. Secondary Outcome

Title	Number of Participants With 50% Response After 24 Hours, Based on Pain Intensity Scores
Description	Individual participant response. Number of participants that reported a 50% or more reduction in pain intensity from the administration of the first dose to 24 hours after the first study drug administration are counted as having a response if their pain intensity decreased by 50% from their baseline value.
Time Frame	Baseline value to 24 hours after first study drug administration

Outcome Measure Data

Analysis Population Description

Full analysis set.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	64	65
Number [participants]	24 37.5%	1 1.5%

17. Secondary Outcome

Title	Number of Participants With 50% Response After 48 Hours, Based on Pain Intensity Scores
Description	Individual participant response. Number of participants that reported a 50% or more reduction in pain intensity from the administration of the first dose to 48 hours after the first study drug administration are counted as having a response if their pain intensity decreased by 50% from their baseline value.
Time Frame	Baseline value to 48 hours after first study drug administration

Outcome Measure Data

Analysis Population Description

Full analysis set.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	64	65
Number [participants]	6 9.4%	0 0%

18. Secondary Outcome

Title	Time to First Rescue Medication
Description	The median time to first rescue medication intake (600 mg ibuprofen) in hours.
Time Frame	up to 48 hours

Outcome Measure Data

Analysis Population Description

Full analysis set.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	64	65
Median (95% Confidence Interval) [hours]	5.4	2.1

19. Secondary Outcome

Title	Time to Perceptible Pain Relief
Description	When the participant began to feel any pain-relieving effect after the administration of the first dose they were requested to stop the first stopwatch. The time was noted. This measured when the participant first felt any difference in the pain.
Time Frame	up to 48 hours

Outcome Measure Data

Analysis Population Description

Participants without pain relief (as measured by the double stopwatch method) were censored at 12 hours from the initial dose or at the time of early withdrawal from the Double-blind Treatment Period, whichever occurred first. Time to perceptible pain relief is not reported for matching placebo arms because of the high number of discontinuations.

Arm/Group Title	Tapentadol Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by tapentadol alone.
Measure Participants	65
Median (95% Confidence Interval) [hours]	0.2

20. Secondary Outcome

Title	Time to Meaningful Pain Relief
Description	The participant was instructed to stop the stopwatch when they had meaningful pain relief. That is, when the pain relief made a real difference, after the first drug administration.
Time Frame	up to 48 hours

Outcome Measure Data

Analysis Population Description

Participants without pain relief (as measured by the double stopwatch method) were censored at 12 hours from the initial dose or at the time of early withdrawal from the Double-blind Treatment Period, whichever occurred first. Time in hours to meaningful pain relief are not reported for matching placebo arm due to the high discontinuation rate.

Arm/Group Title	Tapentadol Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by tapentadol alone. Values collected after 12 hours were censored, i.e. participants scored as having no meaningful pain relief.
Measure Participants	64
Median (95% Confidence Interval) [hours]	0.3

21. Secondary Outcome

Title	Pharmacokinetic Concentrations of Tapentadol
Description	Tapentadol concentrations were measured in participants in the tapentadol treatment arm. 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.
Time Frame	15 minutes to 20 hours after first drug administration

Outcome Measure Data

Analysis Population Description

Participants in the placebo arm were not analyzed. Only those participants contributing data were analyzed. Participants that had an early second study drug administration were not part of the analysis.

Arm/Group Title	Tapentadol Intravenous
Arm/Group Description	Pharmacokinetic samples were taken from all participants, however only samples from the tapentadol treatment group were analyzed.
Measure Participants	17
15 minutes after first infusion	201.2
30 minutes after first infusion	99.5
60 minutes after first infusion	76.4
4 hours after end of first infusion	38.2
3.5 hours after end of fifth infusion	73.2
4 hours after end of fifth infusion	70.3

22. Post-Hoc Outcome

Title	Number of Participants Scored as a Responder Based on Patient Global Impression of Change
Description	Responders are those participants with Patient Global Impression of Change (PGIC) values "Much improved", or "Very much improved". Participants with missing value are considered non-responders.
Time Frame	Fixed time points at 12, 24 and 48 hours after baseline

Outcome Measure Data

Analysis Population Description

Participants with early second dose the PGIC assessment from End-of-double-blind Treatment was taken as the 48 hours value. Assessments done more than 4.5 hours after the 12th infusion were excluded from analysis and participants were considered non-responders.

Arm/Group Title	Tapentadol Intravenous	Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by Tapentadol alone.	Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
Measure Participants	64	65
Responders 12 hours after first dose	31 48.4%	1 1.5%
Responders 24 hours after first dose	39 60.9%	5 7.7%
Responders 48 hours after first dose	43 67.2%	10 15.4%

23. Secondary Outcome

Title	Pharmacokinetic Concentrations of Tapentadol-O-glucuronide
Description	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 can be more easily or quickly removed from the body. Tapentadol-O-glucuronide concentrations were measured in participants in the tapentadol treatment arm. 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.
Time Frame	15 minutes to 20 hours after first drug administration

Outcome Measure Data

Analysis Population Description

Participants in the placebo arm were not analyzed. Only those participants contributing data were analyzed. Participants that had an early second study drug administration were not part of the analysis.

Arm/Group Title	Tapentadol Intravenous
Arm/Group Description	Pharmacokinetic samples were taken from all participants, however only samples from the tapentadol treatment group were analyzed.
Measure Participants	17
15 minutes after first infusion	26.4
30 minutes after first infusion	290.4
60 minutes after first infusion	488.2
4 hours after end of first infusion	452.4
3.5 hours after end of fifth infusion	1048.7
4 hours after end of fifth infusion	945.1

24. Secondary Outcome

Title	Mean Pain Intensity Scores at Relative Time- Tapentadol Randomized Participants
Description	The pain intensity at the relative time points are the pain intensity before and one hour after study drug administration. The pain intensity was measured using the Pain Intensity (PI). Pain intensity was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine.
Time Frame	Baseline; for the first 6 administrations

Outcome Measure Data

Analysis Population Description

Participants contributing data.

Arm/Group Title	Tapentadol Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by Tapentadol alone.
Measure Participants	64
Prior to first dose (n = 64)	7.2 (1.41)
1 hour after first dose (n = 64)	3.6 (1.77)
prior to second dose	7.3 (1.59)
1 hour after second dose	4.7 (2.09)
prior to third dose	7.2 (1.6)
1 hour after third dose	6.1 (2.71)
prior to fourth dose	6.6 (2.21)
1 hour after fourth dose	4.1 (2.96)
prior to fifth dose	4.9 (2.57)
1 hour after fifth dose	2.7 (2.47)
prior to sixth dose	4.5 (2.35)

25. Secondary Outcome

Title	Mean Pain Intensity Scores at Relative Time - Matching Placebo Randomized Participants
Description	The pain intensity at the relative time points are the pain intensity before and one hour after study drug administration. The pain intensity was measured using the Pain Intensity (PI). Pain intensity was assessed on 11-point numerical rating scale from 0 = no pain to 10 = pain as bad as you can imagine.
Time Frame	Baseline; for the first 6 administrations

Outcome Measure Data

Analysis Population Description

Participants contributing data (indicated in brackets)

Arm/Group Title	Matching Placebo Intravenous
Arm/Group Description	Matching Placebo will be given by intravenous infusion. Matching Placebo will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by Tapentadol alone.
Measure Participants	65
Prior to first dose	7.3 (1.54)
1 hour after first dose	7.8 (1.76)
prior to second dose	8.4 (1.30)
1 hour after second dose	8.6 (1.53)
prior to third dose	7.9 (1.65)
1 hour after third dose	7.9 (1.77)
prior to fourth dose	7.3 (2.05)
1 hour after fourth dose	7.1 (2.07)
prior to fifth dose	5.8 (2.04)
1 hour after fifth dose	5.2 (2.24)
prior to sixth dose	5.7 (2.13)
1 hour after sixth dose	4.8 (1.76)

Adverse Events

Time Frame	From administration of first dose of study drug up to 4 days after the administration of the last dose of study drug.
Arm/Group Title	Tapentadol Intravenous		Matching Placebo Intravenous
Arm/Group Description	Tapentadol will be given by intravenous infusion. Tapentadol will be administered every 4 hours. Ibuprofen 600 mg orally may be given as rescue medication for pain not controlled by Tapentadol alone.		Placebo (0.9% sodium chloride and water for injection). Ibuprofen 600 mg orally may be given as rescue medication for pain.
All Cause Mortality
	Tapentadol Intravenous		Matching Placebo Intravenous
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Tapentadol Intravenous		Matching Placebo Intravenous
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/64 (0%)		0/65 (0%)
Other (Not Including Serious) Adverse Events
	Tapentadol Intravenous		Matching Placebo Intravenous
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	63/64 (98.4%)		37/65 (56.9%)
Cardiac disorders
Arrhythmia	0/64 (0%)		1/65 (1.5%)
Palpitations	0/64 (0%)		1/65 (1.5%)
Tachycardia	0/64 (0%)		2/65 (3.1%)
Eye disorders
Vision blurred	1/64 (1.6%)		0/65 (0%)
Visual impairment	1/64 (1.6%)		0/65 (0%)
Gastrointestinal disorders
Abdominal discomfort	1/64 (1.6%)		0/65 (0%)
Abdominal distension	0/64 (0%)		1/65 (1.5%)
Constipation	3/64 (4.7%)		1/65 (1.5%)
Diarrhoea	1/64 (1.6%)		0/65 (0%)
Dry mouth	6/64 (9.4%)		0/65 (0%)
Haematemesis	1/64 (1.6%)		0/65 (0%)
Nausea	43/64 (67.2%)		27/65 (41.5%)
Vomiting	29/64 (45.3%)		11/65 (16.9%)
General disorders
Chest discomfort	1/64 (1.6%)		0/65 (0%)
Chills	2/64 (3.1%)		0/65 (0%)
Feeling abnormal	3/64 (4.7%)		0/65 (0%)
Feeling hot	13/64 (20.3%)		1/65 (1.5%)
Feeling jittery	1/64 (1.6%)		0/65 (0%)
Infusion site erythema	1/64 (1.6%)		0/65 (0%)
Infusion site extravasation	5/64 (7.8%)		1/65 (1.5%)
Infusion site phlebitis	9/64 (14.1%)		0/65 (0%)
Injection site extravasation	1/64 (1.6%)		0/65 (0%)
Injection site induration	1/64 (1.6%)		0/65 (0%)
Injection site phlebitis	1/64 (1.6%)		0/65 (0%)
Local swelling	1/64 (1.6%)		0/65 (0%)
Pain	1/64 (1.6%)		0/65 (0%)
Pyrexia	1/64 (1.6%)		1/65 (1.5%)
Vessel puncture site haematoma	0/64 (0%)		1/65 (1.5%)
Immune system disorders
Seasonal allergy	1/64 (1.6%)		0/65 (0%)
Infections and infestations
Helicobacter infection	1/64 (1.6%)		0/65 (0%)
Upper respiratory tract infection	1/64 (1.6%)		0/65 (0%)
Injury, poisoning and procedural complications
Contusion	1/64 (1.6%)		0/65 (0%)
Excoriation	0/64 (0%)		1/65 (1.5%)
Laceration	1/64 (1.6%)		0/65 (0%)
Tongue injury	0/64 (0%)		1/65 (1.5%)
Investigations
Blood creatine phosphokinase increased	2/64 (3.1%)		0/65 (0%)
Haematocrit decreased	1/64 (1.6%)		0/65 (0%)
Haemoglobin decreased	1/64 (1.6%)		0/65 (0%)
Oxygen saturation decreased	11/64 (17.2%)		0/65 (0%)
Red blood cell count decreased	1/64 (1.6%)		0/65 (0%)
Metabolism and nutrition disorders
Decreased appetite	5/64 (7.8%)		1/65 (1.5%)
Hypokalaemia	0/64 (0%)		1/65 (1.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/64 (1.6%)		0/65 (0%)
Muscle spasms	2/64 (3.1%)		1/65 (1.5%)
Muscle twitching	2/64 (3.1%)		0/65 (0%)
Neck pain	1/64 (1.6%)		0/65 (0%)
Nervous system disorders
Cognitive disorder	2/64 (3.1%)		0/65 (0%)
Dizziness	25/64 (39.1%)		8/65 (12.3%)
Dysarthria	2/64 (3.1%)		0/65 (0%)
Headache	9/64 (14.1%)		2/65 (3.1%)
Hypoaesthesia	0/64 (0%)		1/65 (1.5%)
Myoclonus	1/64 (1.6%)		0/65 (0%)
Nystagmus	2/64 (3.1%)		0/65 (0%)
Paraesthesia	0/64 (0%)		1/65 (1.5%)
Somnolence	27/64 (42.2%)		2/65 (3.1%)
Tremor	1/64 (1.6%)		1/65 (1.5%)
Psychiatric disorders
Nightmare	2/64 (3.1%)		0/65 (0%)
Renal and urinary disorders
Micturition urgency	1/64 (1.6%)		0/65 (0%)
Pyuria	1/64 (1.6%)		0/65 (0%)
Urinary retention	1/64 (1.6%)		0/65 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/64 (1.6%)		0/65 (0%)
Cough	1/64 (1.6%)		0/65 (0%)
Dry throat	1/64 (1.6%)		0/65 (0%)
Dyspnoea	1/64 (1.6%)		0/65 (0%)
Nasal congestion	2/64 (3.1%)		0/65 (0%)
Oropharyngeal pain	1/64 (1.6%)		0/65 (0%)
Pharyngeal hypoaesthesia	1/64 (1.6%)		0/65 (0%)
Productive cough	1/64 (1.6%)		0/65 (0%)
Skin and subcutaneous tissue disorders
Erythema	2/64 (3.1%)		0/65 (0%)
Hyperhidrosis	11/64 (17.2%)		2/65 (3.1%)
Pruritus	10/64 (15.6%)		4/65 (6.2%)
Rash	3/64 (4.7%)		1/65 (1.5%)
Rash pruritic	1/64 (1.6%)		0/65 (0%)
Vascular disorders
Hypertension	0/64 (0%)		2/65 (3.1%)
Hypotension	1/64 (1.6%)		1/65 (1.5%)
Pallor	0/64 (0%)		2/65 (3.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor reserves the right to review any publication pertaining to the trial before it is submitted for publication. Neither party has the right to prohibit publication unless publication can be shown to affect possible patent rights.