Efficacy, Safety, and Pharmacokinetics of Brachial Plexus Block With EXPAREL in Shoulder Surgery

• Sponsor: Pacira Pharmaceuticals, Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02713230
• Collaborator: (none)
• Enrollment: 156
• Locations: 20
• Arms: 3
• Duration (Months): 13.9
• Patients Per Site: 7.8
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study in 155 adult subjects undergoing primary unilateral total shoulder arthroplasty or rotator cuff repair with general anesthesia

Condition or Disease	Intervention/Treatment	Phase
Pain	Drug: bupivacaine liposome injectable suspension; Drug: bupivacaine liposome injectable suspension; Drug: Placebo	Phase 3

Detailed Description

On Day 0, eligible subjects will be randomized in a 1:1 ratio to receive a single dose of EXPAREL 133 mg in 10 mL expanded in volume with 10 mL of normal saline for a total volume of 20 mL or placebo 20 mL. Study drug (EXPAREL or placebo) will be administered in a blinded manner via an ultrasound guided single-dose brachial plexus block at least 1 hour prior to surgery.

Postsurgical assessments will include pain intensity scores using a 10-cm visual analog scale (VAS); total postsurgical opioid consumption; overall benefit of analgesia score (OBAS) questionnaire; subject satisfaction with overall analgesia using a 5 point Likert scale; neurological assessment; sensory function assessment; motor function assessment; discharge readiness; unscheduled phone calls or office visits related to pain; 12-lead ECGs; vital sign measurements; and clinical laboratory tests. Adverse events will be recorded from the time the informed consent form is signed through postsurgical Day 29.

Follow-up visits will be scheduled for all subjects on postsurgical Days 5 and 10. A follow-up phone call will be made on postsurgical Day 29.

A population Pharmacokinetic (PK) analysis will be utilized to limit the number of blood draws with a sampling schedule of baseline (prior to the nerve block) through hospital discharge. There will be two collection sequences for this study and a subject can only be randomized to one sequence.

Study Design

• Study Type: Interventional
• Actual Enrollment: 156 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy, Safety, and Pharmacokinetics of Brachial Plexus Block With EXPAREL for Postsurgical Analgesia in Subjects Undergoing Total Shoulder Arthroplasty or Rotator Cuff Repair
• Study Start Date: May 9, 2016
• Actual Primary Completion Date: Jul 7, 2017
• Actual Study Completion Date: Jul 7, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: EXPAREL 133 mg 10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively	Drug: bupivacaine liposome injectable suspension; 10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline; Other Names: EXPAREL
Active Comparator: EXPAREL 266 mg 20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively	Drug: bupivacaine liposome injectable suspension; 20 mL EXPAREL (bupivacaine liposome injectable suspension); Other Names: EXPAREL
Placebo Comparator: Placebo 20 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively	Drug: Placebo; 20 mL normal saline as single-injection; Other Names: Normal saline

Outcome Measures

Primary Outcome Measures

1. Area Under the Curve (AUC) of Visual Analog Scale (VAS) Pain Intensity Scores [0-48 hours]

   AUC of VAS pain intensity scores through 48 hours, which represents total pain experienced through 48 hours. VAS is a pain scale. The VAS was presented as a straight 10 cm line, where 0 cm is no pain and 10 cm is the worst pain possible. Patients were asked, "How much pain are you experiencing right now? Please place a vertical mark on the line below to indicate the level of pain you are experiencing right now."

Secondary Outcome Measures

1. Total Postsurgical Opioid Consumption Through 48 Hours [0-48 hours]

   Total postsurgical opioid consumption (converted to IV morphine equivalents) through 48 hours

2. Percentage of Opioid-free Participants Through 48 Hours [0-48 hours]

   Percentage of participants who did not receive opioid medication through 48 hours

3. Time to First Opioid Rescue Through 48 Hours [0-48 hours]

   Time to first opioid rescue medication consumed through 48 hours. Time to rescue was estimated from Kaplan-Meier analysis and presented as quartiles (ie, time to rescue for the first 25% / 50% / 75% of subjects within each treatment group).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female, at least 18 years of age at screening.

2. Scheduled to undergo primary unilateral total shoulder arthroplasty or rotator cuff repair.

3. Subjects scheduled for rotator cuff repair must have a magnetic resonance imaging (MRI) with a reading confirming a tear of at least 1 cm.

4. American Society of Anesthesiologists (ASA) physical status 1, 2, or 3.

5. Female subject must be surgically sterile; or at least 2 years postmenopausal; or have a monogamous partner who is surgically sterile; or practicing double-barrier contraception; or practicing abstinence (must agree to use double-barrier contraception in the event of sexual activity); or using an insertable, injectable, transdermal, or combination oral contraceptive approved by the FDA for greater than 2 months prior to screening and commit to the use of an acceptable form of birth control for the duration of the study and for 30 days after completion of the study.

6. Able to demonstrate normal motor function (by obtaining a 5 on the Lovett Scale when exhibiting biceps, wrist, and thumb movement) and sensory function (by exhibiting sensitivity to cold, pinprick, and light touch) in the location where sensory function will be measured throughout the study: 2 cm superior to the coracoid process on the skin overlying the acromioclavicular joint.

7. Able to provide informed consent, adhere to the study visit schedule, and complete all study assessments.

Exclusion Criteria:

1. Currently pregnant, nursing, or planning to become pregnant during the study or within 1 month after study drug administration.

2. Planned concurrent surgical procedure.

3. Concurrent painful physical condition that may require analgesic treatment (such as an NSAID or opioid) in the postsurgical period for pain that is not strictly related to the shoulder surgery and which may confound the postsurgical assessments (e.g., significant pain from other joints, chronic neuropathic pain).

4. History of hypersensitivity or idiosyncratic reaction to amide-type local anesthetics.

5. Smoking history of greater than 25 pack-years.

6. Contraindication to any one of the following: bupivacaine, oxycodone, morphine, or hydromorphone.

7. Use of any of the following medications within the times specified before surgery: long-acting opioid medications or NSAIDs (except for low-dose aspirin used for cardioprotection) within 3 days, or any opioid medication within 24 hours.

8. Initiation of treatment with any of the following medications within 1 month of study drug administration or if the medication(s) are being given to control pain: selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), gabapentin, pregabalin (Lyrica®), or duloxetine (Cymbalta®). If a subject is taking one of these medications for a reason other than pain control, he or she must be on a stable dose for at least 1 month prior to study drug administration.

9. Current use of systemic glucocorticosteroids within 1 month of enrollment in this study.

10. Use of dexmedetomidine hydrochloride (HCl) (Precedex®) within 3 days of study drug administration.

11. History of impaired kidney function, emphysema or other chronic respiratory disease, rheumatoid arthritis, coagulopathy, or loss of sensation in extremities.

12. Impaired kidney function (e.g., serum creatinine level >2 mg/dL [176.8 µmol/L] or blood urea nitrogen level >50 mg/dL [17.9 mmol/L]) or impaired liver function (e.g., serum aspartate aminotransferase [AST] level >3 times the upper limit of normal [ULN] or serum alanine aminotransferase [ALT] level >3 times the ULN.)

13. Uncontrolled anxiety, psychiatric, or neurological disorder that might interfere with study assessments.

14. Any chronic neuromuscular deficit effecting the peripheral nerves or muscles of the surgical extremity.

15. Any chronic condition or disease that would compromise neurological or vascular assessments.

16. Malignancy in the last 2 years, with the exception of non-metastatic basal cell or squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix.

17. Suspected or known history of drug or alcohol abuse within the previous year.

18. Body weight <50 kg (110 pounds) or a body mass index >44 kg/m2.

19. Previous participation in an EXPAREL study.

20. Administration of an investigational drug within 30 days or 5 elimination half-lives of such investigational drug, whichever is longer, prior to study drug administration, or planned administration of another investigational product or procedure during the subject's participation in this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Horizon Research Group, Inc	Mobile	Alabama	United States	36608
2	Denver Metro Orthopedics	Englewood	Colorado	United States	80113
3	Jackson Memorial Hospital/University of Miami	Miami	Florida	United States	33136
4	Pensacola Research Associates	Pensacola	Florida	United States	32504
5	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
6	Massachusetts General Hospital	Boston	Massachusetts	United States	02215
7	Montefiore Medical Center	Bronx	New York	United States	10467
8	Duke University Medical Center	Durham	North Carolina	United States	27710
9	Fairview Hospital	Cleveland	Ohio	United States	44111
10	Indiana Regional Medical Center	Indiana	Pennsylvania	United States	15701
11	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
12	Chan Soon-Shiong Medical Center	Windber	Pennsylvania	United States	15963
13	Hermann Drive Surgical Hospital	Houston	Texas	United States	77004
14	Westside Surgical Hospital	Houston	Texas	United States	77027
15	Plano Surgical Hospital	Plano	Texas	United States	75093
16	Houston Physician's Hospital	Webster	Texas	United States	77598
17	Southampton Orthopedics Sports Medicine	Franklin	Virginia	United States	23851
18	Ziekenhuis Oost-Limburg	Genk		Belgium	3600
19	Aarhus University Hospital	Aarhus		Denmark	8000
20	Regionshospital Silkeborg	Silkeborg		Denmark	8600

Sponsors and Collaborators

• Pacira Pharmaceuticals, Inc

Investigators

• Study Director: James B Jones, MD, PharmD, Pacira Pharmaceuticals, Inc

Study Documents (Full-Text)

• Statistical Analysis Plan - Jun 26, 2017
• Study Protocol - Nov 14, 2016

More Information

Publications

None provided.

• Responsible Party: Pacira Pharmaceuticals, Inc
• ClinicalTrials.gov Identifier: NCT02713230
• Other Study ID Numbers: 402-C-327
• First Posted: Mar 18, 2016
• Last Update Posted: Dec 3, 2020
• Last Verified: Nov 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Additional relevant MeSH terms: Bupivacaine

Study Results

Participant Flow

Recruitment Details	Participants were recruited between May 9, 2016 and July 7, 2017 at 16 sites in the US and Europe
Pre-assignment Detail	"Started" does not include one patient who was a screen failure, was not enrolled, and was randomized to placebo in error.

Arm/Group Title	EXPAREL 133 mg	EXPAREL 266 mg	Placebo
Arm/Group Description	10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively	20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively	20 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively
Period Title: Overall Study
STARTED	69	15	71
COMPLETED	68	15	71
NOT COMPLETED	1	0	0

Baseline Characteristics

Arm/Group Title	EXPAREL 133 mg	EXPAREL 266 mg	Placebo	Total
Arm/Group Description	10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively	20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively	20 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively	Total of all reporting groups
Overall Participants	69	15	71	155
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.6 (9.94)	61.4 (7.73)	58.5 (9.48)	59.7 (9.55)
Sex: Female, Male (Count of Participants)
Female	25 36.2%	7 46.7%	23 32.4%	55 35.5%
Male	44 63.8%	8 53.3%	48 67.6%	100 64.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 4.3%	0 0%	5 7%	8 5.2%
Not Hispanic or Latino	64 92.8%	15 100%	65 91.5%	144 92.9%
Unknown or Not Reported	2 2.9%	0 0%	1 1.4%	3 1.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	1 1.4%	0 0%	0 0%	1 0.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	13 18.8%	4 26.7%	15 21.1%	32 20.6%
White	53 76.8%	11 73.3%	54 76.1%	118 76.1%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	2 2.9%	0 0%	2 2.8%	4 2.6%
Region of Enrollment (Count of Participants)
Belgium	7 10.1%	3 20%	9 12.7%	19 12.3%
United States	52 75.4%	10 66.7%	53 74.6%	115 74.2%
Denmark	10 14.5%	2 13.3%	9 12.7%	21 13.5%
Dominant hand (Count of Participants)
Left hand	10 14.5%	1 6.7%	10 14.1%	21 13.5%
Right hand	59 85.5%	14 93.3%	61 85.9%	134 86.5%
Visual Analog Scale Pain Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	2.43 (2.621)	2.51 (2.641)	2.94 (2.514)	2.68 (2.570)
American Society of Anesthesiologists classification (Count of Participants)
1	15 21.7%	1 6.7%	14 19.7%	30 19.4%
2	36 52.2%	9 60%	37 52.1%	82 52.9%
3	18 26.1%	5 33.3%	20 28.2%	43 27.7%
Greater than or equal to 4	0 0%	0 0%	0 0%	0 0%
Type of surgery (Count of Participants)
Rotator cuff surgery	50 72.5%	7 46.7%	55 77.5%	112 72.3%
Total shoulder arthroplasty	19 27.5%	8 53.3%	16 22.5%	43 27.7%
Nerve block type (Count of Participants)
Interscalene	67 97.1%	15 100%	70 98.6%	152 98.1%
Supraclavicular	2 2.9%	0 0%	1 1.4%	3 1.9%

Outcome Measures

1. Primary Outcome

Title	Area Under the Curve (AUC) of Visual Analog Scale (VAS) Pain Intensity Scores
Description	AUC of VAS pain intensity scores through 48 hours, which represents total pain experienced through 48 hours. VAS is a pain scale. The VAS was presented as a straight 10 cm line, where 0 cm is no pain and 10 cm is the worst pain possible. Patients were asked, "How much pain are you experiencing right now? Please place a vertical mark on the line below to indicate the level of pain you are experiencing right now."
Time Frame	0-48 hours

Outcome Measure Data

Analysis Population Description

Efficacy population: all participants who received study drug and underwent the surgery, with analysis based on randomized treatment. Under protocol amendment 2, the study arm 266 mg dose of EXPAREL was removed from randomization scheme and efficacy endpoints.

Arm/Group Title	EXPAREL 133 mg	Placebo
Arm/Group Description	10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively	20 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively
Measure Participants	69	71
Least Squares Mean (Standard Error) [cm*hr]	136.431 (12.090)	254.119 (11.768)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EXPAREL 133 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LSMD
	Estimated Value	-117.688
	Confidence Interval	(2-Sided) 95%; -150.896 to -84.480
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Total Postsurgical Opioid Consumption Through 48 Hours
Description	Total postsurgical opioid consumption (converted to IV morphine equivalents) through 48 hours
Time Frame	0-48 hours

Outcome Measure Data

Analysis Population Description

Efficacy population: all participants who received study drug and underwent the surgery, with analysis based on randomized treatment. Under protocol amendment 2, the study arm 266 mg dose of EXPAREL was removed from randomization scheme and efficacy endpoints.

Arm/Group Title	EXPAREL 133 mg	Placebo
Arm/Group Description	10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively	20 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively
Measure Participants	69	71
Least Squares Mean (Standard Error) [mg]	11.973 (2.265)	54.303 (10.053)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EXPAREL 133 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LSM treatment ratio
	Estimated Value	0.220
	Confidence Interval	(2-Sided) 95%; 0.131 to 0.371
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Opioid-free Participants Through 48 Hours
Description	Percentage of participants who did not receive opioid medication through 48 hours
Time Frame	0-48 hours

Outcome Measure Data

Analysis Population Description

Efficacy population: all participants who received study drug and underwent the surgery, with analysis based on randomized treatment. Under protocol amendment 2, the study arm 266 mg dose of EXPAREL was removed from randomization scheme and efficacy endpoints.

Arm/Group Title	EXPAREL 133 mg	Placebo
Arm/Group Description	10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively	20 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively
Measure Participants	69	71
Count of Participants [Participants]	9 13%	1 6.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EXPAREL 133 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	0.116
	Confidence Interval	(2-Sided) 95%; 0.032 to 0.200
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Time to First Opioid Rescue Through 48 Hours
Description	Time to first opioid rescue medication consumed through 48 hours. Time to rescue was estimated from Kaplan-Meier analysis and presented as quartiles (ie, time to rescue for the first 25% / 50% / 75% of subjects within each treatment group).
Time Frame	0-48 hours

Outcome Measure Data

Analysis Population Description

Efficacy population: all participants who received study drug and underwent the surgery, with analysis based on randomized treatment. Under protocol amendment 2, the study arm 266 mg dose of EXPAREL was removed from randomization scheme and efficacy endpoints.

Arm/Group Title	EXPAREL 133 mg	Placebo
Arm/Group Description	10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively	20 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively
Measure Participants	69	71
First quartile	0.70	0.38
Median quartile	4.15	0.58
Third quartile	18.82	0.87

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EXPAREL 133 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments

Adverse Events

Time Frame	From screening to postsurgical day 29
Adverse Event Reporting Description	An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related. An AE could therefore have been any unfavorable and unintended sign (eg, abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug without any judgment about causality. Serious AEs were defined as per clinicaltrials.gov.
Arm/Group Title	EXPAREL 133 mg		EXPAREL 266 mg		Placebo
Arm/Group Description	10 mL EXPAREL (bupivacaine liposome injectable suspension) expanded with 10 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively		20 mL EXPAREL (bupivacaine liposome injectable suspension) as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively		20 mL normal saline as single-injection brachial plexus block (interscalene or supraclavicular) ≥1 h preoperatively
All Cause Mortality
	EXPAREL 133 mg		EXPAREL 266 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/69 (0%)		0/15 (0%)		0/71 (0%)
Serious Adverse Events
	EXPAREL 133 mg		EXPAREL 266 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/69 (2.9%)		1/15 (6.7%)		1/71 (1.4%)
Gastrointestinal disorders
Pancreatitis	0/69 (0%)		1/15 (6.7%)		0/71 (0%)
Infections and infestations
Clostridium difficile colitis	0/69 (0%)		0/15 (0%)		1/71 (1.4%)
Pneumonia	1/69 (1.4%)		0/15 (0%)		0/71 (0%)
Metabolism and nutrition disorders
Gout	1/69 (1.4%)		0/15 (0%)		0/71 (0%)
Other (Not Including Serious) Adverse Events
	EXPAREL 133 mg		EXPAREL 266 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	55/69 (79.7%)		11/15 (73.3%)		55/71 (77.5%)
Cardiac disorders
Tachycardia	1/69 (1.4%)		1/15 (6.7%)		0/71 (0%)
Gastrointestinal disorders
Nausea	17/69 (24.6%)		3/15 (20%)		26/71 (36.6%)
Constipation	6/69 (8.7%)		2/15 (13.3%)		9/71 (12.7%)
Vomiting	4/69 (5.8%)		1/15 (6.7%)		7/71 (9.9%)
Dyspepsia	1/69 (1.4%)		0/15 (0%)		4/71 (5.6%)
Abdominal pain	0/69 (0%)		1/15 (6.7%)		0/71 (0%)
General disorders
Pyrexia	6/69 (8.7%)		1/15 (6.7%)		3/71 (4.2%)
Musculoskeletal and connective tissue disorders
Muscle twitching	5/69 (7.2%)		2/15 (13.3%)		8/71 (11.3%)
Nervous system disorders
Dizziness	2/69 (2.9%)		1/15 (6.7%)		9/71 (12.7%)
Headache	7/69 (10.1%)		1/15 (6.7%)		3/71 (4.2%)
Dysgeusia	6/69 (8.7%)		0/15 (0%)		3/71 (4.2%)
Hypoesthesia	6/69 (8.7%)		0/15 (0%)		1/71 (1.4%)
Paresthesia	1/69 (1.4%)		1/15 (6.7%)		1/71 (1.4%)
Sensory loss	2/69 (2.9%)		1/15 (6.7%)		0/71 (0%)
Psychiatric disorders
Insomnia	2/69 (2.9%)		1/15 (6.7%)		0/71 (0%)
Anxiety	1/69 (1.4%)		1/15 (6.7%)		0/71 (0%)
Skin and subcutaneous tissue disorders
Pruritis	3/69 (4.3%)		1/15 (6.7%)		11/71 (15.5%)
Rash	0/69 (0%)		1/15 (6.7%)		1/71 (1.4%)
Vascular disorders
Hypertension	2/69 (2.9%)		3/15 (20%)		6/71 (8.5%)
Hypotension	1/69 (1.4%)		1/15 (6.7%)		2/71 (2.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Results conducted at Site shall not be published before 1st multicenter publication by Sponsor but can proceed if there is no such publication ≤18 months after study completion/termination at all sites and all data have been received. Before submitting manuscript/materials to an outside person/entity, site shall give Sponsor 60 days to review and comment. Site shall, upon request, further delay publication/presentation for ≤120 days to allow Sponsor to protect its interests in Inventions.