Trial Outcomes & Findings for Topiramate for Cryptogenic Sensory Peripheral Neuropathy in Metabolic Syndrome (CSPN) (NCT NCT02878798)

Last Updated: 2023-11-14

Results Overview

Difference in IENFD change between treatment groups over 96 weeks (fibers/mm) (i.e. the slope of change). A skin biopsy is obtained. The sample is stained for nerve fibers. The rate of change in IENFD in fibers/mm is calculated over the 96 week duration of the study and expressed in change in fibers/mm/year (defined as 52 weeks) over the study period (i.e. the slope of change expressed and change in IENFD in fibers/mm over a 52 week period).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

132 participants

Primary outcome timeframe

96 weeks

Results posted on

2023-11-14

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo An overencapsulated placebo of identical color, shape and packaging to topiramate will be used. Placebo: overencapsulated placebo of identical color, shape and packaging to topiramate	Topiramate Oral topiramate topiramate: Oral topiramate at a target dose of 50mg twice daily.
Overall Study STARTED	66	66
Overall Study COMPLETED	59	59
Overall Study NOT COMPLETED	7	7

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo An overencapsulated placebo of identical color, shape and packaging to topiramate will be used. Placebo: overencapsulated placebo of identical color, shape and packaging to topiramate	Topiramate Oral topiramate topiramate: Oral topiramate at a target dose of 50mg twice daily.
Overall Study Withdrawal by Subject	5	4
Overall Study Lost to Follow-up	2	2
Overall Study Protocol Violation	0	1

Baseline Characteristics

Topiramate for Cryptogenic Sensory Peripheral Neuropathy in Metabolic Syndrome (CSPN)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=66 Participants An overencapsulated placebo of identical color, shape and packaging to topiramate will be used. Placebo: overencapsulated placebo of identical color, shape and packaging to topiramate	Topiramate n=66 Participants Oral topiramate topiramate: Oral topiramate at a target dose of 50mg twice daily.	Total n=132 Participants Total of all reporting groups
Age, Continuous	62.7 years STANDARD_DEVIATION 10.7 • n=5 Participants	61.9 years STANDARD_DEVIATION 9.9 • n=7 Participants	62.3 years STANDARD_DEVIATION 10.3 • n=5 Participants
Sex: Female, Male Female	22 Participants n=5 Participants	28 Participants n=7 Participants	50 Participants n=5 Participants
Sex: Female, Male Male	44 Participants n=5 Participants	38 Participants n=7 Participants	82 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	62 Participants n=5 Participants	66 Participants n=7 Participants	128 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	6 Participants n=5 Participants	3 Participants n=7 Participants	9 Participants n=5 Participants
Race (NIH/OMB) White	60 Participants n=5 Participants	62 Participants n=7 Participants	122 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	66 participants n=5 Participants	66 participants n=7 Participants	132 participants n=5 Participants

PRIMARY outcome

Timeframe: 96 weeks

Outcome measures

Outcome measures
Measure	Placebo n=66 Participants An overencapsulated placebo of identical color, shape and packaging to topiramate will be used. Placebo: overencapsulated placebo of identical color, shape and packaging to topiramate	Topiramate n=66 Participants Oral topiramate topiramate: Oral topiramate at a target dose of 50mg twice daily.
Intraepidermal Nerve Fiber Density (IENFD)	-0.6064 fibers/mm/year (52 weeks) Interval -1.1785 to -0.03437	-0.396 fibers/mm/year (52 weeks) Interval -0.9625 to 0.1705

PRIMARY outcome

Timeframe: 96 weeks (expressed as a slope in change of total score/52 weeks)

Difference in NQOL between treatment groups over 96 weeks. The Norfolk QOL-DN is a validated 47-item, patient-reported outcome measure, sensitive to the different features of diabetic neuropathy (DN) including small fiber, large fiber, and autonomic function. A lower score is better. The range of the score is from -4 to 136. The slope of the change in total Norfolk QOL-DD is calculated as the change in total score/52 weeks (one year)

Outcome measures

Outcome measures
Measure	Placebo n=66 Participants An overencapsulated placebo of identical color, shape and packaging to topiramate will be used. Placebo: overencapsulated placebo of identical color, shape and packaging to topiramate	Topiramate n=66 Participants Oral topiramate topiramate: Oral topiramate at a target dose of 50mg twice daily.
Norfolk Quality of Life - Diabetic Neuropathy	3.5815 Change inTotal NQOL-DN score over 52 wks Interval 1.3162 to 5.8467	2.0596 Change inTotal NQOL-DN score over 52 wks Interval -0.2545 to 4.3737

SECONDARY outcome

Timeframe: 96 weeks (expressed as a change in change in pain interference/52weeks)

Pain interference score. Each item is scored from 0-10 with a total possible number of points of 70, higher worse. The range of the score is 0-70. The change in score is expressed as a slope of change in pain interference score/52 weeks (one year)

Outcome measures

Outcome measures
Measure	Placebo n=66 Participants An overencapsulated placebo of identical color, shape and packaging to topiramate will be used. Placebo: overencapsulated placebo of identical color, shape and packaging to topiramate	Topiramate n=66 Participants Oral topiramate topiramate: Oral topiramate at a target dose of 50mg twice daily.
Brief Pain Inventory - Diabetic Neuropathy (BPI-DN) Pain Interference	0.1999 Slope of change in BPI-DN PI over 52 wks Interval -0.3602 to 0.76	0.1767 Slope of change in BPI-DN PI over 52 wks Interval -0.3984 to 0.7517

SECONDARY outcome

Timeframe: 96 weeks (expressed as a slope of change over 52 weeks)

Average pain severity. Each item is scored 0-10 with a total of 40 possible points, higher is worse. The range of the score is 0-40. The slope of the change in this score is expressed as change/one year (defined as 52 weeks)

Outcome measures

Outcome measures
Measure	Placebo n=66 Participants An overencapsulated placebo of identical color, shape and packaging to topiramate will be used. Placebo: overencapsulated placebo of identical color, shape and packaging to topiramate	Topiramate n=66 Participants Oral topiramate topiramate: Oral topiramate at a target dose of 50mg twice daily.
Brief Pain Inventory - Diabetic Neuropathy (BPI-DN) Average Pain Intensity	-0.1046 Slope of change in BPI-DN pain over 52 w Interval -0.3431 to 0.1338	-0.2726 Slope of change in BPI-DN pain over 52 w Interval -0.5176 to -0.0276

SECONDARY outcome

Timeframe: 96 weeks (expressed as a slope of change in total UENS over 52 weeks).

The UENS is a validated examination score of neuropathy severity based on a physical examination (Singleton et al 2008). Total score is 42 (minimum 0 and maximum 42). The higher the score, the worse the outcome is. The change in UENS over the 96 week period is expressed as a slope of change in total UENS over one year defined as 52 weeks.

Outcome measures

Outcome measures
Measure	Placebo n=66 Participants An overencapsulated placebo of identical color, shape and packaging to topiramate will be used. Placebo: overencapsulated placebo of identical color, shape and packaging to topiramate	Topiramate n=66 Participants Oral topiramate topiramate: Oral topiramate at a target dose of 50mg twice daily.
Utah Early Neuropathy Scale	0.4281 Slope of change in Total UENS over 52wks Interval -0.2409 to 1.097	0.3671 Slope of change in Total UENS over 52wks Interval -0.322 to 1.0562

SECONDARY outcome

Timeframe: 96 weeks (slope of change in mV/52weeks)

Change in SSA measured in microvolts. SSA is measured by electrically stimulating a nerve through the skin and recording the response. A larger value is better. The normal values vary based on age, with a minimum of 0 (absent). Across all ages, the lower limit of normal is 6 microvolts, although the normal cutoff declines with aging. The change in SSA over the 96 week study period is expressed as a slope of change in uV/52 weeks (the 52 week log (mV) change of non-zero values).

Outcome measures

Outcome measures
Measure	Placebo n=66 Participants An overencapsulated placebo of identical color, shape and packaging to topiramate will be used. Placebo: overencapsulated placebo of identical color, shape and packaging to topiramate	Topiramate n=66 Participants Oral topiramate topiramate: Oral topiramate at a target dose of 50mg twice daily.
Sural Sensory Amplitude (SSA)	0.0334 slope of change in SSA uV over 52 wks Interval -0.032 to 0.0987	0.044 slope of change in SSA uV over 52 wks Interval -0.0232 to 0.1111

SECONDARY outcome

Timeframe: 96 weeks (expressed as a slope of change in meter/sec over 52 weeks)

PMCV change. PMCV is measured by electrically stimulating the nerve through the skin at two different locations and measuring how fast the response travels between the two in meters/second. A higher value is better. The slope of the change in PMCV is expressed as change in meters/second/52 weeks (one year).

Outcome measures

Outcome measures
Measure	Placebo n=60 Participants An overencapsulated placebo of identical color, shape and packaging to topiramate will be used. Placebo: overencapsulated placebo of identical color, shape and packaging to topiramate	Topiramate n=63 Participants Oral topiramate topiramate: Oral topiramate at a target dose of 50mg twice daily.
Peroneal Motor Conduction Velocity (PMCV)	-0.04363 Slope of change in M/S over 52 wks Interval -0.5073 to 0.42	-0.783 Slope of change in M/S over 52 wks Interval -1.2347 to -0.3314

SECONDARY outcome

Timeframe: 96 weeks (slope of change in kg/m2/52 weeks)

BMI change in kg/m2. BMI is a measure of weight relative to height. The slope of the change in BMI over the study was expressed as change in kg/m2/52 weeks.

Outcome measures

Outcome measures
Measure	Placebo n=66 Participants An overencapsulated placebo of identical color, shape and packaging to topiramate will be used. Placebo: overencapsulated placebo of identical color, shape and packaging to topiramate	Topiramate n=66 Participants Oral topiramate topiramate: Oral topiramate at a target dose of 50mg twice daily.
Body Mass Index (BMI)	-0.1537 Slope of change in BMI kg/m2 over 52wks Interval -0.7461 to 0.4387	-0.2865 Slope of change in BMI kg/m2 over 52wks Interval -0.8952 to 0.3221

SECONDARY outcome

Timeframe: The annual slope of the change in A1C over 96 weeks expressed in change in percent/52 weeks

Slope of the Hemoglobin A1C change. A1C is measured in percent. It provides an estimate of how high blood sugar has been over the past three months. A higher value indicates poor diabetic control.

Outcome measures

Outcome measures
Measure	Placebo n=66 Participants An overencapsulated placebo of identical color, shape and packaging to topiramate will be used. Placebo: overencapsulated placebo of identical color, shape and packaging to topiramate	Topiramate n=66 Participants Oral topiramate topiramate: Oral topiramate at a target dose of 50mg twice daily.
Hemoglobin A1C	0.03 change in %/52 weeks over 96 weeks Interval -0.0281 to 0.088	0.0279 change in %/52 weeks over 96 weeks Interval -0.0299 to 0.0858

SECONDARY outcome

Timeframe: 96 weeks (slope of change mg/dl over 52 weeks)

TRG change. TRG are a type of lipid or fat circulating in the blood. A higher value is associated with increased cardiovascular risk. The slope of the change in TRG was calculated as change in mg/dl over 52 weeks (one year).

Outcome measures

Outcome measures
Measure	Placebo n=66 Participants An overencapsulated placebo of identical color, shape and packaging to topiramate will be used. Placebo: overencapsulated placebo of identical color, shape and packaging to topiramate	Topiramate n=66 Participants Oral topiramate topiramate: Oral topiramate at a target dose of 50mg twice daily.
Serum Triglycerides (TRG)	0.022 change in mg/dl/52 weeks over 96 weeks Interval -0.0258 to 0.0698	-0.0176 change in mg/dl/52 weeks over 96 weeks Interval -0.0654 to 0.0301

SECONDARY outcome

Timeframe: 96 weeks (expressed as a slope of change in mg/dl/52 weeks)

LDL change. LDL is "bad" cholesterol, measured in mg/dL. A higher value is associated with elevated cardiovascular risk. A slope of change is calculated change in LDL in mg/dL/52 weeks (one year)

Outcome measures

Outcome measures
Measure	Placebo n=66 Participants An overencapsulated placebo of identical color, shape and packaging to topiramate will be used. Placebo: overencapsulated placebo of identical color, shape and packaging to topiramate	Topiramate n=66 Participants Oral topiramate topiramate: Oral topiramate at a target dose of 50mg twice daily.
LDL Cholesterol	-6.6584 change in mg/dl/52 weeks at 96 weeks Interval -12.7056 to -0.6112	-4.2736 change in mg/dl/52 weeks at 96 weeks Interval -10.3001 to 1.7529

SECONDARY outcome

Timeframe: 96 weeks (expressed as slope of change in mg/dL/52 weeks)

HDL change. HDL is "good cholesterol", measured in mg/dL. A lower value is associated with higher cardiovascular risk. The slope of change is calculated as change in mg/dL/52 weeks (one year)

Outcome measures

Outcome measures
Measure	Placebo n=66 Participants An overencapsulated placebo of identical color, shape and packaging to topiramate will be used. Placebo: overencapsulated placebo of identical color, shape and packaging to topiramate	Topiramate n=66 Participants Oral topiramate topiramate: Oral topiramate at a target dose of 50mg twice daily.
HDL Cholesterol	0.8156 change in mg/dl/52 weeks at 96 weeks Interval -0.9673 to 2.5985	-0.2391 change in mg/dl/52 weeks at 96 weeks Interval -2.0143 to 1.5361

Adverse Events

Placebo

Serious events: 9 serious events

Other events: 56 other events

Deaths: 0 deaths

Topiramate

Serious events: 4 serious events

Other events: 61 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Dr. A. Gordon Smith

Virginia Commonwealth University

Phone: 801-828-9869

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Placebo n=66 participants at risk An overencapsulated placebo of identical color, shape and packaging to topiramate will be used. Placebo: overencapsulated placebo of identical color, shape and packaging to topiramate	Topiramate n=66 participants at risk Oral topiramate topiramate: Oral topiramate at a target dose of 50mg twice daily.
Eye disorders Cataract	0.00% 0/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.	1.5% 1/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate Cancer	3.0% 2/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.	0.00% 0/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.
Cardiac disorders Aortic Aneurysm	1.5% 1/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.	0.00% 0/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.
Cardiac disorders Atrial Fibrillation	1.5% 1/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.	0.00% 0/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.
Skin and subcutaneous tissue disorders Decubitis Ulcer	1.5% 1/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.	0.00% 0/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.
Cardiac disorders Dressler's Syndrome	1.5% 1/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.	0.00% 0/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.
Nervous system disorders Lumbar Spinal Stenosis	1.5% 1/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.	0.00% 0/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.
Cardiac disorders Myocardial Infarction	1.5% 1/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.	0.00% 0/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.
Respiratory, thoracic and mediastinal disorders Non-Small Cell Lung Cancer	1.5% 1/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.	0.00% 0/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.
Surgical and medical procedures Parathyroidectomy	1.5% 1/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.	0.00% 0/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.
Infections and infestations Pneumonia	1.5% 1/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.	0.00% 0/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.
Infections and infestations Sepsis	1.5% 1/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.	0.00% 0/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.
Musculoskeletal and connective tissue disorders Tendon Rupture	1.5% 1/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.	0.00% 0/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.
Gastrointestinal disorders Appendicitis	0.00% 0/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.	1.5% 1/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.
Gastrointestinal disorders Ileus	0.00% 0/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.	1.5% 1/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.
Infections and infestations Localized Infection	0.00% 0/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.	1.5% 1/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.
Surgical and medical procedures Osteotomy	0.00% 0/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.	1.5% 1/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.
Nervous system disorders Seizure	0.00% 0/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.	1.5% 1/66 • Participants will be monitored for AEs from the time they sign consent until 30 days following permanent discontinuation of study drug. If an observed or reported sign, symptom, or clinically significant (CS) laboratory anomaly is not considered by the Site Investigator to be a component of a specific disease or syndrome, then it should be recorded as a separate AE on the AE CRF. CS laboratory abnormalities, such as those that require intervention, are those that are identified as such by the Site Investigator.