Trial Outcomes & Findings for A Study of LY3303560 in Participants With Early Symptomatic Alzheimer's Disease (NCT NCT03518073)

Last Updated: 2022-08-30

Results Overview

Integrated Alzheimer's Disease Rating Scale (iADRS) is a simple linear combination of scores from 13-item alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog13) and the Alzheimer's disease cooperative study-instrumental activities of daily living scale (ADCS-iADL). It is used to assess whether zagotenemab slows down the cognitive and functional decline associated with early symptomatic Alzheimer's Disease, compared to placebo. The iADRS score ranges from 0 to 144 with lower scores indicating worse performance and higher score better performance. Change from baseline was calculated using Bayesian disease progression model (DPM) with fixed, categorical effects of treatment, pooled site, acetylcholinesterase inhibitor (AChEI) use at baseline (yes/no), and the continuous effects of baseline score and age at baseline. Data presented are posterior mean with 95% credible interval.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

360 participants

Primary outcome timeframe

Baseline, Week 104

Results posted on

2022-08-30

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Participants received intravenous (IV) infusion of placebo once every four weeks (Q4W) for 100 weeks.	Zagotenemab 1400 mg Participants received IV infusion of 1400 milligram (mg) zagotenemab Q4W for 100 weeks.	Zagotenemab 5600 mg Participants received IV infusion of 5600 mg zagotenemab Q4W for 100 weeks.
Overall Study STARTED	118	126	116
Overall Study Received at Least One Dose of Study Drug	118	126	116
Overall Study COMPLETED	74	78	70
Overall Study NOT COMPLETED	44	48	46

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received intravenous (IV) infusion of placebo once every four weeks (Q4W) for 100 weeks.	Zagotenemab 1400 mg Participants received IV infusion of 1400 milligram (mg) zagotenemab Q4W for 100 weeks.	Zagotenemab 5600 mg Participants received IV infusion of 5600 mg zagotenemab Q4W for 100 weeks.
Overall Study Adverse Event	2	4	2
Overall Study Death	2	1	3
Overall Study Lost to Follow-up	1	0	1
Overall Study Physician Decision	5	0	2
Overall Study Progressive disease	1	1	1
Overall Study Protocol Violation	1	0	0
Overall Study Withdrawal by Subject	30	34	29
Overall Study Withdrawal Due To Caregiver Circumstances	1	6	7
Overall Study Covid-19	1	2	1

Baseline Characteristics

All randomized participants with iADRS data at baseline.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=118 Participants Participants received IV infusion of placebo Q4W for 100 weeks.	Zagotenemab 1400 mg n=126 Participants Participants received IV infusion of 1400 mg zagotenemab Q4W for 100 weeks.	Zagotenemab 5600 mg n=116 Participants Participants received IV infusion of 5600 mg zagotenemab Q4W for 100 weeks.	Total n=360 Participants Total of all reporting groups
Age, Continuous	75.30 years STANDARD_DEVIATION 5.22 • n=118 Participants	75.10 years STANDARD_DEVIATION 5.33 • n=126 Participants	75.70 years STANDARD_DEVIATION 5.49 • n=116 Participants	75.40 years STANDARD_DEVIATION 5.33 • n=360 Participants
Sex: Female, Male Female	53 Participants n=118 Participants	72 Participants n=126 Participants	65 Participants n=116 Participants	190 Participants n=360 Participants
Sex: Female, Male Male	65 Participants n=118 Participants	54 Participants n=126 Participants	51 Participants n=116 Participants	170 Participants n=360 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants n=118 Participants	3 Participants n=126 Participants	3 Participants n=116 Participants	10 Participants n=360 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	112 Participants n=118 Participants	120 Participants n=126 Participants	110 Participants n=116 Participants	342 Participants n=360 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=118 Participants	3 Participants n=126 Participants	3 Participants n=116 Participants	8 Participants n=360 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=118 Participants	0 Participants n=126 Participants	0 Participants n=116 Participants	0 Participants n=360 Participants
Race (NIH/OMB) Asian	18 Participants n=118 Participants	18 Participants n=126 Participants	17 Participants n=116 Participants	53 Participants n=360 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=118 Participants	0 Participants n=126 Participants	1 Participants n=116 Participants	1 Participants n=360 Participants
Race (NIH/OMB) Black or African American	2 Participants n=118 Participants	2 Participants n=126 Participants	2 Participants n=116 Participants	6 Participants n=360 Participants
Race (NIH/OMB) White	98 Participants n=118 Participants	106 Participants n=126 Participants	96 Participants n=116 Participants	300 Participants n=360 Participants
Race (NIH/OMB) More than one race	0 Participants n=118 Participants	0 Participants n=126 Participants	0 Participants n=116 Participants	0 Participants n=360 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=118 Participants	0 Participants n=126 Participants	0 Participants n=116 Participants	0 Participants n=360 Participants
Region of Enrollment Canada	15 Participants n=118 Participants	15 Participants n=126 Participants	13 Participants n=116 Participants	43 Participants n=360 Participants
Region of Enrollment Japan	15 Participants n=118 Participants	17 Participants n=126 Participants	17 Participants n=116 Participants	49 Participants n=360 Participants
Region of Enrollment United States	88 Participants n=118 Participants	94 Participants n=126 Participants	86 Participants n=116 Participants	268 Participants n=360 Participants
Integrated Alzheimer's Disease Rating Scale (iADRS)	103.50 score on a scale STANDARD_DEVIATION 13.51 • n=118 Participants • All randomized participants with iADRS data at baseline.	105.96 score on a scale STANDARD_DEVIATION 13.34 • n=124 Participants • All randomized participants with iADRS data at baseline.	103.60 score on a scale STANDARD_DEVIATION 11.65 • n=114 Participants • All randomized participants with iADRS data at baseline.	104.39 score on a scale STANDARD_DEVIATION 12.90 • n=356 Participants • All randomized participants with iADRS data at baseline.

PRIMARY outcome

Timeframe: Baseline, Week 104

Population: All randomized participants with baseline, post-baseline iADRS data.

Outcome measures

Outcome measures
Measure	Placebo n=70 Participants Participants received IV infusion of placebo Q4W for 100 weeks.	Zagotenemab 1400 mg n=72 Participants Participants received IV infusion of 1400 mg zagotenemab Q4W for 100 weeks.	Zagotenemab 5600 mg n=68 Participants Participants received IV infusion of 5600 mg zagotenemab Q4W for 100 weeks.
Change From Baseline on the Integrated Alzheimer's Disease Rating Scale (iADRS)	-13.72 score on a scale Interval -15.325 to -12.161	-15.11 score on a scale Interval -16.779 to -13.479	-14.38 score on a scale Interval -16.054 to -12.727

SECONDARY outcome

Timeframe: Baseline, Week 104

Population: All randomized participants with baseline, post-baseline ADAS-Cog13 data.

The ADAS is a rater-administered instrument that was designed to assess the severity of the dysfunction in the cognitive and noncognitive behaviors characteristic of persons with Alzheimer's Disease (AD). The cognitive subscale of the ADAS consists of 13 items assessing areas of cognitive function most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, digit cancellation, and maze completion measures. The ADAS-Cog13 scale ranges from 0 to 85, with higher scores indicating greater disease severity. Change from baseline was calculated using Bayesian disease progression model (DPM) with fixed, categorical effects of treatment, pooled site, acetylcholinesterase inhibitor (AChEI) use at baseline (yes/no), and the continuous effects of baseline score and age at baseline. Data presented are posterior mean with 95% credible interval.

Outcome measures

Outcome measures
Measure	Placebo n=71 Participants Participants received IV infusion of placebo Q4W for 100 weeks.	Zagotenemab 1400 mg n=76 Participants Participants received IV infusion of 1400 mg zagotenemab Q4W for 100 weeks.	Zagotenemab 5600 mg n=69 Participants Participants received IV infusion of 5600 mg zagotenemab Q4W for 100 weeks.
Change From Baseline on the Alzheimer's Disease Assessment Scale- Cognitive Subscale (ADAS-Cog13) Score	7.13 score on a scale Interval 6.176 to 8.104	7.85 score on a scale Interval 6.867 to 8.848	6.30 score on a scale Interval 5.353 to 7.262

SECONDARY outcome

Timeframe: Baseline, Week 104

Population: All randomized participants with baseline, post-baseline ADCS-iADL data.

The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-ADL measures basic, instrumental activities of daily living by participants (instrumental activity items 6a, 7-23). The range for the ADCS-iADL is 0-59, with lower scores indicating greater disease severity. Change from baseline was calculated using Bayesian disease progression model (DPM) with fixed, categorical effects of treatment, pooled site, acetylcholinesterase inhibitor (AChEI) use at baseline (yes/no), and the continuous effects of baseline score and age at baseline. Data presented are posterior mean with 95% credible interval.

Outcome measures

Outcome measures
Measure	Placebo n=72 Participants Participants received IV infusion of placebo Q4W for 100 weeks.	Zagotenemab 1400 mg n=74 Participants Participants received IV infusion of 1400 mg zagotenemab Q4W for 100 weeks.	Zagotenemab 5600 mg n=69 Participants Participants received IV infusion of 5600 mg zagotenemab Q4W for 100 weeks.
Change From Baseline on the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Scale (ADCS-iADL) Score	-6.67 score on a scale Interval -7.73 to -5.643	-7.06 score on a scale Interval -8.148 to -6.004	-8.05 score on a scale Interval -9.203 to -6.922

SECONDARY outcome

Timeframe: Baseline, Week 104

Population: All randomized participants with baseline, post-baseline CDR-SB data.

CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning: memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score assigned for each of 6 domains; Total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity. Change from baseline was calculated using Bayesian disease progression model (DPM) with fixed, categorical effects of treatment, pooled site, acetylcholinesterase inhibitor (AChEI) use at baseline (yes/no), and the continuous effects of baseline score and age at baseline. Data presented are posterior mean with 95% credible interval.

Outcome measures

Outcome measures
Measure	Placebo n=72 Participants Participants received IV infusion of placebo Q4W for 100 weeks.	Zagotenemab 1400 mg n=75 Participants Participants received IV infusion of 1400 mg zagotenemab Q4W for 100 weeks.	Zagotenemab 5600 mg n=68 Participants Participants received IV infusion of 5600 mg zagotenemab Q4W for 100 weeks.
Change From Baseline on the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) Score	2.26 score on a scale Interval 1.976 to 2.544	2.52 score on a scale Interval 2.233 to 2.815	2.14 score on a scale Interval 1.854 to 2.439

SECONDARY outcome

Timeframe: Baseline, Week 104

Population: All randomized participants with baseline, post-baseline MMSE data.

The MMSE is a brief instrument used to assess cognitive function. The instrument is divided into 2 sections. The first section measures orientation, memory, and attention. The maximum score for the first section is 21. The second section tests the ability of the person to name objects, follow verbal and written commands, write a sentence, and copy figures. The maximum score for the second section is 9. The range for the total MMSE score is 0 to 30, with lower scores indicating greater level of impairment. Change from baseline was calculated using Bayesian disease progression model (DPM) with fixed, categorical effects of treatment, pooled site, acetylcholinesterase inhibitor (AChEI) use at baseline (yes/no), and the continuous effects of baseline score and age at baseline. Data presented are posterior mean with 95% credible interval.

Outcome measures

Outcome measures
Measure	Placebo n=72 Participants Participants received IV infusion of placebo Q4W for 100 weeks.	Zagotenemab 1400 mg n=76 Participants Participants received IV infusion of 1400 mg zagotenemab Q4W for 100 weeks.	Zagotenemab 5600 mg n=68 Participants Participants received IV infusion of 5600 mg zagotenemab Q4W for 100 weeks.
Change From Baseline on the Mini Mental Status Examination (MMSE) Score	-4.29 score on a scale Interval -4.858 to -3.739	-4.44 score on a scale Interval -4.994 to -3.901	-3.83 score on a scale Interval -4.4 to -3.265

SECONDARY outcome

Timeframe: Baseline, Week 104

Population: All randomized participants with baseline, post-baseline PET tau data.

Deposition of abnormal tau protein in the brain associated with AD was assessed by quantitative PET scan using flortaucipir F-18. Flortaucipir is an F-18-labeled small molecule that binds with high affinity and selectivity to aggregated tau, and provides a measure of aggregated tau deposition in the brain, expressed as flortaucipir standardized uptake value ratio (SUVr). Change from baseline was calculated using mixed model repeated measures (MMRM) with fixed, categorical effects of treatment, visit, treatment-by-visit interaction, and continuous effect of baseline SUVr and age. A positive change from baseline indicates increased aggregated tau deposition that is believed to be associated with a more rapid rate of cognitive deterioration.

Outcome measures

Outcome measures
Measure	Placebo n=62 Participants Participants received IV infusion of placebo Q4W for 100 weeks.	Zagotenemab 1400 mg n=66 Participants Participants received IV infusion of 1400 mg zagotenemab Q4W for 100 weeks.	Zagotenemab 5600 mg n=63 Participants Participants received IV infusion of 5600 mg zagotenemab Q4W for 100 weeks.
Change From Baseline in Brain Aggregated Tau Deposition as Measured by Flortaucipir F-18 Positron Emission Tomography (PET) Scan.	0.08 standardized uptake value ratio (SUVr) Standard Error 0.012	0.10 standardized uptake value ratio (SUVr) Standard Error 0.011	0.10 standardized uptake value ratio (SUVr) Standard Error 0.012

SECONDARY outcome

Timeframe: Baseline, Week 104

Population: All randomized participants with baseline, post-baseline vMRI brain volume data.

Alzheimer's disease is also associated with pronounced brain atrophy, reflecting bulk neurodegenerative loss of gray and white matter. Progression of brain atrophy is assessed by vMRI, providing regional quantification of volume loss. Negative change from baseline indicates greater disease severity. Change from baseline was calculated using mixed model repeated measures (MMRM) with fixed, categorical effects of treatment, visit, treatment-by-visit interaction, and continuous effect of baseline vMRI, baseline intracranial volume (ICV) and age.

Outcome measures

Outcome measures
Measure	Placebo n=64 Participants Participants received IV infusion of placebo Q4W for 100 weeks.	Zagotenemab 1400 mg n=65 Participants Participants received IV infusion of 1400 mg zagotenemab Q4W for 100 weeks.	Zagotenemab 5600 mg n=57 Participants Participants received IV infusion of 5600 mg zagotenemab Q4W for 100 weeks.
Change From Baseline in Brain Volume as Measured by Volumetric Magnetic Resonance Imaging (vMRI)	-24.06 cubic centimeter (cm^3) Standard Error 1.101	-23.44 cubic centimeter (cm^3) Standard Error 1.095	-23.55 cubic centimeter (cm^3) Standard Error 1.158

SECONDARY outcome

Timeframe: Baseline through Week 104

Population: All randomized participants who received at least one dose of study drug and had baseline, at least one post baseline C-SSRS assessment.

C-SSRS is a scale capturing occurrence, severity, and frequency of suicide-related thoughts and behaviours, and has a binary response (yes/no). * Suicidal Ideation: a "yes" answer to any one of 5 suicidal ideation questions: Wish to be Dead, Non-specific Active Suicidal Thoughts, Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act, Active Suicidal Ideation with Some Intent to Act without Specific Plan, Active Suicidal Ideation with Specific Plan and Intent. * Suicidal Behaviour: a "yes" answer to any of 5 suicidal behaviour questions: Preparatory Acts or Behaviour, Aborted Attempt, Interrupted Attempt, Actual Attempt (non-fatal), Completed Suicide.

Outcome measures

Outcome measures
Measure	Placebo n=118 Participants Participants received IV infusion of placebo Q4W for 100 weeks.	Zagotenemab 1400 mg n=126 Participants Participants received IV infusion of 1400 mg zagotenemab Q4W for 100 weeks.	Zagotenemab 5600 mg n=116 Participants Participants received IV infusion of 5600 mg zagotenemab Q4W for 100 weeks.
Number of Participants With Suicidal Ideation and Behaviors Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation	5 Participants	5 Participants	5 Participants
Number of Participants With Suicidal Ideation and Behaviors Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Suicidal Behaviour	1 Participants	2 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline through Week 113

Population: All randomized participants who received at least one dose of zagotenemab and had baseline, at least one post baseline ADA assessment.

A TE-ADA evaluable subject is considered to be TE-ADA positive: * If the subject has at least one post baseline titer that is a 4-fold or greater increase in titer from baseline measurement (treatment-boosted). * If baseline result is ADA Not Present, then the subject is TE ADA positive if there is at least one postbaseline result of ADA Present with titer \>= 1:10 (treatment-induced).

Outcome measures

Outcome measures
Measure	Placebo n=126 Participants Participants received IV infusion of placebo Q4W for 100 weeks.	Zagotenemab 1400 mg n=115 Participants Participants received IV infusion of 1400 mg zagotenemab Q4W for 100 weeks.	Zagotenemab 5600 mg Participants received IV infusion of 5600 mg zagotenemab Q4W for 100 weeks.
Number of Participants With Treatment Emergent Anti-Drug Antibodies (TE-ADA) to Zagotenemab	2 Participants	1 Participants	—

Adverse Events

Placebo

Serious events: 14 serious events

Other events: 61 other events

Deaths: 2 deaths

Zagotenemab 1400 mg

Serious events: 22 serious events

Other events: 68 other events

Deaths: 1 deaths

Zagotenemab 5600 mg

Serious events: 19 serious events

Other events: 71 other events

Deaths: 3 deaths

Serious adverse events

Other adverse events

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	Placebo n=118 participants at risk Participants received IV infusion of placebo Q4W for 100 weeks.	Zagotenemab 1400 mg n=126 participants at risk Participants received IV infusion of 1400 mg zagotenemab Q4W for 100 weeks.	Zagotenemab 5600 mg n=116 participants at risk Participants received IV infusion of 5600 mg zagotenemab Q4W for 100 weeks.
Blood and lymphatic system disorders Anaemia	0.85% 1/118 • Number of events 1 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	1.6% 2/126 • Number of events 2 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	5.2% 6/116 • Number of events 6 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Gastrointestinal disorders Diarrhoea	4.2% 5/118 • Number of events 7 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	7.9% 10/126 • Number of events 12 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	9.5% 11/116 • Number of events 13 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Gastrointestinal disorders Nausea	1.7% 2/118 • Number of events 3 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	5.6% 7/126 • Number of events 10 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	5.2% 6/116 • Number of events 6 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Gastrointestinal disorders Vomiting	1.7% 2/118 • Number of events 2 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	5.6% 7/126 • Number of events 8 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.3% 5/116 • Number of events 10 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
General disorders Fatigue	3.4% 4/118 • Number of events 4 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.0% 5/126 • Number of events 5 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	5.2% 6/116 • Number of events 7 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
General disorders Gait disturbance	0.00% 0/118 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	5.6% 7/126 • Number of events 7 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	3.4% 4/116 • Number of events 4 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Infections and infestations Nasopharyngitis	10.2% 12/118 • Number of events 13 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.0% 5/126 • Number of events 5 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	6.9% 8/116 • Number of events 8 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Infections and infestations Upper respiratory tract infection	6.8% 8/118 • Number of events 10 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	3.2% 4/126 • Number of events 4 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	2.6% 3/116 • Number of events 4 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Injury, poisoning and procedural complications Fall	13.6% 16/118 • Number of events 28 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	14.3% 18/126 • Number of events 23 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	12.9% 15/116 • Number of events 18 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Injury, poisoning and procedural complications Skin abrasion	2.5% 3/118 • Number of events 3 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	1.6% 2/126 • Number of events 2 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	6.0% 7/116 • Number of events 8 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Injury, poisoning and procedural complications Skin laceration	5.9% 7/118 • Number of events 11 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	7.1% 9/126 • Number of events 9 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	6.0% 7/116 • Number of events 7 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Musculoskeletal and connective tissue disorders Arthralgia	7.6% 9/118 • Number of events 9 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.8% 6/126 • Number of events 6 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	8.6% 10/116 • Number of events 13 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Musculoskeletal and connective tissue disorders Back pain	4.2% 5/118 • Number of events 5 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	3.2% 4/126 • Number of events 4 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	7.8% 9/116 • Number of events 15 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Musculoskeletal and connective tissue disorders Pain in extremity	4.2% 5/118 • Number of events 6 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.0% 5/126 • Number of events 5 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	6.9% 8/116 • Number of events 8 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Nervous system disorders Dizziness	8.5% 10/118 • Number of events 13 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	7.9% 10/126 • Number of events 16 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	9.5% 11/116 • Number of events 16 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Nervous system disorders Headache	5.9% 7/118 • Number of events 7 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.0% 5/126 • Number of events 9 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	5.2% 6/116 • Number of events 7 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Psychiatric disorders Anxiety	5.9% 7/118 • Number of events 9 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	3.2% 4/126 • Number of events 5 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	7.8% 9/116 • Number of events 11 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Psychiatric disorders Depression	1.7% 2/118 • Number of events 2 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.0% 5/126 • Number of events 6 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	5.2% 6/116 • Number of events 6 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Psychiatric disorders Insomnia	3.4% 4/118 • Number of events 4 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	5.6% 7/126 • Number of events 7 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	5.2% 6/116 • Number of events 6 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Respiratory, thoracic and mediastinal disorders Cough	3.4% 4/118 • Number of events 6 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	4.8% 6/126 • Number of events 6 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	6.0% 7/116 • Number of events 7 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.
Vascular disorders Hypertension	2.5% 3/118 • Number of events 3 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	5.6% 7/126 • Number of events 7 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.	3.4% 4/116 • Number of events 5 • Baseline through End of Study (Up To 113 Weeks) All randomized participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At Risk adjusted accordingly.