Trial Outcomes & Findings for A Study of LY3202626 on Disease Progression in Participants With Mild Alzheimer's Disease Dementia (NCT NCT02791191)

Last Updated: 2021-04-19

Results Overview

The 18F-AV-1451 PET tracer assesses change from baseline in the pharmacodynamic effect of 3 mg and 12 mg doses of LY3202626 in participants with mild Alzheimer's disease (AD), compared with placebo at Week 52.The SUVr of ¹⁸F-AV-1451 was modeled using analysis of covariance (ANCOVA) to include the fixed, categorical effects of treatment dose, and the continuous, fixed covariate of baseline Tau PET SUVr and age at baseline.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

316 participants

Primary outcome timeframe

Baseline, Week 52

Results posted on

2021-04-19

Participant Flow

Participant milestones

Participant milestones
Measure	3 mg LY3202626 3 mg LY3202626 administered orally once daily for 52 weeks.	12 mg LY3202626 12 mg LY3202626 administered orally once daily for 52 weeks.	Placebo Placebo administered orally once daily for 52 weeks.
Overall Study STARTED	55	128	133
Overall Study Received One Dose of Study Drug	55	127	133
Overall Study COMPLETED	17	17	13
Overall Study NOT COMPLETED	38	111	120

Reasons for withdrawal

Reasons for withdrawal
Measure	3 mg LY3202626 3 mg LY3202626 administered orally once daily for 52 weeks.	12 mg LY3202626 12 mg LY3202626 administered orally once daily for 52 weeks.	Placebo Placebo administered orally once daily for 52 weeks.
Overall Study Adverse Event	2	4	5
Overall Study Lack of Efficacy	0	1	0
Overall Study Study Drug Non-Compliance	0	2	0
Overall Study Site Closed by Sponsor	1	1	3
Overall Study Progressive Disease	1	0	0
Overall Study Study Terminated by Sponsor	29	101	109
Overall Study Withdrawal by Subject	3	1	3
Overall Study Subject Withdrew Caregiver Circumstances	2	1	0

Baseline Characteristics

Participants who completed the baseline ¹⁸F-AV-1451 Positron Emission Tomography (PET) and had evaluable Standard Uptake Value Ratio (SUVr).

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	3 mg LY3202626 n=55 Participants 3 mg LY3202626 administered orally once daily for 52 weeks.	12 mg LY3202626 n=128 Participants 12 mg LY3202626 administered orally once daily for 52 weeks.	Placebo n=133 Participants Placebo administered orally once daily for 52 weeks.	Total n=316 Participants Total of all reporting groups
Age, Continuous	73.91 years STANDARD_DEVIATION 6.72 • n=55 Participants	72.73 years STANDARD_DEVIATION 7.15 • n=128 Participants	72.54 years STANDARD_DEVIATION 7.80 • n=133 Participants	72.86 years STANDARD_DEVIATION 7.36 • n=316 Participants
Sex: Female, Male Female	29 Participants n=55 Participants	86 Participants n=128 Participants	77 Participants n=133 Participants	192 Participants n=316 Participants
Sex: Female, Male Male	26 Participants n=55 Participants	42 Participants n=128 Participants	56 Participants n=133 Participants	124 Participants n=316 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=55 Participants	5 Participants n=128 Participants	7 Participants n=133 Participants	13 Participants n=316 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	50 Participants n=55 Participants	108 Participants n=128 Participants	112 Participants n=133 Participants	270 Participants n=316 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants n=55 Participants	15 Participants n=128 Participants	14 Participants n=133 Participants	33 Participants n=316 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=55 Participants	0 Participants n=128 Participants	0 Participants n=133 Participants	0 Participants n=316 Participants
Race (NIH/OMB) Asian	8 Participants n=55 Participants	18 Participants n=128 Participants	13 Participants n=133 Participants	39 Participants n=316 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=55 Participants	0 Participants n=128 Participants	1 Participants n=133 Participants	2 Participants n=316 Participants
Race (NIH/OMB) Black or African American	1 Participants n=55 Participants	5 Participants n=128 Participants	4 Participants n=133 Participants	10 Participants n=316 Participants
Race (NIH/OMB) White	45 Participants n=55 Participants	104 Participants n=128 Participants	113 Participants n=133 Participants	262 Participants n=316 Participants
Race (NIH/OMB) More than one race	0 Participants n=55 Participants	1 Participants n=128 Participants	2 Participants n=133 Participants	3 Participants n=316 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=55 Participants	0 Participants n=128 Participants	0 Participants n=133 Participants	0 Participants n=316 Participants
Region of Enrollment Canada	0 Participants n=55 Participants	1 Participants n=128 Participants	1 Participants n=133 Participants	2 Participants n=316 Participants
Region of Enrollment United States	43 Participants n=55 Participants	86 Participants n=128 Participants	105 Participants n=133 Participants	234 Participants n=316 Participants
Region of Enrollment Japan	7 Participants n=55 Participants	18 Participants n=128 Participants	12 Participants n=133 Participants	37 Participants n=316 Participants
Region of Enrollment Australia	5 Participants n=55 Participants	23 Participants n=128 Participants	15 Participants n=133 Participants	43 Participants n=316 Participants
Flortaucipir Standard Uptake Value Ratio (SUVr)	1.32 standard uptake value ratio (SUVr) STANDARD_DEVIATION 0.24 • n=52 Participants • Participants who completed the baseline ¹⁸F-AV-1451 Positron Emission Tomography (PET) and had evaluable Standard Uptake Value Ratio (SUVr).	1.36 standard uptake value ratio (SUVr) STANDARD_DEVIATION 0.28 • n=121 Participants • Participants who completed the baseline ¹⁸F-AV-1451 Positron Emission Tomography (PET) and had evaluable Standard Uptake Value Ratio (SUVr).	1.42 standard uptake value ratio (SUVr) STANDARD_DEVIATION 0.35 • n=119 Participants • Participants who completed the baseline ¹⁸F-AV-1451 Positron Emission Tomography (PET) and had evaluable Standard Uptake Value Ratio (SUVr).	1.38 standard uptake value ratio (SUVr) STANDARD_DEVIATION 0.31 • n=292 Participants • Participants who completed the baseline ¹⁸F-AV-1451 Positron Emission Tomography (PET) and had evaluable Standard Uptake Value Ratio (SUVr).

PRIMARY outcome

Timeframe: Baseline, Week 52

Population: All participants who received at least one dose of study drug, and have baseline and at least one post-baseline scan.

Outcome measures

Outcome measures
Measure	3 mg LY3202626 n=15 Participants 3 mg LY3202626 administered orally once daily for 52 weeks.	12 mg LY3202626 n=15 Participants 12 mg LY3202626 administered orally once daily for 52 weeks.	Placebo n=11 Participants Placebo administered orally once daily for 52 weeks.
Change From Baseline in ¹⁸F-AV-1451 Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVr) at 52 Weeks	0.02 Standard Uptake Value Ratio (SUVr) Standard Deviation 0.04	0.03 Standard Uptake Value Ratio (SUVr) Standard Deviation 0.04	0.01 Standard Uptake Value Ratio (SUVr) Standard Deviation 0.08

SECONDARY outcome

Timeframe: Week 52

Population: All participants who received at least one dose of study drug.

Percentage of participants with treatment-emergent MRI findings at Week 52 are summarized here. The mixed-effect model for repeated measures (MMRM) analysis was adjusted for fixed effects of treatment, visit (categorical covariate), treatment-by-visit interaction, baseline age, baseline score (continuous covariate) and baseline-by-visit interaction.

Outcome measures

Outcome measures
Measure	3 mg LY3202626 n=41 Participants 3 mg LY3202626 administered orally once daily for 52 weeks.	12 mg LY3202626 n=75 Participants 12 mg LY3202626 administered orally once daily for 52 weeks.	Placebo n=62 Participants Placebo administered orally once daily for 52 weeks.
Percentage of Participants With Emergent Magnetic Resonance Imaging (MRI) Findings Other Infarct	0.0 percentage of participants	0.0 percentage of participants	1.6 percentage of participants
Percentage of Participants With Emergent Magnetic Resonance Imaging (MRI) Findings White Matter Disease	2.4 percentage of participants	1.3 percentage of participants	1.6 percentage of participants
Percentage of Participants With Emergent Magnetic Resonance Imaging (MRI) Findings Cortical Infarct	2.4 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants With Emergent Magnetic Resonance Imaging (MRI) Findings Cortical Superficial Siderous	0.0 percentage of participants	1.3 percentage of participants	0.0 percentage of participants
Percentage of Participants With Emergent Magnetic Resonance Imaging (MRI) Findings Lacunar Infarct	0.0 percentage of participants	0.0 percentage of participants	1.6 percentage of participants

SECONDARY outcome

Timeframe: Week 52

Population: All participants who received at least one dose of study drug.

Percentage of participants with presence of amyloid-related imaging abnormalities-edema (ARIA-E, also known as vasogenic edema) and percentage of an increase in amyloid-related imaging abnormalities-hemorrhage (ARIA-H, also known as also known as microhemorrhage) at Week 52 are summarized here. The mixed-effect model for repeated measures (MMRM) analysis was adjusted for fixed effects of treatment, visit (categorical covariate), treatment-by-visit interaction, baseline age, baseline score (continuous covariate) and baseline-by-visit interaction.

Outcome measures

Outcome measures
Measure	3 mg LY3202626 n=41 Participants 3 mg LY3202626 administered orally once daily for 52 weeks.	12 mg LY3202626 n=75 Participants 12 mg LY3202626 administered orally once daily for 52 weeks.	Placebo n=62 Participants Placebo administered orally once daily for 52 weeks.
Percentage of Participants With Amyloid-Related Imaging Abnormalities (ARIA) Increase in Microhemorrhages	4.7 percentage of participants	6.3 percentage of participants	7.5 percentage of participants
Percentage of Participants With Amyloid-Related Imaging Abnormalities (ARIA) Presence of Vasogenic Edema	0.0 percentage of participants	0.0 percentage of participants	1.6 percentage of participants

SECONDARY outcome

Timeframe: Baseline through Week 52

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

The Columbia-Suicide Severity Rating Scale (C-SSRS) captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation is defined as a "yes" answer to any 1 of 5 suicidal ideation questions, which includes a wish to be dead and 4 different categories of active suicidal ideation. Suicidal behavior is defined as a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation and behavior are defined as treatment-emergent (TE) if not present during the period up through randomization. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Event module.

Outcome measures

Outcome measures
Measure	3 mg LY3202626 n=55 Participants 3 mg LY3202626 administered orally once daily for 52 weeks.	12 mg LY3202626 n=127 Participants 12 mg LY3202626 administered orally once daily for 52 weeks.	Placebo n=133 Participants Placebo administered orally once daily for 52 weeks.
Percentage of Participants With Suicidal Ideation and Behaviors Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Scores TE Suicidal Ideation	7.27 percentage of participants	7.09 percentage of participants	3.76 percentage of participants
Percentage of Participants With Suicidal Ideation and Behaviors Assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) Scores TE Suicidal Behavior	1.82 percentage of participants	0.79 percentage of participants	0.00 percentage of participants

SECONDARY outcome

Timeframe: Week 2, 4, and 12: Predose and Postdose prior to departing; Week 8 and 16: Postdose after arriving and prior to departing; Week 24: Postdose after cognitive testing

Population: All participants who received at least one dose of study drug and have evaluable PK data.

PK: AUC \[T,SS\] of LY3202626

Outcome measures

Outcome measures
Measure	3 mg LY3202626 n=55 Participants 3 mg LY3202626 administered orally once daily for 52 weeks.	12 mg LY3202626 n=127 Participants 12 mg LY3202626 administered orally once daily for 52 weeks.	Placebo Placebo administered orally once daily for 52 weeks.
Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve at Steady State (AUC [T,SS]) of LY3202626	158 nanogramhour per milliliter (ngh/mL) Geometric Coefficient of Variation 55.1	641 nanogramhour per milliliter (ngh/mL) Geometric Coefficient of Variation 58.0	—

SECONDARY outcome

Timeframe: Baseline, Week 52

Population: All participants who received at least one dose of study drug, and have baseline and at least one post-baseline measure.

A mixed model repeated measures (MMRM) analysis will be used to evaluate the change from baseline to Week 52 in plasma Aβ₁-₄₀, Aβ₁-₄₂, and Aβ 1-x. The model for the fixed effects will include terms for the following independent effects: log transformed baseline plasma Aβ, treatment, visit, treatment-by-visit interaction.

Outcome measures

Outcome measures
Measure	3 mg LY3202626 n=55 Participants 3 mg LY3202626 administered orally once daily for 52 weeks.	12 mg LY3202626 n=127 Participants 12 mg LY3202626 administered orally once daily for 52 weeks.	Placebo n=133 Participants Placebo administered orally once daily for 52 weeks.
Change From Baseline in Plasma Amyloid Beta Aβ₁-₄₀, ₁-₄₂, and 1-x Concentration Amyloid Beta 1-42	-46.3 nanograms per liter (ng/L) Standard Deviation 38.7	-50.0 nanograms per liter (ng/L) Standard Deviation 34.1	0.0 nanograms per liter (ng/L) Standard Deviation 5.8
Change From Baseline in Plasma Amyloid Beta Aβ₁-₄₀, ₁-₄₂, and 1-x Concentration Amyloid Beta	-258.7 nanograms per liter (ng/L) Standard Deviation 64	-286.1 nanograms per liter (ng/L) Standard Deviation 85.9	-12.0 nanograms per liter (ng/L) Standard Deviation 80.5
Change From Baseline in Plasma Amyloid Beta Aβ₁-₄₀, ₁-₄₂, and 1-x Concentration Amyloid Beta 1-40	-157.3 nanograms per liter (ng/L) Standard Deviation 65.6	-149.3 nanograms per liter (ng/L) Standard Deviation 38.0	-17.0 nanograms per liter (ng/L) Standard Deviation 38.2

SECONDARY outcome

Timeframe: Baseline, Week 52

Population: All participants who received at least one dose of study drug, and have baseline and at least one post-baseline ADAS-Cog₁₃ measure.

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 AD. The cognitive subscale of the ADAS that was used as the primary efficacy measure consists of 13 items assessing areas of cognitive function most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, digit cancellation. The ADAS--Cog13 scale ranges from 0 to 85. Higher scores indicate greater disease severity. A mixed model repeated measures (MMRM) was used in analysis. The model included fixed, categorical effects of treatment, visit and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline, baseline-by-visit, and age at baseline.

Outcome measures

Outcome measures
Measure	3 mg LY3202626 n=17 Participants 3 mg LY3202626 administered orally once daily for 52 weeks.	12 mg LY3202626 n=19 Participants 12 mg LY3202626 administered orally once daily for 52 weeks.	Placebo n=15 Participants Placebo administered orally once daily for 52 weeks.
Change From Baseline on the 13-item Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog₁₃)	3.05 units on a scale Standard Error 1.40	1.88 units on a scale Standard Error 1.33	2.97 units on a scale Standard Error 1.51

SECONDARY outcome

Timeframe: Baseline, Week 52

Population: All participants who received at least one dose of study drug, and have baseline and at least one post-baseline ADCS-iADL measure.

The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-ADL measures both basic and instrumental activities (instrumental activity items 7-23) of daily living by participants. The range for the ADCS-iADL is 0-56 with higher scores reflecting better performance. ADCS-iADL was analyzed using mixed-model repeated measures (MMRM), Least Square (LS) Mean was controlled for treatment, visit, treatment-by-visit interaction, baseline age, baseline score and baseline-by-visit interaction.

Outcome measures

Outcome measures
Measure	3 mg LY3202626 n=17 Participants 3 mg LY3202626 administered orally once daily for 52 weeks.	12 mg LY3202626 n=19 Participants 12 mg LY3202626 administered orally once daily for 52 weeks.	Placebo n=15 Participants Placebo administered orally once daily for 52 weeks.
Change From Baseline on the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Inventory (ADCS-iADL)	-3.97 units on a scale Standard Error 1.34	-4.63 units on a scale Standard Error 1.24	-7.32 units on a scale Standard Error 1.38

SECONDARY outcome

Timeframe: Baseline, Week 52

Population: All participants who received at least one dose of study drug, and have baseline and at least one post-baseline iADRS measure.

The iADRS comprises scores form the ADAS-Cog and the ADCS-iADL. The iADRS is calculated as a linear combination of the total scores of the ADAS-Cog13 9score range 0 to 85 with higher scores reflecting worse performance and the ADCS-iADL (score range 0-56 with higher scores reflecting better performance). The iADRS score ranges from 0 to 141 with lower scores indicating worse performance. iADRS was analyzed using mixed-model repeated measures (MMRM); Least Square (LS) Mean was controlled for treatment, visit, treatment-by-visit interaction, baseline age, baseline score and baseline-by-visit interaction.

Outcome measures

Outcome measures
Measure	3 mg LY3202626 n=16 Participants 3 mg LY3202626 administered orally once daily for 52 weeks.	12 mg LY3202626 n=19 Participants 12 mg LY3202626 administered orally once daily for 52 weeks.	Placebo n=15 Participants Placebo administered orally once daily for 52 weeks.
Change From Baseline on the Integrated Alzheimer's Disease Rating Scale (iADRS)	-6.01 units on a scale Standard Error 2.07	-6.45 units on a scale Standard Error 1.90	-10.32 units on a scale Standard Error 2.15

Adverse Events

3 mg LY3202626

Serious events: 10 serious events

Other events: 46 other events

Deaths: 0 deaths

12 mg LY3202626

Serious events: 8 serious events

Other events: 97 other events

Deaths: 0 deaths

Placebo

Serious events: 10 serious events

Other events: 91 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5079

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	3 mg LY3202626 n=55 participants at risk 3 mg LY3202626 administered orally once daily for 52 weeks.	12 mg LY3202626 n=127 participants at risk 12 mg LY3202626 administered orally once daily for 52 weeks	Placebo n=133 participants at risk Placebo administered orally once daily for 52 weeks.
Blood and lymphatic system disorders Haemorrhagic anaemia	0.00% 0/55 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.75% 1/133 • Number of events 1 • Up to 56 Weeks All randomized participants.
Cardiac disorders Angina pectoris	1.8% 1/55 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.75% 1/133 • Number of events 1 • Up to 56 Weeks All randomized participants.
Cardiac disorders Cardiac failure congestive	0.00% 0/55 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.75% 1/133 • Number of events 1 • Up to 56 Weeks All randomized participants.
Cardiac disorders Coronary artery disease	1.8% 1/55 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.
Gastrointestinal disorders Duodenal ulcer	1.8% 1/55 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.
Gastrointestinal disorders Gastrointestinal haemorrhage	1.8% 1/55 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.
Gastrointestinal disorders Small intestinal obstruction	1.8% 1/55 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.
General disorders Chest discomfort	0.00% 0/55 • Up to 56 Weeks All randomized participants.	0.79% 1/127 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.
General disorders Gait disturbance	0.00% 0/55 • Up to 56 Weeks All randomized participants.	1.6% 2/127 • Number of events 2 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.
General disorders Pyrexia	0.00% 0/55 • Up to 56 Weeks All randomized participants.	0.79% 1/127 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.
Infections and infestations Cystitis	1.8% 1/55 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.
Infections and infestations Influenza	0.00% 0/55 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.75% 1/133 • Number of events 1 • Up to 56 Weeks All randomized participants.
Infections and infestations Pneumonia	1.8% 1/55 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.
Infections and infestations Pyuria	1.8% 1/55 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.
Injury, poisoning and procedural complications Accidental overdose	0.00% 0/55 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.75% 1/133 • Number of events 1 • Up to 56 Weeks All randomized participants.
Injury, poisoning and procedural complications Ankle fracture	1.8% 1/55 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.
Injury, poisoning and procedural complications Confusion postoperative	1.8% 1/55 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.
Injury, poisoning and procedural complications Fall	1.8% 1/55 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.79% 1/127 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.75% 1/133 • Number of events 1 • Up to 56 Weeks All randomized participants.
Injury, poisoning and procedural complications Hip fracture	0.00% 0/55 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.75% 1/133 • Number of events 1 • Up to 56 Weeks All randomized participants.
Injury, poisoning and procedural complications Spinal compression fracture	0.00% 0/55 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.75% 1/133 • Number of events 1 • Up to 56 Weeks All randomized participants.
Metabolism and nutrition disorders Dehydration	0.00% 0/55 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.75% 1/133 • Number of events 1 • Up to 56 Weeks All randomized participants.
Metabolism and nutrition disorders Diabetes mellitus inadequate control	1.8% 1/55 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.
Metabolism and nutrition disorders Hypocalcaemia	0.00% 0/55 • Up to 56 Weeks All randomized participants.	0.79% 1/127 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.
Metabolism and nutrition disorders Lactic acidosis	0.00% 0/55 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.75% 1/133 • Number of events 1 • Up to 56 Weeks All randomized participants.
Musculoskeletal and connective tissue disorders Spinal column stenosis	0.00% 0/55 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.75% 1/133 • Number of events 1 • Up to 56 Weeks All randomized participants.
Nervous system disorders Metabolic encephalopathy	1.8% 1/55 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.
Nervous system disorders Syncope	0.00% 0/55 • Up to 56 Weeks All randomized participants.	0.79% 1/127 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.75% 1/133 • Number of events 1 • Up to 56 Weeks All randomized participants.
Nervous system disorders Transient global amnesia	0.00% 0/55 • Up to 56 Weeks All randomized participants.	0.79% 1/127 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.
Product Issues Device breakage	1.8% 1/55 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.
Psychiatric disorders Aggression	0.00% 0/55 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.75% 1/133 • Number of events 1 • Up to 56 Weeks All randomized participants.
Psychiatric disorders Suicidal ideation	0.00% 0/55 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.75% 1/133 • Number of events 1 • Up to 56 Weeks All randomized participants.
Psychiatric disorders Suicide attempt	1.8% 1/55 • Number of events 1 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.
Renal and urinary disorders Urinary retention	1.8% 1/55 • Number of events 3 • Up to 56 Weeks All randomized participants.	0.00% 0/127 • Up to 56 Weeks All randomized participants.	0.00% 0/133 • Up to 56 Weeks All randomized participants.