Trial Outcomes & Findings for Open-Label Study of Leuco-methylthioninium Bis(Hydromethanesulfonate) (LMTM) in Subjects With Alzheimer's Disease or Behavioral Variant Frontotemporal Dementia (bvFTD) (NCT NCT02245568)

Last Updated: 2023-05-24

Results Overview

Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

913 participants

Primary outcome timeframe

Up to 34 months

Results posted on

2023-05-24

Participant Flow

Subjects who completed a Phase 2 or 3 study of LMTM were eligible to enroll, pending their ability to meet the inclusion/exclusion criteria. A total of 913 subjects enrolled; however, data for 16 subjects in Spain were later excluded (GCP issues) and 1 UK subject was never dosed. Thus, 896 subjects are included in all analyses except disposition.

Participant milestones

Participant milestones
Measure	LMTM 100-300 mg/Day The initial LMTM dose was 200 mg/day (one 100-mg tablet twice daily), except in subjects with bvFTD who were taking a reduced dose (i.e., 100 mg/day) upon entering this extension study. The dose could be increased (after at least 13 weeks of treatment) or decreased (at any time at or after 2 weeks of treatment) by the Investigator in 100-mg increments or decrements. The maximum allowable dose was 300 mg/day (or in those countries where limited by a Competent Authority or Ethics Committee, 200 mg/day).
Overall Study STARTED	913
Overall Study COMPLETED	60
Overall Study NOT COMPLETED	853

Reasons for withdrawal

Reasons for withdrawal
Measure	LMTM 100-300 mg/Day The initial LMTM dose was 200 mg/day (one 100-mg tablet twice daily), except in subjects with bvFTD who were taking a reduced dose (i.e., 100 mg/day) upon entering this extension study. The dose could be increased (after at least 13 weeks of treatment) or decreased (at any time at or after 2 weeks of treatment) by the Investigator in 100-mg increments or decrements. The maximum allowable dose was 300 mg/day (or in those countries where limited by a Competent Authority or Ethics Committee, 200 mg/day).
Overall Study Study terminated by Sponsor	346
Overall Study Adverse Event	144
Overall Study Lack of Efficacy	98
Overall Study Withdrawal by Caregiver	85
Overall Study Withdrawal by Subject	77
Overall Study Withdrawal by Legal Representative	31
Overall Study Missing (Site closure)	16
Overall Study Physician Decision	14
Overall Study Non-compliance with study drug	11
Overall Study Death	9
Overall Study Blue staining	6
Overall Study Worsening dementia/caregiver withdrawal	6
Overall Study Intolerance/dosing issues/interruption	5
Overall Study Lost to Follow-up	5

Baseline Characteristics

Open-Label Study of Leuco-methylthioninium Bis(Hydromethanesulfonate) (LMTM) in Subjects With Alzheimer's Disease or Behavioral Variant Frontotemporal Dementia (bvFTD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	LMTM 100-300 mg/Day n=896 Participants The initial LMTM dose was 200 mg/day (one 100-mg tablet twice daily), except in subjects with bvFTD who were taking a reduced dose (i.e., 100 mg/day) upon entering this extension study. The dose could be increased (after at least 13 weeks of treatment) or decreased (at any time at or after 2 weeks of treatment) by the Investigator in 100-mg increments or decrements. The maximum allowable dose was 300 mg/day (or in those countries where limited by a Competent Authority or Ethics Committee, 200 mg/day).
Age, Continuous	69.2 years n=5 Participants
Sex: Female, Male Female	478 Participants n=5 Participants
Sex: Female, Male Male	418 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	24 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	864 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	8 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	6 Participants n=5 Participants
Race (NIH/OMB) Asian	72 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants
Race (NIH/OMB) Black or African American	18 Participants n=5 Participants
Race (NIH/OMB) White	783 Participants n=5 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	14 Participants n=5 Participants
Region of Enrollment Singapore	22 participants n=5 Participants
Region of Enrollment United States	459 participants n=5 Participants
Region of Enrollment United Kingdom	161 participants n=5 Participants
Region of Enrollment Malaysia	8 participants n=5 Participants
Region of Enrollment Russia	35 participants n=5 Participants
Region of Enrollment Spain	23 participants n=5 Participants
Region of Enrollment Canada	51 participants n=5 Participants
Region of Enrollment South Korea	13 participants n=5 Participants
Region of Enrollment Netherlands	2 participants n=5 Participants
Region of Enrollment Belgium	12 participants n=5 Participants
Region of Enrollment Finland	18 participants n=5 Participants
Region of Enrollment Taiwan	16 participants n=5 Participants
Region of Enrollment Australia	41 participants n=5 Participants
Region of Enrollment France	11 participants n=5 Participants
Region of Enrollment Germany	12 participants n=5 Participants
Region of Enrollment Croatia	11 participants n=5 Participants
Region of Enrollment Romania	1 participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 34 months

Population: The safety population was composed of participants dosed with 100-300 mg LMTM who were used for analysis. Safety was assessed over time by means of adverse event and concomitant medication recording; clinical laboratory tests; vital sign measurements and weight; 12-lead electrocardiograms; and targeted physical and neurological examinations.

Outcome measures

Outcome measures
Measure	LMTM 100-300 mg/Day n=896 Participants The initial LMTM dose was 200 mg/day (one 100-mg tablet twice daily), except in subjects with bvFTD who were taking a reduced dose (i.e., 100 mg/day) upon entering this extension study. The dose could be increased (after at least 13 weeks of treatment) or decreased (at any time at or after 2 weeks of treatment) by the Investigator in 100-mg increments or decrements. The maximum allowable dose was 300 mg/day (or in those countries where limited by a Competent Authority or Ethics Committee, 200 mg/day).
Number of Participants With Serious or Non-serious Adverse Events	734 Participants

Adverse Events

LMTM 100-300 mg/Day

Serious events: 146 serious events

Other events: 717 other events

Deaths: 15 deaths

Serious adverse events

Serious adverse events
Measure	LMTM 100-300 mg/Day n=896 participants at risk The initial LMTM dose was 200 mg/day (one 100-mg tablet twice daily), except in subjects with bvFTD who were taking a reduced dose (i.e., 100 mg/day) upon entering this extension study. The dose could be increased (after at least 13 weeks of treatment) or decreased (at any time at or after 2 weeks of treatment) by the Investigator in 100-mg increments or decrements. The maximum allowable dose was 300 mg/day (or in those countries where limited by a Competent Authority or Ethics Committee, 200 mg/day).
Blood and lymphatic system disorders Anaemia	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Blood and lymphatic system disorders Haemolytic anaemia	0.22% 2/896 • Number of events 2 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Blood and lymphatic system disorders Neutropenia	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Blood and lymphatic system disorders Thrombocytopenia	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Cardiac disorders Acute coronary syndrome	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Cardiac disorders Acute myocardial infarction	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Cardiac disorders Atrial fibrillation	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Cardiac disorders Atrial flutter	0.22% 2/896 • Number of events 2 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Cardiac disorders Atrioventricular block	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Cardiac disorders Bradycardia	0.22% 2/896 • Number of events 3 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Cardiac disorders Cardiac arrest	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Cardiac disorders Cardiac failure congestive	0.22% 2/896 • Number of events 2 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Cardiac disorders Cardio-respiratory arrest	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Cardiac disorders Myocardial infarction	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Cardiac disorders Pericardial effusion	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Cardiac disorders Sick sinus syndrome	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Congenital, familial and genetic disorders Hydrocele	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Gastrointestinal disorders Abdominal pain	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Gastrointestinal disorders Colitis microscopic	0.22% 2/896 • Number of events 2 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Gastrointestinal disorders Diarrhoea	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Gastrointestinal disorders Duodenal ulcer perforation	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Gastrointestinal disorders Faecaloma	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Gastrointestinal disorders Gastritis	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Gastrointestinal disorders Intestinal obstruction	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Gastrointestinal disorders Large intestinal obstruction	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Gastrointestinal disorders Nausea	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Gastrointestinal disorders Pancreatitis	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Gastrointestinal disorders Vomiting	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
General disorders Chest pain	0.45% 4/896 • Number of events 4 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Hepatobiliary disorders Cholecystitis	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Hepatobiliary disorders Cholelithiasis	0.22% 2/896 • Number of events 2 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Immune system disorders Hypersensitivity	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Infections and infestations Appendicitis	0.33% 3/896 • Number of events 3 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Infections and infestations Bacterial pyelonephritis	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Infections and infestations Bronchitis	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Infections and infestations Cellulitis	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Infections and infestations Cholecystitis infective	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Infections and infestations Clostridium difficile infection	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Infections and infestations Lower respiratory tract infection	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Infections and infestations Pneumonia	0.67% 6/896 • Number of events 6 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Infections and infestations Sepsis	0.45% 4/896 • Number of events 5 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Infections and infestations Urinary tract infection	1.2% 11/896 • Number of events 11 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Infections and infestations Urosepsis	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Infections and infestations Viral upper respiratory tract infection	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Injury, poisoning and procedural complications Concussion	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Injury, poisoning and procedural complications Facial bones fracture	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Injury, poisoning and procedural complications Fall	1.0% 9/896 • Number of events 9 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Injury, poisoning and procedural complications Femoral neck fracture	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Injury, poisoning and procedural complications Femur fracture	0.22% 2/896 • Number of events 2 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Injury, poisoning and procedural complications Hip fracture	0.22% 2/896 • Number of events 2 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Injury, poisoning and procedural complications Humerus fracture	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Injury, poisoning and procedural complications Overdose	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Injury, poisoning and procedural complications Pelvic fracture	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Injury, poisoning and procedural complications Pulmonary contusion	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Injury, poisoning and procedural complications Rib fracture	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Injury, poisoning and procedural complications Road traffic accident	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Injury, poisoning and procedural complications Spinal compression fracture	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Injury, poisoning and procedural complications Subdural haematoma	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Injury, poisoning and procedural complications Upper limb fracture	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Investigations Blood glucose increased	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Investigations Liver function test abnormal	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Investigations Weight decreased	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Metabolism and nutrition disorders Dehydration	0.45% 4/896 • Number of events 4 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Metabolism and nutrition disorders Diabetic ketoacidosis	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Metabolism and nutrition disorders Hypercalcaemia	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Metabolism and nutrition disorders Hypokalaemia	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Metabolism and nutrition disorders Hypovolaemia	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Musculoskeletal and connective tissue disorders Back pain	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Musculoskeletal and connective tissue disorders Costochondritis	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Musculoskeletal and connective tissue disorders Rotator cuff syndrome	0.22% 2/896 • Number of events 2 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Musculoskeletal and connective tissue disorders Spondylolisthesis	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) B-cell lymphoma	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer recurrent	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Chronic lymphocytic leukaemia	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic neoplasm	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-Hodgkin's lymphoma	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Oesophageal carcinoma	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian cancer	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pancreatic carcinoma	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cell carcinoma	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of lung	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tonsil cancer	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Altered state of consciousness	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Cerebral haemorrhage	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Cerebrovascular accident	0.22% 2/896 • Number of events 2 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Coordination abnormal	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Dementia	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Dementia Alzheimer's type	0.33% 3/896 • Number of events 3 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Grand mal convlusion	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Headache	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Ischaemic stroke	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Lacunar infarction	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Loss of consciousness	0.22% 2/896 • Number of events 2 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Migraine	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Presyncope	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Seizure like phenomena	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Serotonin syndrome	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Syncope	0.67% 6/896 • Number of events 7 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Transient ischaemic attack	0.45% 4/896 • Number of events 4 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Tremor	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders VIIth nerve paralysis	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Psychiatric disorders Abnormal behavior	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Psychiatric disorders Aggression	0.33% 3/896 • Number of events 3 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Psychiatric disorders Agitation	0.45% 4/896 • Number of events 4 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Psychiatric disorders Confusional state	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Psychiatric disorders Delirium	0.33% 3/896 • Number of events 3 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Psychiatric disorders Hallucination, visual	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Psychiatric disorders Hypersexuality	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Psychiatric disorders Mental status changes	0.33% 3/896 • Number of events 4 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Psychiatric disorders Staring	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Psychiatric disorders Suicidal ideation	0.33% 3/896 • Number of events 3 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Psychiatric disorders Suicidal attempt	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Renal and urinary disorders Bladder mass	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Renal and urinary disorders Bladder prolapse	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Renal and urinary disorders Cystitis noninfective	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Renal and urinary disorders Haematuria	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Renal and urinary disorders Nephrolithiasis	0.22% 2/896 • Number of events 2 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Renal and urinary disorders Nephropathy	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Renal and urinary disorders Renal failure, acute	0.22% 2/896 • Number of events 2 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Renal and urinary disorders Renal impairment	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Renal and urinary disorders Urinary tract obstruction	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Reproductive system and breast disorders Uterine prolapse	0.22% 2/896 • Number of events 2 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Respiratory, thoracic and mediastinal disorders Acute pulmonary oedema	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.45% 4/896 • Number of events 4 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.11% 1/896 • Number of events 2 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.33% 3/896 • Number of events 3 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Skin and subcutaneous tissue disorders Hyperhidrosis	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Vascular disorders Circulatory collapse	0.22% 2/896 • Number of events 3 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Vascular disorders Deep vein thrombosis	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Vascular disorders Hypertensive crisis	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Vascular disorders Hypotension	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Vascular disorders Orthostatic hypotension	0.22% 2/896 • Number of events 2 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Vascular disorders Thrombosis	0.11% 1/896 • Number of events 1 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.

Other adverse events

Other adverse events
Measure	LMTM 100-300 mg/Day n=896 participants at risk The initial LMTM dose was 200 mg/day (one 100-mg tablet twice daily), except in subjects with bvFTD who were taking a reduced dose (i.e., 100 mg/day) upon entering this extension study. The dose could be increased (after at least 13 weeks of treatment) or decreased (at any time at or after 2 weeks of treatment) by the Investigator in 100-mg increments or decrements. The maximum allowable dose was 300 mg/day (or in those countries where limited by a Competent Authority or Ethics Committee, 200 mg/day).
Blood and lymphatic system disorders Anaemia	4.8% 43/896 • Number of events 45 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Gastrointestinal disorders Diarrhoea	13.7% 123/896 • Number of events 174 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Gastrointestinal disorders Nausea	4.9% 44/896 • Number of events 56 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Gastrointestinal disorders Constipation	2.0% 18/896 • Number of events 19 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Gastrointestinal disorders Vomiting	4.0% 36/896 • Number of events 40 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
General disorders Fatigue	2.2% 20/896 • Number of events 23 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Infections and infestations Urinary tract infection	5.5% 49/896 • Number of events 72 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Infections and infestations Lower respiratory tract infection	2.0% 18/896 • Number of events 21 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Infections and infestations Nasopharyngitis	3.0% 27/896 • Number of events 31 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Infections and infestations Upper respiratory tract infection	3.0% 27/896 • Number of events 34 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Injury, poisoning and procedural complications Fall	6.9% 62/896 • Number of events 79 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Investigations Blood creatine phosphokinase increased	2.3% 21/896 • Number of events 21 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Investigations Creatinine renal clearance decreased	3.7% 33/896 • Number of events 37 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Investigations Haemoglobin decreased	4.5% 40/896 • Number of events 44 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Investigations Weight decreased	3.3% 30/896 • Number of events 31 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Musculoskeletal and connective tissue disorders Arthralgia	3.0% 27/896 • Number of events 34 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Musculoskeletal and connective tissue disorders Back pain	2.0% 18/896 • Number of events 21 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Dizziness	2.6% 23/896 • Number of events 31 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Nervous system disorders Headache	3.2% 29/896 • Number of events 33 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Psychiatric disorders Agitation	5.1% 46/896 • Number of events 59 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Psychiatric disorders Anxiety	3.6% 32/896 • Number of events 35 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Psychiatric disorders Confusional state	3.8% 34/896 • Number of events 39 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Psychiatric disorders Depression	2.3% 21/896 • Number of events 21 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Psychiatric disorders Insomnia	2.1% 19/896 • Number of events 21 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Renal and urinary disorders Pollakiuria	6.1% 55/896 • Number of events 58 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Renal and urinary disorders Urinary incontinence	6.7% 60/896 • Number of events 67 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Renal and urinary disorders Dysuria	4.4% 39/896 • Number of events 45 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Renal and urinary disorders Micturition urgency	3.2% 29/896 • Number of events 30 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Respiratory, thoracic and mediastinal disorders Cough	2.7% 24/896 • Number of events 24 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.
Vascular disorders Hypertension	2.2% 20/896 • Number of events 20 • Up to 34 months Study-emergent adverse events (including the onset of new adverse events or worsening of pre-existing adverse events) were recorded from the time of first dose in this study to the end of study participation. All laboratory test, vital sign, or electrocardiogram parameter abnormalities deemed clinically significant by the Investigator were to be reported as adverse events.

Additional Information

Dr. Diane Downie

TauRx Therapeutics Ltd

Phone: +44 1224440905

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place