Trial Outcomes & Findings for A Trial of Tocilizumab in ALS Subjects (NCT NCT02469896)

Last Updated: 2019-12-18

Results Overview

Tolerability will be assessed by on the proportion of participants remaining on study drug through all 3 doses and remaining on study and free from possibly drug-related and dose-limiting SAEs to the end of follow-up. Safety will be assessed by the occurrence of severe adverse events (SAEs), overall rates of adverse events (AEs), clinically significant abnormal laboratory tests, and changes in vital signs.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

22 participants

Primary outcome timeframe

16 weeks

Results posted on

2019-12-18

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo 8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	Active Drug 16 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Overall Study STARTED	8	14
Overall Study COMPLETED	6	14
Overall Study NOT COMPLETED	2	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo 8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	Active Drug 16 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Overall Study Withdrawal by Subject	2	0

Baseline Characteristics

A Trial of Tocilizumab in ALS Subjects

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=8 Participants 8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	Active Drug n=14 Participants 16 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion	Total n=22 Participants Total of all reporting groups
Age, Continuous	59.2 Years STANDARD_DEVIATION 8.6 • n=93 Participants	61.9 Years STANDARD_DEVIATION 8.7 • n=4 Participants	60.9 Years STANDARD_DEVIATION 8.6 • n=27 Participants
Sex: Female, Male Female	3 Participants n=93 Participants	3 Participants n=4 Participants	6 Participants n=27 Participants
Sex: Female, Male Male	5 Participants n=93 Participants	11 Participants n=4 Participants	16 Participants n=27 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	7 Participants n=93 Participants	14 Participants n=4 Participants	21 Participants n=27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Race (NIH/OMB) White	7 Participants n=93 Participants	14 Participants n=4 Participants	21 Participants n=27 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Region of Enrollment United States	8 Participants n=93 Participants	14 Participants n=4 Participants	22 Participants n=27 Participants

PRIMARY outcome

Timeframe: 16 weeks

Outcome measures

Outcome measures
Measure	Placebo Tolerability n=8 Participants 8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	Active Drug Tolerability n=14 Participants 14 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Number of Patients Tolerant to Study Drug	6 Participants	12 Participants

PRIMARY outcome

Timeframe: 16 weeks

Safety will be assessed by the occurrence of all-cause mortality.

Outcome measures

Outcome measures
Measure	Placebo Tolerability n=8 Participants 8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	Active Drug Tolerability n=14 Participants 14 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Rates of All-cause Mortality Died	0 Participants	0 Participants
Rates of All-cause Mortality Alive	8 Participants	14 Participants

SECONDARY outcome

Timeframe: 16 weeks

Population: Discrepancies in the number of subjects analyzed are a result of subjects with missed data collection during the specific time points.

Efficacy will be assessed by the change in the rate of change of SVC as measured by change in percent predicted per month. The SVC is a measure of lung capacity that is reported as the percent of the predicted value expected based on gender and height. In ALS patients, this measure declines over time as a result of progressive respiratory muscle weakness.

Outcome measures

Outcome measures
Measure	Placebo Tolerability n=8 Participants 8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	Active Drug Tolerability n=14 Participants 14 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Rate of Decline in Slow Vital Capacity (SVC)	-0.765 Percentage points change per month Standard Error 0.829	-0.666 Percentage points change per month Standard Error 0.560

SECONDARY outcome

Timeframe: 16 weeks

Population: Discrepancies in the number of subjects analyzed are a result of subjects with missed data collection during the specific time points.

Efficacy will be assessed by the mean change in ALSFRS-R total score.The ALSFRS-R scale measures the functional capabilities of an ALS patient in multiple domains such as swallowing, speech, fine motor, and breathing functions. It ranges from a maximum score of 48 for normal functioning to 0 for death or dependance on mechanical ventilation and declines by approximately 1 point per month on average for an ALS patient.

Outcome measures

Outcome measures
Measure	Placebo Tolerability n=8 Participants 8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	Active Drug Tolerability n=14 Participants 14 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Rate of Decline ALS Functional Rating Scale Revised (ALSFRS-R)	-0.583 units on a scale Standard Error 0.313	-0.591 units on a scale Standard Error 0.211

SECONDARY outcome

Timeframe: 16 weeks

Population: Discrepancies in the number of subjects analyzed are a result of subjects with missed data collection during the specific time points.

Efficacy will be assessed by the change in the rate of change of HHD upper and lower extremity mega-scores. HHD utilizes an electronic pressure sensor to measure strength of individual muscles in kilograms. To calculate megascores, the mean and standard deviation of each muscle or muscle group, without regard to laterality, will be calculated from the baseline assessment of all participants. Strength estimates of each bilateral muscle or muscle group will be converted to Z scores by subtracting the relevant mean and dividing by the relevant standard deviation. Z scores for all upper extremity measurements (shoulder flexion, elbow flexion, elbow extension, wrist extension, and first dorsal interosseous contraction) and all lower extremity measurements (hip flexion, knee flexion, knee extension, and ankle dorsiflexion) will be averaged to yield upper and lower extremity megascores. Larger values indicate greater strength.

Outcome measures

Outcome measures
Measure	Placebo Tolerability n=8 Participants 8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	Active Drug Tolerability n=14 Participants 14 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Rate of Decline Handheld Dynamometry (HHD) HHD Upper extremity mega-score	-0.028 Z-score Standard Error 0.035	-0.070 Z-score Standard Error 0.024
Rate of Decline Handheld Dynamometry (HHD) HHD Lower extremity mega-score	-0.018 Z-score Standard Error 0.039	-0.032 Z-score Standard Error 0.026

SECONDARY outcome

Timeframe: 16 weeks

Population: Discrepancies in the number of subjects analyzed are a result of subjects with missed data collection during the specific time points.

Target engagement will be assessed by comparing the PBMC fold change in cytokine gene expression from baseline to week 4-16 average of ALS patients receiving drug versus placebo.

Outcome measures

Outcome measures
Measure	Placebo Tolerability n=8 Participants 8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	Active Drug Tolerability n=14 Participants 14 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Change in Peripheral Blood Mononuclear Cell (PBMC) Gene Expression PBMC IL-6 fold-change	1.21 Fold change in gene expression Interval 0.6 to 2.54	1.39 Fold change in gene expression Interval 0.52 to 5.0
Change in Peripheral Blood Mononuclear Cell (PBMC) Gene Expression PBMC IL-8 fold-change	1.33 Fold change in gene expression Interval 0.08 to 39.4	1.79 Fold change in gene expression Interval 0.38 to 14.8
Change in Peripheral Blood Mononuclear Cell (PBMC) Gene Expression PBMC Matrix Metalloproteinase 1 (MMP1)fold-change	1.01 Fold change in gene expression Interval 0.37 to 2.13	1.21 Fold change in gene expression Interval 0.42 to 3.28

SECONDARY outcome

Timeframe: 16 weeks

Population: Discrepancies in the number of subjects analyzed are a result of subjects with missed data collection during the specific time points.

Target engagement will be assessed by mean change in plasma cytokine concentration between weeks 4 and 16 in ALS subjects receiving placebo or active drug.

Outcome measures

Outcome measures
Measure	Placebo Tolerability n=8 Participants 8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	Active Drug Tolerability n=14 Participants 14 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Changes in Cytokine Levels in the Plasma CRP (ug/mL)	1.051 Fold change in concentration Interval 0.279 to 3.952	0.049 Fold change in concentration Interval 0.019 to 0.126
Changes in Cytokine Levels in the Plasma IL-1beta (pg/mL)	0.969 Fold change in concentration Interval 0.608 to 1.545	1.266 Fold change in concentration Interval 0.871 to 1.84
Changes in Cytokine Levels in the Plasma IL-6 (pg/mL)	0.897 Fold change in concentration Interval 0.532 to 1.515	17.974 Fold change in concentration Interval 12.9 to 25.043
Changes in Cytokine Levels in the Plasma IL-8 (pg/mL)	1.241 Fold change in concentration Interval 0.862 to 1.787	1.569 Fold change in concentration Interval 1.169 to 2.105
Changes in Cytokine Levels in the Plasma IL-17 (pg/mL)	0.962 Fold change in concentration Interval 0.47 to 1.967	1.342 Fold change in concentration Interval 0.809 to 2.226
Changes in Cytokine Levels in the Plasma Tumor necrosis factor (TNF)-alpha (pg/mL)	1.180 Fold change in concentration Interval 0.981 to 1.419	1.054 Fold change in concentration Interval 0.923 to 1.204

SECONDARY outcome

Timeframe: 8 weeks

Target engagement will be assessed by the mean change in CSF cytokine concentration between baseline and week 8 in ALS subjects receiving placebo or active drug.

Outcome measures

Outcome measures
Measure	Placebo Tolerability n=8 Participants 8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	Active Drug Tolerability n=14 Participants 14 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Change in Mean Concentration Cytokines in the Cerebrospinal Fluid (CSF) CRP (ng/mL)	0.641 Fold change in concentration Interval 0.216 to 1.903	0.107 Fold change in concentration Interval 0.044 to 0.26
Change in Mean Concentration Cytokines in the Cerebrospinal Fluid (CSF) IL-1beta (pg/mL)	1.498 Fold change in concentration Interval 0.542 to 4.138	1.110 Fold change in concentration Interval 0.459 to 2.679
Change in Mean Concentration Cytokines in the Cerebrospinal Fluid (CSF) IL-6 (pg/mL)	1.242 Fold change in concentration Interval 0.781 to 1.974	4.115 Fold change in concentration Interval 2.813 to 6.018
Change in Mean Concentration Cytokines in the Cerebrospinal Fluid (CSF) IL-8 (pg/mL)	0.946 Fold change in concentration Interval 0.758 to 1.181	1.020 Fold change in concentration Interval 0.854 to 1.218
Change in Mean Concentration Cytokines in the Cerebrospinal Fluid (CSF) TNF-alpha (pg/mL)	0.989 Fold change in concentration Interval 0.727 to 1.346	1.066 Fold change in concentration Interval 0.833 to 1.365

SECONDARY outcome

Timeframe: 8 weeks

Population: Discrepancies in the number of subjects analyzed are a result of subjects with missed data collection during the specific time points.

Target engagement will be assessed by comparing the mean change in CSF sIL-6 receptor concentrations (ng/mL) between baseline and week 8 of the placebo and active drug groups.

Outcome measures

Outcome measures
Measure	Placebo Tolerability n=8 Participants 8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	Active Drug Tolerability n=14 Participants 14 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Change in CSF Soluble Interleukin-6 (sIL-6) Receptor Concentrations	1.029 ng/mL Interval 0.886 to 1.195	1.836 ng/mL Interval 1.621 to 2.08

SECONDARY outcome

Timeframe: 8 weeks

Population: Only 2 patients met inclusion criteria for the PET portion of the study and thus, the data could not be statistically analyzed.

Measure the effects of tocilizumab on reducing glial activation measured by PBR28 PET in a subset of trial participants.

Outcome measures

Outcome measures
Measure	Placebo Tolerability n=1 Participants 8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	Active Drug Tolerability n=1 Participants 14 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Peripheral Benzodiazepine Receptor 28 (PBR28) Positron Emission Tomography (PET) Baseline	1.225282 Standardized Uptake Variable Ratio(SUVR)	1.059685 Standardized Uptake Variable Ratio(SUVR)
Peripheral Benzodiazepine Receptor 28 (PBR28) Positron Emission Tomography (PET) Week 8	1.361542 Standardized Uptake Variable Ratio(SUVR)	1.056888 Standardized Uptake Variable Ratio(SUVR)

Adverse Events

Placebo

Serious events: 1 serious events

Other events: 6 other events

Deaths: 0 deaths

Active Drug

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=8 participants at risk 8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	Active Drug n=14 participants at risk 16 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Respiratory, thoracic and mediastinal disorders Pneumonia Aspiration	12.5% 1/8 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	0.00% 0/14 • Adverse events were collected over the study lasting up to 16 weeks in each subject.

Other adverse events

Additional Information

Shafeeq Ladha, MD

Barrow Neurological Institute

Phone: 602-406-8989

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Placebo n=8 participants at risk 8 subjects will receive matching IV placebo every 4 weeks for 3 months. Placebo: IV Infusion	Active Drug n=14 participants at risk 16 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months. Tocilizumab: IV Infusion
Blood and lymphatic system disorders Neutropenia	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Ear and labyrinth disorders Ear Pruritus	12.5% 1/8 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	0.00% 0/14 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Gastrointestinal disorders Abdominal Distension	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Gastrointestinal disorders Abdominal Pain	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Gastrointestinal disorders Aphthous Stomatitis	12.5% 1/8 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	0.00% 0/14 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Gastrointestinal disorders Constipation	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Gastrointestinal disorders Faecal Incontinence	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Gastrointestinal disorders Nausea	25.0% 2/8 • Number of events 4 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Gastrointestinal disorders Salivary Hypersecretion	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	14.3% 2/14 • Number of events 2 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
General disorders Catheter Site Related Reaction	12.5% 1/8 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	0.00% 0/14 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
General disorders Fatigue	12.5% 1/8 • Number of events 2 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	14.3% 2/14 • Number of events 2 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
General disorders Infusion Site Pruritus	12.5% 1/8 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	0.00% 0/14 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
General disorders Injection Site Pain	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
General disorders Puncture Site Pain	50.0% 4/8 • Number of events 4 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	14.3% 2/14 • Number of events 2 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Infections and infestations Catheter Site Infection	12.5% 1/8 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	0.00% 0/14 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Infections and infestations Clostridium Difficile Colitis	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Infections and infestations Gingival Abscess	12.5% 1/8 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	0.00% 0/14 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Infections and infestations Nasopharyngitis	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	14.3% 2/14 • Number of events 2 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Infections and infestations Pneumonia	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Infections and infestations Upper Respiratory Tract Infection	12.5% 1/8 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Infections and infestations Urinary Tract Infection	12.5% 1/8 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	0.00% 0/14 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Injury, poisoning and procedural complications Contusion	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Injury, poisoning and procedural complications Fall	25.0% 2/8 • Number of events 3 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	21.4% 3/14 • Number of events 4 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Injury, poisoning and procedural complications Foot Fracture	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Injury, poisoning and procedural complications Post Lumbar Puncture Syndrome	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	14.3% 2/14 • Number of events 2 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Injury, poisoning and procedural complications Procedural Pain	12.5% 1/8 • Number of events 2 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	21.4% 3/14 • Number of events 4 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Investigations Alanine Aminotransferase Increased	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Investigations Aspartate Aminotransferase Increased	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Investigations Blood Pressure Increased	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	14.3% 2/14 • Number of events 2 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Investigations Platelet Count Increased	12.5% 1/8 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	0.00% 0/14 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Investigations White Blood Cell Count Increased	12.5% 1/8 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	0.00% 0/14 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Musculoskeletal and connective tissue disorders Muscular Weakness	12.5% 1/8 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	21.4% 3/14 • Number of events 4 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Musculoskeletal and connective tissue disorders Musculoskeletal Pain	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Nervous system disorders Dizziness	25.0% 2/8 • Number of events 3 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Nervous system disorders Headache	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	14.3% 2/14 • Number of events 3 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Nervous system disorders Presyncope	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Renal and urinary disorders Urinary Tract Pain	12.5% 1/8 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	0.00% 0/14 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Respiratory, thoracic and mediastinal disorders Cough	25.0% 2/8 • Number of events 2 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	0.00% 0/14 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Respiratory, thoracic and mediastinal disorders Dysphonia	0.00% 0/8 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	14.3% 2/14 • Number of events 2 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Respiratory, thoracic and mediastinal disorders Dyspnoea	12.5% 1/8 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	21.4% 3/14 • Number of events 3 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Respiratory, thoracic and mediastinal disorders Oropharyngeal Pain	12.5% 1/8 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.
Skin and subcutaneous tissue disorders Pruritus	12.5% 1/8 • Number of events 1 • Adverse events were collected over the study lasting up to 16 weeks in each subject.	7.1% 1/14 • Number of events 3 • Adverse events were collected over the study lasting up to 16 weeks in each subject.