A Study to Assess the Safety and Tolerability of Nusiners... | NCT02462759

ID	Type	Description	Link
2014-003657-33	EudraCT Number

Label	Type	Description	Intervention Names
Nusinersen	Experimental	Administered by intrathecal injection.	Drug: Nusinersen
Sham Procedure	Sham Comparator	Small needle prick on the lower back at the location where the IT injection is normally made.	Procedure: Sham Procedure

Name	Type	Description	Arm Group Labels	Other Names
Nusinersen	Drug	Administered by intrathecal injection.	Nusinersen	BIIB058

Measure	Description	Time Frame
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly.	Part 1 and 2: From first dose/sham procedure to end of study (up to 1080 days)
Number of Participants With Change From Baseline in Clinical Laboratory Parameters	Clinically significant changes in laboratory parameters were evaluated for assessing the safety of ISIS 396443.	Part 1 and 2: From first dose/sham procedure to end of study (up to 1080 days)
Number of Participants With Change From Baseline in Electrocardiograms (ECGs)	Clinically significant changes in ECG measurements were evaluated for assessing the safety of ISIS 396443.	Part 1: Day 2, 29 and 422; Part 2: Day 1 to 596
Number of Participants With Change From Baseline in Vital Signs	Clinically significant changes in vital signs were evaluated for assessing the safety of ISIS 396443. Vital signs that were assessed included resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, pulse oximetry, and transcutaneous carbon dioxide.	Part 1: Day 2, 29 and 422; Part 2: Day 1 to 596
Change From Baseline in Head Circumference

Measure	Description	Time Frame
Plasma Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study	Study days were windowed for integrated analysis and labelled as follows: Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659.	Pre-dose on Days 64, 183, 540 and 659

Name	Affiliation	Role
Medical Director	Biogen	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
David Geffen School of Medicine at UCLA		Los Angeles	California	90095-8344	United States
Connecticut Childrens Medical

PubMed Identifier	Type	Citation	Retractions
33501671	Derived	Acsadi G, Crawford TO, Muller-Felber W, Shieh PB, Richardson R, Natarajan N, Castro D, Ramirez-Schrempp D, Gambino G, Sun P, Farwell W. Safety and efficacy of nusinersen in spinal muscular atrophy: The EMBRACE study. Muscle Nerve. 2021 May;63(5):668-677. doi: 10.1002/mus.27187. Epub 2021 Feb 16.

Label	URL
Clinical Study Report (CSR) Synopsis - a results summary	View source

ID	Title	Description
FG000	Sham Procedure (Part 1)	Sham procedure on Day 1, 15, 29, 64, 183 and 302.
FG001	ISIS 396443 (Part 1)	Single dose of 9.6 milligrams (mg) to 12.0 mg ISIS 396443, based on participant's age, intrathecal bolus injection loading doses on Day 1, 15, 29, 64 and maintenance doses, every 4 months, on Day 183 and 302.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
SAP	No	Yes	No	Statistical Analysis Plan	Jul 16, 2018	Sep 18, 2019

ID	Title	Description
BG000	Sham Procedure (Part 1)	Sham procedure on Day 1, 15, 29, 64, 183 and 302.
BG001	ISIS 396443 (Part 1)	Single dose of 9.6 milligrams (mg) to 12.0 mg ISIS 396443, based on participant's age, intrathecal bolus injection loading doses on Day 1, 15, 29, 64 and maintenance doses, every 4 months, on Day 183 and 302.
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG0007 BG00114 BG00221

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly.

The safety population included all participants who were randomized and received at least 1 dose of study treatment or sham procedure.

Posted

Count of Participants

Participants

Part 1 and 2: From first dose/sham procedure to end of study (up to 1080 days)

ID	Title	Description
OG000	Sham Procedure in Part 1	Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.
OG001	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.
OG002	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Units	Counts
Participants	OG0007 OG0016 OG00214

Title

Denominators

Categories

AEs

Title	Measurements
	OG0006 OG0016 OG00214

SAEs

Primary

Number of Participants With Change From Baseline in Clinical Laboratory Parameters

Clinically significant changes in laboratory parameters were evaluated for assessing the safety of ISIS 396443.

The safety population included all participants who were randomized and received at least 1 dose of study treatment or sham procedure.

Posted

Count of Participants

Participants

Part 1 and 2: From first dose/sham procedure to end of study (up to 1080 days)

ID	Title	Description
OG000	Sham Procedure in Part 1	Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.
OG001	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.
OG002	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Primary

Number of Participants With Change From Baseline in Electrocardiograms (ECGs)

Clinically significant changes in ECG measurements were evaluated for assessing the safety of ISIS 396443.

The safety population included all participants who were randomized and received at least 1 dose of study treatment or sham procedure.

Posted

Count of Participants

Participants

Part 1: Day 2, 29 and 422; Part 2: Day 1 to 596

ID	Title	Description
OG000	Sham Procedure in Part 1	Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.
OG001	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.
OG002	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Primary

Number of Participants With Change From Baseline in Vital Signs

Clinically significant changes in vital signs were evaluated for assessing the safety of ISIS 396443. Vital signs that were assessed included resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, pulse oximetry, and transcutaneous carbon dioxide.

The safety population included all participants who were randomized and received at least 1 dose of study treatment or sham procedure.

Posted

Count of Participants

Participants

Part 1: Day 2, 29 and 422; Part 2: Day 1 to 596

ID	Title	Description
OG000	Sham Procedure in Part 1	Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.
OG001	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.
OG002	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Primary

Change From Baseline in Head Circumference

Participants were analyzed for change in growth parameter of head circumference to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the head circumference percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline; Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138.

Safety population: participants who were randomized and received at least 1 dose of study treatment or sham procedure. Number analyzed indicates participants who were evaluated for the specified time points. Due the early termination of Part 2, no participants in the ISIS 396443 Part 2(participants on sham in Part 1) were on study beyond Day 659.

Posted

Mean

Standard Deviation

centimeter (cm)

Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138

ID	Title	Description
OG000	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.
OG001	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Primary

Change From Baseline in Chest Circumference

Participants were analyzed for change in growth parameter of chest circumference to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the chest circumference percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline; Days>1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138.

Posted

Mean

Standard Deviation

Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138

ID	Title	Description
OG000	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.
OG001	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Primary

Change From Baseline in Arm Circumference

Participants were analyzed for change in growth parameter of arm circumference to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the arm circumference percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline; Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138.

Posted

Mean

Standard Deviation

Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138

ID	Title	Description
OG000	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.
OG001	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Primary

Change From Baseline in Weight for Age

Participants were analyzed for change in growth parameter of weight for age to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the weight for age percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline; Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138.

Posted

Mean

Standard Deviation

kilogram (kg)

Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138

ID	Title	Description
OG000	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.
OG001	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Primary

Change From Baseline in Weight

Participants were analyzed for change in growth parameter of weight to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the weight percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline; Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138.

Posted

Mean

Standard Deviation

Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138

ID	Title	Description
OG000	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.
OG001	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Primary

Change From Baseline in Head to Chest Circumference (HCC) Ratio

Participants were analyzed for change in growth parameter of HCC to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the HCC circumference percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline; Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138.

Posted

Mean

Standard Deviation

ratio

Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138

ID	Title	Description
OG000	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.
OG001	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Primary

Change From Baseline in Body Length

Participants were analyzed for change in growth parameter of body length to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the body length percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline; Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138.

Posted

Mean

Standard Deviation

Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138

ID	Title	Description
OG000	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.
OG001	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Primary

Number of Participants With Change From Baseline in Neurological Examination Outcomes

Neurological examinations included assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, reflexes, mood, speech/language and hearing.

The safety population included all participants who were randomized and received at least 1 dose of study treatment or sham procedure.

Posted

Count of Participants

Participants

Part 1: Baseline to Day 422; Part 2: Baseline to Day 596

ID	Title	Description
OG000	Sham Procedure in Part 1	Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.
OG001	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.
OG002	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Primary

Number of Participants With Change From Baseline in Activated Partial Thromboplastin Time [aPTT]

Activated partial thromboplastin time was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of aPTT at baseline to low values postbaseline. "Shift to high" measured change in normal, high and unknown values of aPTT at baseline to high values postbaseline.

The safety population included all participants who were randomized and received at least 1 dose of study treatment or sham procedure. Number analyzed indicates participants whose baseline value was not low (or high) and who had at least one post-baseline measurement.

Posted

Count of Participants

Participants

Part 2: Up to 1080 days

ID	Title	Description
OG000	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.
OG001	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Units

Primary

Number of Participants With Change From Baseline in Partial Thromboplastin Time [PTT]

PTT was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of PTT at baseline to low values postbaseline. "Shift to high" measured change in normal, high and unknown values of PTT at baseline to high values postbaseline.

Posted

Count of Participants

Participants

Part 2: Up to 1080 days

ID	Title	Description
OG000	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.
OG001	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Units	Counts

Primary

Number of Participants With Change From Baseline in International Normalized Ratio [INR])

INR was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of INR at baseline to low values postbaseline. "Shift to high" measured change in normal, high and unknown values of INR at baseline to high values postbaseline.

Posted

Count of Participants

Participants

Part 2: Up to 1080 days

ID	Title	Description
OG000	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.
OG001	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Units	Counts

Primary

Number of Participants With Presence of Urine Total Protein Post-baseline

Urine total protein was evaluated to assess safety.

The safety population included all participants who were randomized and received at least 1 dose of study treatment or sham procedure.

Posted

Count of Participants

Participants

Part 2: Up to 1080 days

ID	Title	Description
OG000	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.
OG001	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Units	Counts
Participants	OG000

Secondary

Plasma Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study

Study days were windowed for integrated analysis and labelled as follows: Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659.

The pharmacokinetic (PK) population included all participants who were randomized and have at least 1 evaluable post dose or post sham-procedure PK sample.

Posted

Mean

Standard Deviation

nanogram per milliliter (ng/mL)

Pre-dose on Days 64, 183, 540 and 659

ID	Title	Description
OG000	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.

Units	Counts
Participants	OG000

Secondary

Plasma Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study

Study days were windowed for integrated analysis and labelled as follows: Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138.

The PK population included all participants who were randomized and have at least 1 evaluable post dose or post sham-procedure PK sample. Number analyzed indicates participants who were evaluated for the specified time points.

Posted

Mean

Standard Deviation

ng/mL

Pre-dose on Days 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138

ID	Title	Description
OG000	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Units	Counts
Participants	OG000

Secondary

Cerebrospinal Fluid (CSF) Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study

CSF samples were analyzed for ISIS 396443 concentrations in participants. Study days were windowed for integrated analysis and labelled as follows: Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540.

Posted

Mean

Standard Error

ng/mL

Pre-dose on Days 15, 29, 64, 183, 302, 422 and 540

ID	Title	Description
OG000	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.

Units	Counts
Participants	OG000

Secondary

CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study

Posted

Mean

Standard Deviation

ng/mL

Pre-dose on Days 15, 29, 64, 183, 302, 422, 540, 659, 778, 898 and 1018

ID	Title	Description
OG000	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Units	Counts
Participants

Secondary

Number of Participants With Plasma Antibodies to ISIS 396443

The safety population included all participants who were randomized and received at least 1 dose of study treatment or sham procedure.

Posted

Count of Participants

Participants

Part 2: Baseline to Day 596

ID	Title	Description
OG000	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.
OG001	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

Units	Counts
Participants	OG000

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Cardio-respiratory arrest	Cardiac disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0010 affected14 at risk EG0020 affected6 at risk
Sinus bradycardia	Cardiac disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Dental caries	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Dysphagia	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Vomiting	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Brain death	General disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0010 affected14 at risk EG0020 affected6 at risk
Bronchiolitis	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0010 affected14 at risk EG0020 affected6 at risk
Bronchitis moraxella	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Enterovirus infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Gastroenteritis	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0021 affected6 at risk
Gastroenteritis norovirus	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Gastroenteritis viral	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Lower respiratory tract infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Parainfluenzae virus infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0021 affected6 at risk
Pneumonia	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0017 affected14 at risk EG0023 affected6 at risk
Pneumonia haemophilus	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Pneumonia moraxella	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Pneumonia pneumococcal	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Pneumonia respiratory syncytial viral	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Respiratory syncytial virus bronchiolitis	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0021 affected6 at risk
Respiratory syncytial virus infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0021 affected6 at risk
Respiratory tract infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0011 affected14 at risk EG0021 affected6 at risk
Rhinovirus infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0012 affected14 at risk EG0022 affected6 at risk
Staphylococcal infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Nasopharyngitis	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0021 affected6 at risk
Femur fracture	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Failure to thrive	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Metabolic acidosis	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Hypoxic-ischaemic encephalopathy	Nervous system disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0010 affected14 at risk EG0020 affected6 at risk
Loss of consciousness	Nervous system disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0010 affected14 at risk EG0020 affected6 at risk
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0011 affected14 at risk EG0021 affected6 at risk
Bronchial secretion retention	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Hypoventilation	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Hypoxia	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Pneumonia aspiration	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0013 affected14 at risk EG0021 affected6 at risk
Respiratory distress	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0012 affected14 at risk EG0022 affected6 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Leukocytosis	Blood and lymphatic system disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Thrombocytosis	Blood and lymphatic system disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Bradycardia	Cardiac disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Sinus tachycardia	Cardiac disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Tachycardia	Cardiac disorders	MedDRA 20.0	Systematic Assessment	EG0002 affected7 at risk EG0013 affected14 at risk EG0020 affected6 at risk
Congenital nystagmus	Congenital, familial and genetic disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Plagiocephaly	Congenital, familial and genetic disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Ear pain	Ear and labyrinth disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Myopia	Eye disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Ocular hyperaemia	Eye disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Abdominal discomfort	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Aphthous ulcer	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0010 affected14 at risk EG0020 affected6 at risk
Constipation	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0014 affected14 at risk EG0020 affected6 at risk
Dental caries	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0015 affected14 at risk EG0021 affected6 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Dysphagia	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Flatulence	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Gastrooesophageal reflux disease	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Gingival pain	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Lip swelling	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Oral contusion	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Salivary hypersecretion	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0021 affected6 at risk
Teething	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0002 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Vomiting	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0017 affected14 at risk EG0022 affected6 at risk
Asthenia	General disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Complication associated with device	General disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Fatigue	General disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Influenza like illness	General disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Oedema peripheral	General disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Pyrexia	General disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG00112 affected14 at risk EG0024 affected6 at risk
Swelling	General disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Drug hypersensitivity	Immune system disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Seasonal allergy	Immune system disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Bronchiolitis	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Bronchitis	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Cellulitis	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Conjunctivitis	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0014 affected14 at risk EG0020 affected6 at risk
Conjunctivitis bacterial	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Ear infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Gastroenteritis	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0015 affected14 at risk EG0020 affected6 at risk
Gastroenteritis adenovirus	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Gastroenteritis norovirus	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Gastroenteritis viral	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0021 affected6 at risk
Hand-foot-and-mouth disease	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Influenza	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Lower respiratory tract infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0015 affected14 at risk EG0021 affected6 at risk
Otitis externa	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Otitis media	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Otitis media acute	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Parainfluenzae virus infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Pharyngitis streptococcal	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Pneumonia	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0017 affected14 at risk EG0022 affected6 at risk
Pneumonia haemophilus	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Pneumonia moraxella	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Respiratory syncytial virus infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0013 affected14 at risk EG0021 affected6 at risk
Respiratory tract infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0015 affected14 at risk EG0021 affected6 at risk
Rhinovirus infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Sinusitis	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Stoma site infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0002 affected7 at risk EG0019 affected14 at risk EG0023 affected6 at risk
Urinary tract infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Vaginal infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Viral rash	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Viral upper respiratory tract infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0015 affected14 at risk EG0021 affected6 at risk
Ankle fracture	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Arthropod bite	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Contusion	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Fall	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0022 affected6 at risk
Femur fracture	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Incision site erythema	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Incision site pain	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Joint dislocation	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0013 affected14 at risk EG0020 affected6 at risk
Laceration	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Muscle strain	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0010 affected14 at risk EG0020 affected6 at risk
Procedural pain	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0013 affected14 at risk EG0020 affected6 at risk
Procedural vomiting	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0010 affected14 at risk EG0020 affected6 at risk
Skin abrasion	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0021 affected6 at risk
Stoma site haemorrhage	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Stoma site hypergranulation	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Thermal burn	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Traumatic haematoma	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Upper limb fracture	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Vaccination complication	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Aspiration bronchial	Investigations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Blood urea increased	Investigations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Bone density decreased	Investigations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Carnitine decreased	Investigations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Enterobacter test positive	Investigations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Full blood count increased	Investigations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Heart rate increased	Investigations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Oxygen saturation decreased	Investigations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0021 affected6 at risk
Pco2 increased	Investigations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Urine output decreased	Investigations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Urine output increased	Investigations	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0010 affected14 at risk EG0020 affected6 at risk
Weight decreased	Investigations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0021 affected6 at risk
Weight increased	Investigations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
White blood cell count increased	Investigations	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0013 affected14 at risk EG0020 affected6 at risk
Failure to thrive	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Feeding disorder	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Hyperchloraemia	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Hypernatraemia	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Hypochloraemia	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Hyponatraemia	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Hypophagia	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Metabolic acidosis	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Weight gain poor	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0021 affected6 at risk
Hip deformity	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Joint contracture	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0021 affected6 at risk
Joint hyperextension	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Muscle tightness	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Musculoskeletal stiffness	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Osteopenia	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0021 affected6 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0016 affected14 at risk EG0022 affected6 at risk
Scoliosis	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0014 affected14 at risk EG0020 affected6 at risk
Spinal pain	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Tendinous contracture	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Torticollis	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Cranial nerve disorder	Nervous system disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Dysarthria	Nervous system disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0021 affected6 at risk
Headache	Nervous system disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Device extrusion	Product Issues	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Dysphemia	Psychiatric disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Intermittent explosive disorder	Psychiatric disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0010 affected14 at risk EG0020 affected6 at risk
Irritability	Psychiatric disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Acute kidney injury	Renal and urinary disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Urinary retention	Renal and urinary disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Penile adhesion	Reproductive system and breast disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Aspiration	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0010 affected14 at risk EG0020 affected6 at risk
Atelectasis	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0021 affected6 at risk
Bronchial secretion retention	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Chronic respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG00111 affected14 at risk EG0023 affected6 at risk
Dysphonia	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Hypoventilation	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Hypoxia	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0002 affected7 at risk EG0013 affected14 at risk EG0020 affected6 at risk
Increased bronchial secretion	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0010 affected14 at risk EG0020 affected6 at risk
Larynx irritation	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0010 affected14 at risk EG0020 affected6 at risk
Lower respiratory tract congestion	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0022 affected6 at risk
Nasal congestion	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0016 affected14 at risk EG0022 affected6 at risk
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Pneumonia aspiration	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Productive cough	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Pulmonary congestion	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Restrictive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Rhinitis allergic	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0016 affected14 at risk EG0021 affected6 at risk
Sinus congestion	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk
Sleep apnoea syndrome	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Tachypnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Tonsillar hypertrophy	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0021 affected6 at risk
Upper respiratory tract congestion	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Upper-airway cough syndrome	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0021 affected6 at risk
Use of accessory respiratory muscles	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Decubitus ulcer	Skin and subcutaneous tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Dermatitis contact	Skin and subcutaneous tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Dermatitis diaper	Skin and subcutaneous tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Dry skin	Skin and subcutaneous tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Erythema	Skin and subcutaneous tissue disorders	MedDRA 20.0	Systematic Assessment	EG0002 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Miliaria	Skin and subcutaneous tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Petechiae	Skin and subcutaneous tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Rash erythematous	Skin and subcutaneous tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Rash generalised	Skin and subcutaneous tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Rash macular	Skin and subcutaneous tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Rash papular	Skin and subcutaneous tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Skin irritation	Skin and subcutaneous tissue disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0011 affected14 at risk EG0020 affected6 at risk
Urticaria	Skin and subcutaneous tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0012 affected14 at risk EG0020 affected6 at risk
Flushing	Vascular disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0010 affected14 at risk EG0020 affected6 at risk
Haematoma	Vascular disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0011 affected14 at risk EG0021 affected6 at risk
Hypertension	Vascular disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected7 at risk EG0010 affected14 at risk EG0020 affected6 at risk
Hypotension	Vascular disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected7 at risk EG0010 affected14 at risk EG0021 affected6 at risk

ID	Term
D013118	Spinal Cord Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D016472	Motor Neuron Disease
D019636	Neurodegenerative Diseases
D009468	Neuromuscular Diseases

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Sham Procedure in Part 1	Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	1	7	3	7	6	7
EG001	ISIS 396443 Part 1 & 2	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.	0	14	9	14	14	14
EG002	ISIS 396443 Part 2(Participants on Sham in Part 1)	Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.	0	6	4	6	6	6