Trial Outcomes & Findings for A Study to Assess the Safety and Tolerability of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy (SMA). (NCT NCT02462759)

Last Updated: 2021-02-17

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

21 participants

Primary outcome timeframe

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

Results posted on

2021-02-17

Participant Flow

Participants were recruited from sites in the US and Germany. Part 1 was terminated early as positive efficacy results were observed in interim analysis of study NCT02193074 and it was considered unethical to continue this part of study. Part 2 was also terminated early to rollover and continue to follow participants in study NCT02594124.

Total of 21 participants with SMA were randomized in Part 1 of the study(7 participants in sham procedure group,14 participants in ISIS 396443 group).1 participant died in sham procedure group of Part 1.Total of 20 participants were enrolled to receive ISIS 396443 in open-label phase of Part 2.Integrated analysis was performed for Part 1 and 2.

Participant milestones

Participant milestones
Measure	Sham Procedure (Part 1) Sham procedure on Day 1, 15, 29, 64, 183 and 302.	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.	ISIS 396443 (Part 2) Participants who were in Sham procedure group in Part 1, received single dose of 12.0 mg ISIS 396443 intrathecal bolus injection loading doses on Day 1, 15, 29, 64 and maintenance doses, every 4 months, on Day 183, 302, 421, 540, 659 and 778 in Part 2; participants who were in ISIS 396443 group in Part 1 continued to receive a single dose of 9.6 mg to 12.0 mg ISIS 396443 intrathecal bolus injection maintenance doses on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2.
Part 1: Double Blind STARTED	7	14	0
Part 1: Double Blind COMPLETED	6	14	0
Part 1: Double Blind NOT COMPLETED	1	0	0
Part 2: Open-Label Phase STARTED	0	0	20
Part 2: Open-Label Phase COMPLETED	0	0	20
Part 2: Open-Label Phase NOT COMPLETED	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Sham Procedure (Part 1) Sham procedure on Day 1, 15, 29, 64, 183 and 302.	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.	ISIS 396443 (Part 2) Participants who were in Sham procedure group in Part 1, received single dose of 12.0 mg ISIS 396443 intrathecal bolus injection loading doses on Day 1, 15, 29, 64 and maintenance doses, every 4 months, on Day 183, 302, 421, 540, 659 and 778 in Part 2; participants who were in ISIS 396443 group in Part 1 continued to receive a single dose of 9.6 mg to 12.0 mg ISIS 396443 intrathecal bolus injection maintenance doses on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2.
Part 1: Double Blind Death	1	0	0

Baseline Characteristics

A Study to Assess the Safety and Tolerability of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy (SMA).

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sham Procedure (Part 1) n=7 Participants Sham procedure on Day 1, 15, 29, 64, 183 and 302.	ISIS 396443 (Part 1) n=14 Participants 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.	Total n=21 Participants Total of all reporting groups
Age, Continuous	24.4 months STANDARD_DEVIATION 13.83 • n=5 Participants	19.4 months STANDARD_DEVIATION 10.12 • n=7 Participants	21.1 months STANDARD_DEVIATION 11.39 • n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	9 Participants n=7 Participants	11 Participants n=5 Participants
Race/Ethnicity, Customized Ethnicity: Hispanic or Latino	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Ethnicity: Not Hispanic or Latino	4 Participants n=5 Participants	9 Participants n=7 Participants	13 Participants n=5 Participants
Race/Ethnicity, Customized Ethnicity: Not reported due to confidentiality	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants
Race/Ethnicity, Customized Race: Asian	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Race/Ethnicity, Customized Race: White	2 Participants n=5 Participants	7 Participants n=7 Participants	9 Participants n=5 Participants
Race/Ethnicity, Customized Race: Other	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Race: Not reported due to confidentiality	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants

PRIMARY outcome

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

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

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=7 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	ISIS 396443 Part 2(Participants on Sham in Part 1) n=6 Participants Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.	ISIS 396443 Part 1 & 2 n=14 Participants 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.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) AEs	6 Participants	6 Participants	14 Participants
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) SAEs	3 Participants	4 Participants	9 Participants

PRIMARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=7 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	ISIS 396443 Part 2(Participants on Sham in Part 1) n=6 Participants Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.	ISIS 396443 Part 1 & 2 n=14 Participants 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.
Number of Participants With Change From Baseline in Clinical Laboratory Parameters	0 Participants	0 Participants	0 Participants

PRIMARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=7 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	ISIS 396443 Part 2(Participants on Sham in Part 1) n=6 Participants Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.	ISIS 396443 Part 1 & 2 n=14 Participants 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.
Number of Participants With Change From Baseline in Electrocardiograms (ECGs)	0 Participants	0 Participants	0 Participants

PRIMARY outcome

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

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

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.

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=7 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	ISIS 396443 Part 2(Participants on Sham in Part 1) n=6 Participants Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.	ISIS 396443 Part 1 & 2 n=14 Participants 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.
Number of Participants With Change From Baseline in Vital Signs	0 Participants	0 Participants	0 Participants

PRIMARY outcome

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

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=6 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	ISIS 396443 Part 2(Participants on Sham in Part 1) n=14 Participants Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.	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.
Change From Baseline in Head Circumference Baseline	50.8 centimeter (cm) Standard Deviation 3.83	47.3 centimeter (cm) Standard Deviation 1.51	—
Change From Baseline in Head Circumference Change at Day 15	-0.7 centimeter (cm) Standard Deviation 3.34	0.1 centimeter (cm) Standard Deviation 0.36	—
Change From Baseline in Head Circumference Change at Day 29	0.0 centimeter (cm) Standard Deviation 2.76	0.3 centimeter (cm) Standard Deviation 0.65	—
Change From Baseline in Head Circumference Change at Day 64	0.1 centimeter (cm) Standard Deviation 2.64	0.5 centimeter (cm) Standard Deviation 0.73	—
Change From Baseline in Head Circumference Change at Day 183	0.3 centimeter (cm) Standard Deviation 3.10	1.0 centimeter (cm) Standard Deviation 1.12	—
Change From Baseline in Head Circumference Change at Day 302	1.0 centimeter (cm) Standard Deviation 3.28	1.6 centimeter (cm) Standard Deviation 1.05	—
Change From Baseline in Head Circumference Change at Day 422	0.9 centimeter (cm) Standard Deviation 2.47	2.0 centimeter (cm) Standard Deviation 1.24	—
Change From Baseline in Head Circumference Change at Day 540	1.3 centimeter (cm) Standard Deviation 1.97	2.5 centimeter (cm) Standard Deviation 1.24	—
Change From Baseline in Head Circumference Change at Day 659	1.5 centimeter (cm) Standard Deviation 2.53	2.6 centimeter (cm) Standard Deviation 1.37	—
Change From Baseline in Head Circumference Change at Day 778	—	2.8 centimeter (cm) Standard Deviation 0.92	—
Change From Baseline in Head Circumference Change at Day 898	—	3.5 centimeter (cm) Standard Deviation 1.05	—
Change From Baseline in Head Circumference Change at Day 1018	—	3.5 centimeter (cm) Standard Deviation 2.06	—
Change From Baseline in Head Circumference Change at Day 1138	—	4.0 centimeter (cm) Standard Deviation 0	—

PRIMARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=6 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	ISIS 396443 Part 2(Participants on Sham in Part 1) n=14 Participants Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.	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.
Change From Baseline in Chest Circumference Baseline	51.3 cm Standard Deviation 5.45	46.9 cm Standard Deviation 3.91	—
Change From Baseline in Chest Circumference Change at Day 15	-0.2 cm Standard Deviation 3.86	-0.4 cm Standard Deviation 1.53	—
Change From Baseline in Chest Circumference Change at Day 29	-1.1 cm Standard Deviation 2.70	0.2 cm Standard Deviation 1.39	—
Change From Baseline in Chest Circumference Change at Day 64	-0.9 cm Standard Deviation 3.50	0.2 cm Standard Deviation 1.92	—
Change From Baseline in Chest Circumference Change at Day 183	0.2 cm Standard Deviation 3.04	1.4 cm Standard Deviation 2.02	—
Change From Baseline in Chest Circumference Change at Day 302	1.2 cm Standard Deviation 3.07	1.6 cm Standard Deviation 2.86	—
Change From Baseline in Chest Circumference Change at Day 422	0.5 cm Standard Deviation 3.72	2.8 cm Standard Deviation 2.73	—
Change From Baseline in Chest Circumference Change at Day 540	1.8 cm Standard Deviation 2.42	3.8 cm Standard Deviation 3.23	—
Change From Baseline in Chest Circumference Change at Day 659	2.9 cm Standard Deviation 3.85	5.1 cm Standard Deviation 3.29	—
Change From Baseline in Chest Circumference Change at Day 778	—	5.5 cm Standard Deviation 3.52	—
Change From Baseline in Chest Circumference Change at Day 898	—	7.1 cm Standard Deviation 3.04	—
Change From Baseline in Chest Circumference Change at Day 1018	—	9.7 cm Standard Deviation 4.92	—
Change From Baseline in Chest Circumference Change at Day 1138	—	9.1 cm Standard Deviation 0	—

PRIMARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=6 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	ISIS 396443 Part 2(Participants on Sham in Part 1) n=14 Participants Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.	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.
Change From Baseline in Arm Circumference Baseline	16.2 cm Standard Deviation 1.19	14.5 cm Standard Deviation 1.85	—
Change From Baseline in Arm Circumference Change at Day 15	-0.4 cm Standard Deviation 1.04	0.3 cm Standard Deviation 0.61	—
Change From Baseline in Arm Circumference Change at Day 29	-0.5 cm Standard Deviation 1.08	-0.1 cm Standard Deviation 0.54	—
Change From Baseline in Arm Circumference Change at Day 64	-0.3 cm Standard Deviation 0.49	-0.4 cm Standard Deviation 0.89	—
Change From Baseline in Arm Circumference Change at Day 183	0.0 cm Standard Deviation 0.89	0.0 cm Standard Deviation 0.85	—
Change From Baseline in Arm Circumference Change at Day 302	-0.6 cm Standard Deviation 0.89	0.2 cm Standard Deviation 1.17	—
Change From Baseline in Arm Circumference Change at Day 422	-0.6 cm Standard Deviation 1.82	0.5 cm Standard Deviation 1.71	—
Change From Baseline in Arm Circumference Change at Day 540	-0.2 cm Standard Deviation 2.24	0.5 cm Standard Deviation 1.89	—
Change From Baseline in Arm Circumference Change at Day 659	0.6 cm Standard Deviation 0.93	0.6 cm Standard Deviation 1.93	—
Change From Baseline in Arm Circumference Change at Day 778	—	0.0 cm Standard Deviation 2.18	—
Change From Baseline in Arm Circumference Change at Day 898	—	0.8 cm Standard Deviation 2.70	—
Change From Baseline in Arm Circumference Change at Day 1018	—	1.0 cm Standard Deviation 2.02	—
Change From Baseline in Arm Circumference Change at Day 1138	—	1.5 cm Standard Deviation 0	—

PRIMARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=6 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	ISIS 396443 Part 2(Participants on Sham in Part 1) n=14 Participants Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.	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.
Change From Baseline in Weight for Age Baseline	42.5 kilogram (kg) Standard Deviation 40.87	25.3 kilogram (kg) Standard Deviation 28.41	—
Change From Baseline in Weight for Age Change at Day 15	-1.3 kilogram (kg) Standard Deviation 1.41	3.6 kilogram (kg) Standard Deviation 12.12	—
Change From Baseline in Weight for Age Change at Day 29	-2.4 kilogram (kg) Standard Deviation 1.61	-1.4 kilogram (kg) Standard Deviation 4.82	—
Change From Baseline in Weight for Age Change at Day 64	-2.9 kilogram (kg) Standard Deviation 2.58	0.5 kilogram (kg) Standard Deviation 8.17	—
Change From Baseline in Weight for Age Change at Day 183	-3.8 kilogram (kg) Standard Deviation 6.93	-5.9 kilogram (kg) Standard Deviation 8.73	—
Change From Baseline in Weight for Age Change at Day 302	-10.1 kilogram (kg) Standard Deviation 13.04	-8.0 kilogram (kg) Standard Deviation 15.42	—
Change From Baseline in Weight for Age Change at Day 422	-6.3 kilogram (kg) Standard Deviation 9.45	-7.5 kilogram (kg) Standard Deviation 17.52	—
Change From Baseline in Weight for Age Change at Day 540	-7.0 kilogram (kg) Standard Deviation 6.56	-8.1 kilogram (kg) Standard Deviation 17.26	—
Change From Baseline in Weight for Age Change at Day 659	-8.5 kilogram (kg) Standard Deviation 17.64	-10.5 kilogram (kg) Standard Deviation 22.23	—
Change From Baseline in Weight for Age Change at Day 778	—	-13.2 kilogram (kg) Standard Deviation 16.95	—
Change From Baseline in Weight for Age Change at Day 898	—	-10.5 kilogram (kg) Standard Deviation 24.10	—
Change From Baseline in Weight for Age Change at Day 1018	—	-7.0 kilogram (kg) Standard Deviation 34.14	—
Change From Baseline in Weight for Age Change at Day 1138	—	0.3 kilogram (kg) Standard Deviation 0	—

PRIMARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=6 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	ISIS 396443 Part 2(Participants on Sham in Part 1) n=14 Participants Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.	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.
Change From Baseline in Weight Change at Day 1138	—	5.0 kg Standard Deviation 0	—
Change From Baseline in Weight Baseline	13.0 kg Standard Deviation 2.00	9.5 kg Standard Deviation 1.37	—
Change From Baseline in Weight Change at Day 15	-0.1 kg Standard Deviation 0.23	0.2 kg Standard Deviation 0.44	—
Change From Baseline in Weight Change at Day 29	-0.1 kg Standard Deviation 0.26	0.1 kg Standard Deviation 0.23	—
Change From Baseline in Weight Change at Day 64	0.0 kg Standard Deviation 0.39	0.4 kg Standard Deviation 0.42	—
Change From Baseline in Weight Change at Day 183	0.8 kg Standard Deviation 0.61	0.7 kg Standard Deviation 0.48	—
Change From Baseline in Weight Change at Day 302	0.7 kg Standard Deviation 1.04	1.3 kg Standard Deviation 0.87	—
Change From Baseline in Weight Change at Day 422	1.8 kg Standard Deviation 1.03	1.9 kg Standard Deviation 1.02	—
Change From Baseline in Weight Change at Day 540	2.3 kg Standard Deviation 1.33	2.2 kg Standard Deviation 1.17	—
Change From Baseline in Weight Change at Day 659	3.1 kg Standard Deviation 1.39	2.8 kg Standard Deviation 1.41	—
Change From Baseline in Weight Change at Day 778	—	3.2 kg Standard Deviation 1.87	—
Change From Baseline in Weight Change at Day 898	—	3.9 kg Standard Deviation 2.86	—
Change From Baseline in Weight Change at Day 1018	—	4.3 kg Standard Deviation 1.96	—

PRIMARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=6 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	ISIS 396443 Part 2(Participants on Sham in Part 1) n=14 Participants Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.	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.
Change From Baseline in Head to Chest Circumference (HCC) Ratio Baseline	1.0 ratio Standard Deviation 0.05	1.0 ratio Standard Deviation 0.08	—
Change From Baseline in Head to Chest Circumference (HCC) Ratio Change at Day 15	0.0 ratio Standard Deviation 0.03	0.0 ratio Standard Deviation 0.03	—
Change From Baseline in Head to Chest Circumference (HCC) Ratio Change at Day 29	0.0 ratio Standard Deviation 0.04	0.0 ratio Standard Deviation 0.04	—
Change From Baseline in Head to Chest Circumference (HCC) Ratio Change at Day 64	0.0 ratio Standard Deviation 0.04	0.0 ratio Standard Deviation 0.05	—
Change From Baseline in Head to Chest Circumference (HCC) Ratio Change at Day 183	0.0 ratio Standard Deviation 0.05	0.0 ratio Standard Deviation 0.05	—
Change From Baseline in Head to Chest Circumference (HCC) Ratio Change at Day 302	0.0 ratio Standard Deviation 0.03	0.0 ratio Standard Deviation 0.06	—
Change From Baseline in Head to Chest Circumference (HCC) Ratio Change at Day 422	0.0 ratio Standard Deviation 0.04	0.0 ratio Standard Deviation 0.06	—
Change From Baseline in Head to Chest Circumference (HCC) Ratio Change at Day 540	0.0 ratio Standard Deviation 0.03	0.0 ratio Standard Deviation 0.06	—
Change From Baseline in Head to Chest Circumference (HCC) Ratio Change at Day 659	0.0 ratio Standard Deviation 0.03	-0.1 ratio Standard Deviation 0.06	—
Change From Baseline in Head to Chest Circumference (HCC) Ratio Change at Day 778	—	-0.1 ratio Standard Deviation 0.07	—
Change From Baseline in Head to Chest Circumference (HCC) Ratio Change at Day 898	—	-0.1 ratio Standard Deviation 0.06	—
Change From Baseline in Head to Chest Circumference (HCC) Ratio Change at Day 1018	—	-0.1 ratio Standard Deviation 0.10	—
Change From Baseline in Head to Chest Circumference (HCC) Ratio Change at Day 1138	—	-0.1 ratio Standard Deviation 0	—

PRIMARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=6 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	ISIS 396443 Part 2(Participants on Sham in Part 1) n=14 Participants Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.	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.
Change From Baseline in Body Length Baseline	95.0 cm Standard Deviation 9.48	79.9 cm Standard Deviation 5.25	—
Change From Baseline in Body Length Change at Day 15	-1.6 cm Standard Deviation 3.19	-0.1 cm Standard Deviation 1.81	—
Change From Baseline in Body Length Change at Day 29	-0.9 cm Standard Deviation 3.49	0.9 cm Standard Deviation 1.66	—
Change From Baseline in Body Length Change at Day 64	0.5 cm Standard Deviation 4.77	1.8 cm Standard Deviation 2.40	—
Change From Baseline in Body Length Change at Day 183	3.0 cm Standard Deviation 4.16	5.6 cm Standard Deviation 2.36	—
Change From Baseline in Body Length Change at Day 302	2.9 cm Standard Deviation 5.76	7.1 cm Standard Deviation 2.70	—
Change From Baseline in Body Length Change at Day 422	4.2 cm Standard Deviation 5.42	9.3 cm Standard Deviation 3.09	—
Change From Baseline in Body Length Change at Day 540	4.6 cm Standard Deviation 7.18	11.6 cm Standard Deviation 3.93	—
Change From Baseline in Body Length Change at Day 659	10.8 cm Standard Deviation 4.12	13.1 cm Standard Deviation 3.79	—
Change From Baseline in Body Length Change at Day 778	—	14.8 cm Standard Deviation 3.94	—
Change From Baseline in Body Length Change at Day 898	—	17.2 cm Standard Deviation 5.62	—
Change From Baseline in Body Length Change at Day 1018	—	19.0 cm Standard Deviation 6.67	—
Change From Baseline in Body Length Change at Day 1138	—	15.8 cm Standard Deviation 0	—

PRIMARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=7 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	ISIS 396443 Part 2(Participants on Sham in Part 1) n=6 Participants Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.	ISIS 396443 Part 1 & 2 n=14 Participants 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.
Number of Participants With Change From Baseline in Neurological Examination Outcomes Mental Status	0 Participants	1 Participants	3 Participants
Number of Participants With Change From Baseline in Neurological Examination Outcomes Level of consciousness	0 Participants	1 Participants	2 Participants
Number of Participants With Change From Baseline in Neurological Examination Outcomes Sensory function	0 Participants	0 Participants	0 Participants
Number of Participants With Change From Baseline in Neurological Examination Outcomes Motor function	0 Participants	0 Participants	0 Participants
Number of Participants With Change From Baseline in Neurological Examination Outcomes Cranial nerve function: Eye Movement	0 Participants	0 Participants	1 Participants
Number of Participants With Change From Baseline in Neurological Examination Outcomes Cranial nerve function: Vision	0 Participants	0 Participants	1 Participants
Number of Participants With Change From Baseline in Neurological Examination Outcomes Reflexes	0 Participants	0 Participants	0 Participants
Number of Participants With Change From Baseline in Neurological Examination Outcomes Mood	5 Participants	5 Participants	12 Participants
Number of Participants With Change From Baseline in Neurological Examination Outcomes Speech/Language	0 Participants	1 Participants	1 Participants
Number of Participants With Change From Baseline in Neurological Examination Outcomes Hearing	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Part 2: Up to 1080 days

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=6 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	ISIS 396443 Part 2(Participants on Sham in Part 1) n=14 Participants Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.	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.
Number of Participants With Change From Baseline in Activated Partial Thromboplastin Time [aPTT] Shift to Low	0 Participants	0 Participants	—
Number of Participants With Change From Baseline in Activated Partial Thromboplastin Time [aPTT] Shift to High	0 Participants	0 Participants	—

PRIMARY outcome

Timeframe: Part 2: Up to 1080 days

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.

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=6 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	ISIS 396443 Part 2(Participants on Sham in Part 1) n=14 Participants Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.	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.
Number of Participants With Change From Baseline in Partial Thromboplastin Time [PTT] Shift to Low	0 Participants	0 Participants	—
Number of Participants With Change From Baseline in Partial Thromboplastin Time [PTT] Shift to High	0 Participants	0 Participants	—

PRIMARY outcome

Timeframe: Part 2: Up to 1080 days

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.

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=6 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	ISIS 396443 Part 2(Participants on Sham in Part 1) n=14 Participants Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.	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.
Number of Participants With Change From Baseline in International Normalized Ratio [INR]) Shift to Low	0 Participants	0 Participants	—
Number of Participants With Change From Baseline in International Normalized Ratio [INR]) Shift to High	0 Participants	0 Participants	—

PRIMARY outcome

Timeframe: Part 2: Up to 1080 days

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

Urine total protein was evaluated to assess safety.

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=6 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	ISIS 396443 Part 2(Participants on Sham in Part 1) n=14 Participants Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.	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.
Number of Participants With Presence of Urine Total Protein Post-baseline Baseline	0 Participants	1 Participants	—
Number of Participants With Presence of Urine Total Protein Post-baseline High/Postive	2 Participants	8 Participants	—

SECONDARY outcome

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

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

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.

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=6 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	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.	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.
Plasma Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study Day 64	1.983 nanogram per milliliter (ng/mL) Standard Deviation 0.7320	—	—
Plasma Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study Day 183	0.776 nanogram per milliliter (ng/mL) Standard Deviation 0.3994	—	—
Plasma Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study Day 540	0.425 nanogram per milliliter (ng/mL) Standard Deviation 0.2200	—	—
Plasma Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study Day 659	0.365 nanogram per milliliter (ng/mL) Standard Deviation 0.1146	—	—

SECONDARY outcome

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

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=14 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	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.	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.
Plasma Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 64	2.139 ng/mL Standard Deviation 0.8811	—	—
Plasma Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 183	1.059 ng/mL Standard Deviation 0.5569	—	—
Plasma Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 302	0.667 ng/mL Standard Deviation 0.1852	—	—
Plasma Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 422	0.858 ng/mL Standard Deviation 0.4636	—	—
Plasma Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 540	0.608 ng/mL Standard Deviation 0.2736	—	—
Plasma Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 659	0.739 ng/mL Standard Deviation 0.2812	—	—
Plasma Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 778	0.590 ng/mL Standard Deviation 0.3414	—	—
Plasma Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 898	0.661 ng/mL Standard Deviation 0.2558	—	—
Plasma Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 1018	0.329 ng/mL Standard Deviation 0.1020	—	—
Plasma Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 1138	0.423 ng/mL Standard Deviation 0	—	—

SECONDARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=6 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	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.	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.
Cerebrospinal Fluid (CSF) Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study Day 1	NA ng/mL Standard Error NA Mean was below the lower limit of quantification (LLOQ) hence standard deviation was not evaluated. LLOQ is 50 picogram per millilitre.	—	—
Cerebrospinal Fluid (CSF) Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study Day 15	3.094 ng/mL Standard Error 1.2172	—	—
Cerebrospinal Fluid (CSF) Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study Day 29	4.805 ng/mL Standard Error 2.6706	—	—
Cerebrospinal Fluid (CSF) Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study Day 64	4.357 ng/mL Standard Error 2.3229	—	—
Cerebrospinal Fluid (CSF) Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study Day 183	4.110 ng/mL Standard Error 2.4535	—	—
Cerebrospinal Fluid (CSF) Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study Day 302	5.397 ng/mL Standard Error 2.7503	—	—
Cerebrospinal Fluid (CSF) Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study Day 422	6.460 ng/mL Standard Error 2.9428	—	—
Cerebrospinal Fluid (CSF) Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study Day 540	8.405 ng/mL Standard Error 6.2423	—	—

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=14 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	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.	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.
CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 1	NA ng/mL Standard Deviation NA Mean was below the lower limit of quantification (LLOQ) hence standard deviation was not evaluated. LLOQ is 50 picogram per millilitre.	—	—
CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 15	3.925 ng/mL Standard Deviation 2.0525	—	—
CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 29	7.273 ng/mL Standard Deviation 4.4786	—	—
CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 64	7.176 ng/mL Standard Deviation 2.8487	—	—
CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 183	8.226 ng/mL Standard Deviation 3.6450	—	—
CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 302	8.968 ng/mL Standard Deviation 3.1188	—	—
CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 422	9.251 ng/mL Standard Deviation 4.0631	—	—
CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 540	9.026 ng/mL Standard Deviation 2.6864	—	—
CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 659	9.785 ng/mL Standard Deviation 3.3725	—	—
CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 778	8.632 ng/mL Standard Deviation 2.4131	—	—
CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 898	11.321 ng/mL Standard Deviation 8.9351	—	—
CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study Day 1018	7.010 ng/mL Standard Deviation 0	—	—

SECONDARY outcome

Timeframe: Part 2: Baseline to Day 596

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

Outcome measures

Outcome measures
Measure	Sham Procedure in Part 1 n=6 Participants Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.	ISIS 396443 Part 2(Participants on Sham in Part 1) n=14 Participants Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.	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.
Number of Participants With Plasma Antibodies to ISIS 396443	0 Participants	0 Participants	—

Adverse Events

Sham Procedure in Part 1

Serious events: 3 serious events

Other events: 6 other events

Deaths: 1 deaths

ISIS 396443 Part 1 & 2

Serious events: 9 serious events

Other events: 14 other events

Deaths: 0 deaths

ISIS 396443 Part 2(Participants on Sham in Part 1)

Serious events: 4 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Biogen Study Medical Director

Biogen

Phone: 866-633-4636

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.
Publication restrictions are in place

Restriction type: OTHER