Spinal Muscular Atrophy
Conditions
Keywords
EMBRACE, SMA
Brief summary
The primary objective of Part 1 of this study is to assess the safety and tolerability of Nusinersen in participants with SMA who are not eligible to participate in the clinical studies ISIS 396443-CS3B (NCT02193074) or ISIS 396443-CS4 (NCT02292537). The secondary objective of Part 1 of this study is to examine the pharmacokinetics (PK) of Nusinersen in participants with SMA. The primary objective of Part 2 of this study is to assess the long-term safety and tolerability of Nusinersen in participants with SMA who participated in Part 1 and completed their End of Part 1 Evaluation assessments. The secondary objective of Part 2 of this study is to examine the PK of Nusinersen in participants with SMA who participated in Part 1 and completed their End of Part 1 Evaluation assessments.
Detailed description
Part 2 is an Open Label extension phase.
Interventions
DRUGNusinersen
Administered by intrathecal injection.
PROCEDURESham Procedure
Small needle prick on the lower back at the location where the IT injection is normally made.
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Genetic documentation of 5q SMA homozygous gene deletion, mutation, or compound heterozygote. * Onset of clinical signs and symptoms consistent with SMA at ≤6 months of age and have documentation of 3 SMN2 copies OR onset of clinical signs and symptoms consistent with SMA at ≤6 months of age, \>7 months of age (211 days) at screening, and have documentation of 2 SMN2 copies OR onset of clinical signs and symptoms consistent with SMA at \>6 months of age, are ≤18 months of age at screening, and have documentation of 2 or 3 SMN2 copies. * Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is planned for study procedures. * Medical care, such as routine immunizations meets and is expected to continue to meet guidelines set out in the Consensus Statement for Standard of Care in SMA, in the opinion of the Investigator. * Participants with 2 SMN2 copies must reside within approximately 9 hours' ground-travel distance from a participating study site for the duration of the study. Key
Exclusion criteria
* Meets additional study related criteria. * Any previous exposure to ISIS 396443; previous dosing in this study or previous studies with ISIS 396443. * Signs or symptoms of SMA present at birth or within the first week after birth. * Ventilation for ≥16 hours per day continuously for \>21 days at screening. * Permanent tracheostomy, implanted shunt for CSF drainage, or implanted central nervous system (CNS) catheter at screening. * History of brain or spinal cord disease that would interfere with the LP procedure, CSF circulation, or safety assessments. * Hospitalization for surgery (e.g., scoliosis surgery), pulmonary event, or nutritional support within 2 months prior to screening, or hospitalization for surgery planned during the study. * Clinically significant abnormalities in hematology or clinical chemistry parameters or Electrocardiogram (ECG), as assessed by the Investigator. * Treatment with an investigational drug for SMA (e.g., albuterol/salbutamol, riluzole, carnitine, sodium phenylbutyrate, valproate, hydroxyurea), biological agent, or device within 30 days prior to screening. Any history of gene therapy, prior antisense oligonucleotide (ASO) treatment, or cell transplantation. For Part 2 only: To be eligible to participate in Part 2 of this study, participants must meet the following eligibility criteria at the time of consent to participate in Part 2: Participation in Part 1 and completion of the End of Part 1 Evaluation assessments. Ability of parent(s) or legal guardian(s) to understand the purpose and risks of the study and to provide signed and dated informed consent on the Part 2 informed consent form (ICF) and authorization to use confidential health information in accordance with national and local participant privacy regulations. Able to complete all study procedures, measurements, and visits, and parent or legal guardian/participant has adequately supportive psychosocial circumstances, in the opinion of the Investigator. Participants will be excluded from the Part 2 if they meet the following exclusion criterion at the time of consent into Part 2 of the study: Any significant change in clinical status, including laboratory tests that, in the opinion of the Investigator, would make them unsuitable to participate in Part 2. The Investigator must reassess the subject's medical fitness for participation and consider any diseases that would preclude treatment. NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Presence of Urine Total Protein Post-baseline | Part 2: Up to 1080 days | Urine total protein was evaluated to assess safety. |
| Change From Baseline in Body Length | 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. |
| Number of Participants With Change From Baseline in Neurological Examination Outcomes | Part 1: Baseline to Day 422; Part 2: Baseline to Day 596 | Neurological examinations included assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, reflexes, mood, speech/language and hearing. |
| Number of Participants With Change From Baseline in Activated Partial Thromboplastin Time [aPTT] | Part 2: Up to 1080 days | 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. |
| Number of Participants With Change From Baseline in Partial Thromboplastin Time [PTT] | 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. |
| Number of Participants With Change From Baseline in International Normalized Ratio [INR]) | 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. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Part 1 and 2: From first dose/sham procedure to end of study (up to 1080 days) | 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. |
| Number of Participants With Change From Baseline in Clinical Laboratory Parameters | Part 1 and 2: From first dose/sham procedure to end of study (up to 1080 days) | Clinically significant changes in laboratory parameters were evaluated for assessing the safety of ISIS 396443. |
| Number of Participants With Change From Baseline in Electrocardiograms (ECGs) | Part 1: Day 2, 29 and 422; Part 2: Day 1 to 596 | Clinically significant changes in ECG measurements were evaluated for assessing the safety of ISIS 396443. |
| Number of Participants With Change From Baseline in Vital Signs | Part 1: Day 2, 29 and 422; Part 2: Day 1 to 596 | 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. |
| Change From Baseline in Head Circumference | 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 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. |
| Change From Baseline in Chest Circumference | 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. |
| Change From Baseline in Arm Circumference | 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. |
| Change From Baseline in Weight for Age | 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. |
| Change From Baseline in Weight | 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. |
| Change From Baseline in Head to Chest Circumference (HCC) Ratio | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study | Pre-dose on Days 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138 | 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. |
| Cerebrospinal Fluid (CSF) Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study | 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. |
| CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study | Pre-dose on Days 15, 29, 64, 183, 302, 422, 540, 659, 778, 898 and 1018 | 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;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. |
| Number of Participants With Plasma Antibodies to ISIS 396443 | Part 2: Baseline to Day 596 | — |
| Plasma Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study | Pre-dose on Days 64, 183, 540 and 659 | 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. |
Countries
Germany, United States
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Sham Procedure (Part 1) Sham procedure on Day 1, 15, 29, 64, 183 and 302. | 7 |
| 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. | 14 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part 1: Double Blind | Death | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Sham Procedure (Part 1) | ISIS 396443 (Part 1) | Total |
|---|---|---|---|
| Age, Continuous | 24.4 months STANDARD_DEVIATION 13.83 | 19.4 months STANDARD_DEVIATION 10.12 | 21.1 months STANDARD_DEVIATION 11.39 |
| Race/Ethnicity, Customized Ethnicity: Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Ethnicity: Not Hispanic or Latino | 4 Participants | 9 Participants | 13 Participants |
| Race/Ethnicity, Customized Ethnicity: Not reported due to confidentiality | 1 Participants | 4 Participants | 5 Participants |
| Race/Ethnicity, Customized Race: Asian | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Race: Not reported due to confidentiality | 1 Participants | 4 Participants | 5 Participants |
| Race/Ethnicity, Customized Race: Other | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race: White | 2 Participants | 7 Participants | 9 Participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 2 Participants | 9 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 7 | 0 / 14 | 0 / 6 |
| other Total, other adverse events | 6 / 7 | 14 / 14 | 6 / 6 |
| serious Total, serious adverse events | 3 / 7 | 9 / 14 | 4 / 6 |
Outcome results
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Procedure in Part 1 | Change From Baseline in Arm Circumference | Change at Day 29 | -0.5 cm | Standard Deviation 1.08 |
| Sham Procedure in Part 1 | Change From Baseline in Arm Circumference | Change at Day 540 | -0.2 cm | Standard Deviation 2.24 |
| Sham Procedure in Part 1 | Change From Baseline in Arm Circumference | Change at Day 183 | 0.0 cm | Standard Deviation 0.89 |
| Sham Procedure in Part 1 | Change From Baseline in Arm Circumference | Change at Day 659 | 0.6 cm | Standard Deviation 0.93 |
| Sham Procedure in Part 1 | Change From Baseline in Arm Circumference | Change at Day 15 | -0.4 cm | Standard Deviation 1.04 |
| Sham Procedure in Part 1 | Change From Baseline in Arm Circumference | Change at Day 302 | -0.6 cm | Standard Deviation 0.89 |
| Sham Procedure in Part 1 | Change From Baseline in Arm Circumference | Change at Day 64 | -0.3 cm | Standard Deviation 0.49 |
| Sham Procedure in Part 1 | Change From Baseline in Arm Circumference | Change at Day 422 | -0.6 cm | Standard Deviation 1.82 |
| Sham Procedure in Part 1 | Change From Baseline in Arm Circumference | Baseline | 16.2 cm | Standard Deviation 1.19 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Arm Circumference | Change at Day 659 | 0.6 cm | Standard Deviation 1.93 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Arm Circumference | Change at Day 778 | 0.0 cm | Standard Deviation 2.18 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Arm Circumference | Change at Day 898 | 0.8 cm | Standard Deviation 2.7 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Arm Circumference | Change at Day 1018 | 1.0 cm | Standard Deviation 2.02 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Arm Circumference | Change at Day 1138 | 1.5 cm | Standard Deviation 0 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Arm Circumference | Baseline | 14.5 cm | Standard Deviation 1.85 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Arm Circumference | Change at Day 15 | 0.3 cm | Standard Deviation 0.61 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Arm Circumference | Change at Day 29 | -0.1 cm | Standard Deviation 0.54 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Arm Circumference | Change at Day 64 | -0.4 cm | Standard Deviation 0.89 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Arm Circumference | Change at Day 183 | 0.0 cm | Standard Deviation 0.85 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Arm Circumference | Change at Day 302 | 0.2 cm | Standard Deviation 1.17 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Arm Circumference | Change at Day 422 | 0.5 cm | Standard Deviation 1.71 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Arm Circumference | Change at Day 540 | 0.5 cm | Standard Deviation 1.89 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Procedure in Part 1 | Change From Baseline in Body Length | Change at Day 29 | -0.9 cm | Standard Deviation 3.49 |
| Sham Procedure in Part 1 | Change From Baseline in Body Length | Change at Day 540 | 4.6 cm | Standard Deviation 7.18 |
| Sham Procedure in Part 1 | Change From Baseline in Body Length | Change at Day 183 | 3.0 cm | Standard Deviation 4.16 |
| Sham Procedure in Part 1 | Change From Baseline in Body Length | Change at Day 659 | 10.8 cm | Standard Deviation 4.12 |
| Sham Procedure in Part 1 | Change From Baseline in Body Length | Change at Day 15 | -1.6 cm | Standard Deviation 3.19 |
| Sham Procedure in Part 1 | Change From Baseline in Body Length | Change at Day 302 | 2.9 cm | Standard Deviation 5.76 |
| Sham Procedure in Part 1 | Change From Baseline in Body Length | Change at Day 64 | 0.5 cm | Standard Deviation 4.77 |
| Sham Procedure in Part 1 | Change From Baseline in Body Length | Change at Day 422 | 4.2 cm | Standard Deviation 5.42 |
| Sham Procedure in Part 1 | Change From Baseline in Body Length | Baseline | 95.0 cm | Standard Deviation 9.48 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Body Length | Change at Day 659 | 13.1 cm | Standard Deviation 3.79 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Body Length | Change at Day 778 | 14.8 cm | Standard Deviation 3.94 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Body Length | Change at Day 898 | 17.2 cm | Standard Deviation 5.62 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Body Length | Change at Day 1018 | 19.0 cm | Standard Deviation 6.67 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Body Length | Change at Day 1138 | 15.8 cm | Standard Deviation 0 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Body Length | Baseline | 79.9 cm | Standard Deviation 5.25 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Body Length | Change at Day 15 | -0.1 cm | Standard Deviation 1.81 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Body Length | Change at Day 29 | 0.9 cm | Standard Deviation 1.66 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Body Length | Change at Day 64 | 1.8 cm | Standard Deviation 2.4 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Body Length | Change at Day 183 | 5.6 cm | Standard Deviation 2.36 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Body Length | Change at Day 302 | 7.1 cm | Standard Deviation 2.7 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Body Length | Change at Day 422 | 9.3 cm | Standard Deviation 3.09 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Body Length | Change at Day 540 | 11.6 cm | Standard Deviation 3.93 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Procedure in Part 1 | Change From Baseline in Chest Circumference | Change at Day 29 | -1.1 cm | Standard Deviation 2.7 |
| Sham Procedure in Part 1 | Change From Baseline in Chest Circumference | Change at Day 540 | 1.8 cm | Standard Deviation 2.42 |
| Sham Procedure in Part 1 | Change From Baseline in Chest Circumference | Change at Day 183 | 0.2 cm | Standard Deviation 3.04 |
| Sham Procedure in Part 1 | Change From Baseline in Chest Circumference | Change at Day 659 | 2.9 cm | Standard Deviation 3.85 |
| Sham Procedure in Part 1 | Change From Baseline in Chest Circumference | Change at Day 15 | -0.2 cm | Standard Deviation 3.86 |
| Sham Procedure in Part 1 | Change From Baseline in Chest Circumference | Change at Day 302 | 1.2 cm | Standard Deviation 3.07 |
| Sham Procedure in Part 1 | Change From Baseline in Chest Circumference | Change at Day 64 | -0.9 cm | Standard Deviation 3.5 |
| Sham Procedure in Part 1 | Change From Baseline in Chest Circumference | Change at Day 422 | 0.5 cm | Standard Deviation 3.72 |
| Sham Procedure in Part 1 | Change From Baseline in Chest Circumference | Baseline | 51.3 cm | Standard Deviation 5.45 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Chest Circumference | Change at Day 659 | 5.1 cm | Standard Deviation 3.29 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Chest Circumference | Change at Day 778 | 5.5 cm | Standard Deviation 3.52 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Chest Circumference | Change at Day 898 | 7.1 cm | Standard Deviation 3.04 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Chest Circumference | Change at Day 1018 | 9.7 cm | Standard Deviation 4.92 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Chest Circumference | Change at Day 1138 | 9.1 cm | Standard Deviation 0 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Chest Circumference | Baseline | 46.9 cm | Standard Deviation 3.91 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Chest Circumference | Change at Day 15 | -0.4 cm | Standard Deviation 1.53 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Chest Circumference | Change at Day 29 | 0.2 cm | Standard Deviation 1.39 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Chest Circumference | Change at Day 64 | 0.2 cm | Standard Deviation 1.92 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Chest Circumference | Change at Day 183 | 1.4 cm | Standard Deviation 2.02 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Chest Circumference | Change at Day 302 | 1.6 cm | Standard Deviation 2.86 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Chest Circumference | Change at Day 422 | 2.8 cm | Standard Deviation 2.73 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Chest Circumference | Change at Day 540 | 3.8 cm | Standard Deviation 3.23 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Procedure in Part 1 | Change From Baseline in Head Circumference | Change at Day 29 | 0.0 centimeter (cm) | Standard Deviation 2.76 |
| Sham Procedure in Part 1 | Change From Baseline in Head Circumference | Change at Day 540 | 1.3 centimeter (cm) | Standard Deviation 1.97 |
| Sham Procedure in Part 1 | Change From Baseline in Head Circumference | Change at Day 183 | 0.3 centimeter (cm) | Standard Deviation 3.1 |
| Sham Procedure in Part 1 | Change From Baseline in Head Circumference | Change at Day 659 | 1.5 centimeter (cm) | Standard Deviation 2.53 |
| Sham Procedure in Part 1 | Change From Baseline in Head Circumference | Change at Day 15 | -0.7 centimeter (cm) | Standard Deviation 3.34 |
| Sham Procedure in Part 1 | Change From Baseline in Head Circumference | Change at Day 302 | 1.0 centimeter (cm) | Standard Deviation 3.28 |
| Sham Procedure in Part 1 | Change From Baseline in Head Circumference | Change at Day 64 | 0.1 centimeter (cm) | Standard Deviation 2.64 |
| Sham Procedure in Part 1 | Change From Baseline in Head Circumference | Change at Day 422 | 0.9 centimeter (cm) | Standard Deviation 2.47 |
| Sham Procedure in Part 1 | Change From Baseline in Head Circumference | Baseline | 50.8 centimeter (cm) | Standard Deviation 3.83 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head Circumference | Change at Day 659 | 2.6 centimeter (cm) | Standard Deviation 1.37 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head Circumference | Change at Day 778 | 2.8 centimeter (cm) | Standard Deviation 0.92 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head Circumference | Change at Day 898 | 3.5 centimeter (cm) | Standard Deviation 1.05 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head Circumference | Change at Day 1018 | 3.5 centimeter (cm) | Standard Deviation 2.06 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head Circumference | Change at Day 1138 | 4.0 centimeter (cm) | Standard Deviation 0 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head Circumference | Baseline | 47.3 centimeter (cm) | Standard Deviation 1.51 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head Circumference | Change at Day 15 | 0.1 centimeter (cm) | Standard Deviation 0.36 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head Circumference | Change at Day 29 | 0.3 centimeter (cm) | Standard Deviation 0.65 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head Circumference | Change at Day 64 | 0.5 centimeter (cm) | Standard Deviation 0.73 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head Circumference | Change at Day 183 | 1.0 centimeter (cm) | Standard Deviation 1.12 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head Circumference | Change at Day 302 | 1.6 centimeter (cm) | Standard Deviation 1.05 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head Circumference | Change at Day 422 | 2.0 centimeter (cm) | Standard Deviation 1.24 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head Circumference | Change at Day 540 | 2.5 centimeter (cm) | Standard Deviation 1.24 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Procedure in Part 1 | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 29 | 0.0 ratio | Standard Deviation 0.04 |
| Sham Procedure in Part 1 | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 540 | 0.0 ratio | Standard Deviation 0.03 |
| Sham Procedure in Part 1 | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 183 | 0.0 ratio | Standard Deviation 0.05 |
| Sham Procedure in Part 1 | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 659 | 0.0 ratio | Standard Deviation 0.03 |
| Sham Procedure in Part 1 | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 15 | 0.0 ratio | Standard Deviation 0.03 |
| Sham Procedure in Part 1 | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 302 | 0.0 ratio | Standard Deviation 0.03 |
| Sham Procedure in Part 1 | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 64 | 0.0 ratio | Standard Deviation 0.04 |
| Sham Procedure in Part 1 | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 422 | 0.0 ratio | Standard Deviation 0.04 |
| Sham Procedure in Part 1 | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Baseline | 1.0 ratio | Standard Deviation 0.05 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 659 | -0.1 ratio | Standard Deviation 0.06 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 778 | -0.1 ratio | Standard Deviation 0.07 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 898 | -0.1 ratio | Standard Deviation 0.06 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 1018 | -0.1 ratio | Standard Deviation 0.1 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 1138 | -0.1 ratio | Standard Deviation 0 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Baseline | 1.0 ratio | Standard Deviation 0.08 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 15 | 0.0 ratio | Standard Deviation 0.03 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 29 | 0.0 ratio | Standard Deviation 0.04 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 64 | 0.0 ratio | Standard Deviation 0.05 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 183 | 0.0 ratio | Standard Deviation 0.05 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 302 | 0.0 ratio | Standard Deviation 0.06 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 422 | 0.0 ratio | Standard Deviation 0.06 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Head to Chest Circumference (HCC) Ratio | Change at Day 540 | 0.0 ratio | Standard Deviation 0.06 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Procedure in Part 1 | Change From Baseline in Weight | Change at Day 64 | 0.0 kg | Standard Deviation 0.39 |
| Sham Procedure in Part 1 | Change From Baseline in Weight | Change at Day 540 | 2.3 kg | Standard Deviation 1.33 |
| Sham Procedure in Part 1 | Change From Baseline in Weight | Change at Day 15 | -0.1 kg | Standard Deviation 0.23 |
| Sham Procedure in Part 1 | Change From Baseline in Weight | Change at Day 659 | 3.1 kg | Standard Deviation 1.39 |
| Sham Procedure in Part 1 | Change From Baseline in Weight | Change at Day 183 | 0.8 kg | Standard Deviation 0.61 |
| Sham Procedure in Part 1 | Change From Baseline in Weight | Change at Day 29 | -0.1 kg | Standard Deviation 0.26 |
| Sham Procedure in Part 1 | Change From Baseline in Weight | Change at Day 302 | 0.7 kg | Standard Deviation 1.04 |
| Sham Procedure in Part 1 | Change From Baseline in Weight | Baseline | 13.0 kg | Standard Deviation 2 |
| Sham Procedure in Part 1 | Change From Baseline in Weight | Change at Day 422 | 1.8 kg | Standard Deviation 1.03 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight | Change at Day 778 | 3.2 kg | Standard Deviation 1.87 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight | Change at Day 898 | 3.9 kg | Standard Deviation 2.86 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight | Change at Day 1018 | 4.3 kg | Standard Deviation 1.96 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight | Change at Day 15 | 0.2 kg | Standard Deviation 0.44 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight | Change at Day 1138 | 5.0 kg | Standard Deviation 0 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight | Baseline | 9.5 kg | Standard Deviation 1.37 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight | Change at Day 29 | 0.1 kg | Standard Deviation 0.23 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight | Change at Day 64 | 0.4 kg | Standard Deviation 0.42 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight | Change at Day 183 | 0.7 kg | Standard Deviation 0.48 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight | Change at Day 302 | 1.3 kg | Standard Deviation 0.87 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight | Change at Day 422 | 1.9 kg | Standard Deviation 1.02 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight | Change at Day 540 | 2.2 kg | Standard Deviation 1.17 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight | Change at Day 659 | 2.8 kg | Standard Deviation 1.41 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Procedure in Part 1 | Change From Baseline in Weight for Age | Change at Day 29 | -2.4 kilogram (kg) | Standard Deviation 1.61 |
| Sham Procedure in Part 1 | Change From Baseline in Weight for Age | Change at Day 540 | -7.0 kilogram (kg) | Standard Deviation 6.56 |
| Sham Procedure in Part 1 | Change From Baseline in Weight for Age | Change at Day 183 | -3.8 kilogram (kg) | Standard Deviation 6.93 |
| Sham Procedure in Part 1 | Change From Baseline in Weight for Age | Change at Day 659 | -8.5 kilogram (kg) | Standard Deviation 17.64 |
| Sham Procedure in Part 1 | Change From Baseline in Weight for Age | Change at Day 15 | -1.3 kilogram (kg) | Standard Deviation 1.41 |
| Sham Procedure in Part 1 | Change From Baseline in Weight for Age | Change at Day 302 | -10.1 kilogram (kg) | Standard Deviation 13.04 |
| Sham Procedure in Part 1 | Change From Baseline in Weight for Age | Change at Day 64 | -2.9 kilogram (kg) | Standard Deviation 2.58 |
| Sham Procedure in Part 1 | Change From Baseline in Weight for Age | Change at Day 422 | -6.3 kilogram (kg) | Standard Deviation 9.45 |
| Sham Procedure in Part 1 | Change From Baseline in Weight for Age | Baseline | 42.5 kilogram (kg) | Standard Deviation 40.87 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight for Age | Change at Day 659 | -10.5 kilogram (kg) | Standard Deviation 22.23 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight for Age | Change at Day 778 | -13.2 kilogram (kg) | Standard Deviation 16.95 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight for Age | Change at Day 898 | -10.5 kilogram (kg) | Standard Deviation 24.1 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight for Age | Change at Day 1018 | -7.0 kilogram (kg) | Standard Deviation 34.14 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight for Age | Change at Day 1138 | 0.3 kilogram (kg) | Standard Deviation 0 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight for Age | Baseline | 25.3 kilogram (kg) | Standard Deviation 28.41 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight for Age | Change at Day 15 | 3.6 kilogram (kg) | Standard Deviation 12.12 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight for Age | Change at Day 29 | -1.4 kilogram (kg) | Standard Deviation 4.82 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight for Age | Change at Day 64 | 0.5 kilogram (kg) | Standard Deviation 8.17 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight for Age | Change at Day 183 | -5.9 kilogram (kg) | Standard Deviation 8.73 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight for Age | Change at Day 302 | -8.0 kilogram (kg) | Standard Deviation 15.42 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight for Age | Change at Day 422 | -7.5 kilogram (kg) | Standard Deviation 17.52 |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Change From Baseline in Weight for Age | Change at Day 540 | -8.1 kilogram (kg) | Standard Deviation 17.26 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sham Procedure in Part 1 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 6 Participants |
| Sham Procedure in Part 1 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 3 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 6 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 4 Participants |
| ISIS 396443 Part 1 & 2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 14 Participants |
| ISIS 396443 Part 1 & 2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 9 Participants |
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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in Activated Partial Thromboplastin Time [aPTT] | Shift to Low | 0 Participants |
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in Activated Partial Thromboplastin Time [aPTT] | Shift to High | 0 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in Activated Partial Thromboplastin Time [aPTT] | Shift to Low | 0 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in Activated Partial Thromboplastin Time [aPTT] | Shift to High | 0 Participants |
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in Clinical Laboratory Parameters | 0 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in Clinical Laboratory Parameters | 0 Participants |
| ISIS 396443 Part 1 & 2 | Number of Participants With Change From Baseline in Clinical Laboratory Parameters | 0 Participants |
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in Electrocardiograms (ECGs) | 0 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in Electrocardiograms (ECGs) | 0 Participants |
| ISIS 396443 Part 1 & 2 | Number of Participants With Change From Baseline in Electrocardiograms (ECGs) | 0 Participants |
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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in International Normalized Ratio [INR]) | Shift to Low | 0 Participants |
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in International Normalized Ratio [INR]) | Shift to High | 0 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in International Normalized Ratio [INR]) | Shift to Low | 0 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in International Normalized Ratio [INR]) | Shift to High | 0 Participants |
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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Reflexes | 0 Participants |
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Sensory function | 0 Participants |
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Mood | 5 Participants |
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Speech/Language | 0 Participants |
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Mental Status | 0 Participants |
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Hearing | 0 Participants |
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Motor function | 0 Participants |
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Level of consciousness | 0 Participants |
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Cranial nerve function: Eye Movement | 0 Participants |
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Cranial nerve function: Vision | 0 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Reflexes | 0 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Motor function | 0 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Cranial nerve function: Vision | 0 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Mood | 5 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Sensory function | 0 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Mental Status | 1 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Speech/Language | 1 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Cranial nerve function: Eye Movement | 0 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Level of consciousness | 1 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Hearing | 0 Participants |
| ISIS 396443 Part 1 & 2 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Hearing | 0 Participants |
| ISIS 396443 Part 1 & 2 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Mental Status | 3 Participants |
| ISIS 396443 Part 1 & 2 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Level of consciousness | 2 Participants |
| ISIS 396443 Part 1 & 2 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Sensory function | 0 Participants |
| ISIS 396443 Part 1 & 2 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Motor function | 0 Participants |
| ISIS 396443 Part 1 & 2 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Cranial nerve function: Eye Movement | 1 Participants |
| ISIS 396443 Part 1 & 2 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Cranial nerve function: Vision | 1 Participants |
| ISIS 396443 Part 1 & 2 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Reflexes | 0 Participants |
| ISIS 396443 Part 1 & 2 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Mood | 12 Participants |
| ISIS 396443 Part 1 & 2 | Number of Participants With Change From Baseline in Neurological Examination Outcomes | Speech/Language | 1 Participants |
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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in Partial Thromboplastin Time [PTT] | Shift to Low | 0 Participants |
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in Partial Thromboplastin Time [PTT] | Shift to High | 0 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in Partial Thromboplastin Time [PTT] | Shift to Low | 0 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in Partial Thromboplastin Time [PTT] | Shift to High | 0 Participants |
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sham Procedure in Part 1 | Number of Participants With Change From Baseline in Vital Signs | 0 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Change From Baseline in Vital Signs | 0 Participants |
| ISIS 396443 Part 1 & 2 | Number of Participants With Change From Baseline in Vital Signs | 0 Participants |
Primary
Number of Participants With Presence of Urine Total Protein Post-baseline
Urine total protein was evaluated to assess safety.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sham Procedure in Part 1 | Number of Participants With Presence of Urine Total Protein Post-baseline | Baseline | 0 Participants |
| Sham Procedure in Part 1 | Number of Participants With Presence of Urine Total Protein Post-baseline | High/Postive | 2 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Presence of Urine Total Protein Post-baseline | Baseline | 1 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Presence of Urine Total Protein Post-baseline | High/Postive | 8 Participants |
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.
Time frame: Pre-dose on Days 15, 29, 64, 183, 302, 422 and 540
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Procedure in Part 1 | 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 | — |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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
CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 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;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.
Time frame: Pre-dose on Days 15, 29, 64, 183, 302, 422, 540, 659, 778, 898 and 1018
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Procedure in Part 1 | 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 | — |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 3.645 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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
Number of Participants With Plasma Antibodies to ISIS 396443
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sham Procedure in Part 1 | Number of Participants With Plasma Antibodies to ISIS 396443 | 0 Participants |
| ISIS 396443 Part 2(Participants on Sham in Part 1) | Number of Participants With Plasma Antibodies to ISIS 396443 | 0 Participants |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 0.102 |
| Sham Procedure in Part 1 | 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
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sham Procedure in Part 1 | 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 0.732 |
| Sham Procedure in Part 1 | 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 |
| Sham Procedure in Part 1 | 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 0.22 |
| Sham Procedure in Part 1 | 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 |