EMBRACE: A Study to Assess the Safety and Tolerability of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy (SMA).
Sponsor
Biogen (Industry)
Overall Status
Terminated
CT.gov ID
NCT02462759
Collaborator
(none)
21
7
2
37.2
3
0.1
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
Part 2 is an Open Label extension phase.
Study Design
Study Type:
Interventional
Actual Enrollment
:
21 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase 2, Randomized, Double-blind, Sham-procedure Controlled Study to Assess the Safety and Tolerability and Explore the Efficacy of ISIS 396443 (BIIB058) Administered Intrathecally in Subjects With Spinal Muscular Atrophy Who Are Not Eligible to Participate in the Clinical Studies ISIS 396443-CS3B or ISIS 396443-CS4
Actual Study Start Date
:
Aug 19, 2015
Actual Primary Completion Date
:
Sep 24, 2018
Actual Study Completion Date
:
Sep 24, 2018
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Nusinersen Administered by intrathecal injection. |
Drug: Nusinersen
Administered by intrathecal injection.
Other Names:
|
| Sham Comparator: Sham Procedure Small needle prick on the lower back at the location where the IT injection is normally made. |
Procedure: Sham Procedure
Small needle prick on the lower back at the location where the IT injection is normally made.
|
Outcome Measures
Primary Outcome Measures
- 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.
- 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 Presence of Urine Total Protein Post-baseline [Part 2: Up to 1080 days]
Urine total protein was evaluated to assess safety.
Secondary Outcome Measures
- 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.
- 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]
Eligibility Criteria
Criteria
Ages Eligible for Study:
N/A
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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/Exclusion criteria may apply.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | David Geffen School of Medicine at UCLA | Los Angeles | California | United States | 90095-8344 |
| 2 | Connecticut Childrens Medical | Hartford | Connecticut | United States | 06106 |
| 3 | The Johns Hopkins Hospital | Baltimore | Maryland | United States | 21287 |
| 4 | Gillette Children's Specialty Healthcare | Saint Paul | Minnesota | United States | 55101 |
| 5 | The University of Texas Southwestern Medical Center | Dallas | Texas | United States | 75235 |
| 6 | Seattle Children's Research Institute | Seattle | Washington | United States | 98105 |
| 7 | LMU-Campus Innenstadt | Muenchen | Germany | 80337 |
Sponsors and Collaborators
- Biogen
Investigators
- Study Director: Medical Director, Biogen
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.Responsible Party:
Biogen
ClinicalTrials.gov Identifier:
NCT02462759
Other Study ID Numbers:
- 232SM202
- 2014-003657-33
First Posted:
Jun 4, 2015
Last Update Posted:
Feb 17, 2021
Last Verified:
Feb 1, 2021
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Biogen
Additional relevant MeSH terms:
Study Results
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 Detail | 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. |
| Arm/Group Title | Sham Procedure (Part 1) | ISIS 396443 (Part 1) | ISIS 396443 (Part 2) |
|---|---|---|---|
| Arm/Group Description | Sham procedure on Day 1, 15, 29, 64, 183 and 302. | 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. | 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. |
| Period Title: Part 1: Double Blind | |||
| STARTED | 7 | 14 | 0 |
| COMPLETED | 6 | 14 | 0 |
| NOT COMPLETED | 1 | 0 | 0 |
| Period Title: Part 1: Double Blind | |||
| STARTED | 0 | 0 | 20 |
| COMPLETED | 0 | 0 | 20 |
| NOT COMPLETED | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Sham Procedure (Part 1) | ISIS 396443 (Part 1) | Total |
|---|---|---|---|
| Arm/Group Description | Sham procedure on Day 1, 15, 29, 64, 183 and 302. | 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 of all reporting groups |
| Overall Participants | 7 | 14 | 21 |
| Age (months) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [months] |
24.4
(13.83)
|
19.4
(10.12)
|
21.1
(11.39)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
5
71.4%
|
5
35.7%
|
10
47.6%
|
| Male |
2
28.6%
|
9
64.3%
|
11
52.4%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| Ethnicity: Hispanic or Latino |
2
28.6%
|
1
7.1%
|
3
14.3%
|
| Ethnicity: Not Hispanic or Latino |
4
57.1%
|
9
64.3%
|
13
61.9%
|
| Ethnicity: Not reported due to confidentiality |
1
14.3%
|
4
28.6%
|
5
23.8%
|
| Race: Asian |
3
42.9%
|
2
14.3%
|
5
23.8%
|
| Race: White |
2
28.6%
|
7
50%
|
9
42.9%
|
| Race: Other |
1
14.3%
|
1
7.1%
|
2
9.5%
|
| Race: Not reported due to confidentiality |
1
14.3%
|
4
28.6%
|
5
23.8%
|
Outcome Measures
| Title | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The safety population included all participants who were randomized and received at least 1 dose of study treatment or sham procedure. |
| Arm/Group Title | Sham Procedure in Part 1 | ISIS 396443 Part 2(Participants on Sham in Part 1) | ISIS 396443 Part 1 & 2 |
|---|---|---|---|
| Arm/Group Description | Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study. | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 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. |
| Measure Participants | 7 | 6 | 14 |
| AEs |
6
85.7%
|
6
42.9%
|
14
66.7%
|
| SAEs |
3
42.9%
|
4
28.6%
|
9
42.9%
|
| Title | Number of Participants With Change From Baseline in Clinical Laboratory Parameters |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| The safety population included all participants who were randomized and received at least 1 dose of study treatment or sham procedure. |
| Arm/Group Title | Sham Procedure in Part 1 | ISIS 396443 Part 2(Participants on Sham in Part 1) | ISIS 396443 Part 1 & 2 |
|---|---|---|---|
| Arm/Group Description | Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study. | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 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. |
| Measure Participants | 7 | 6 | 14 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
0
0%
|
| Title | Number of Participants With Change From Baseline in Electrocardiograms (ECGs) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The safety population included all participants who were randomized and received at least 1 dose of study treatment or sham procedure. |
| Arm/Group Title | Sham Procedure in Part 1 | ISIS 396443 Part 2(Participants on Sham in Part 1) | ISIS 396443 Part 1 & 2 |
|---|---|---|---|
| Arm/Group Description | Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study. | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 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. |
| Measure Participants | 7 | 6 | 14 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
0
0%
|
| Title | Number of Participants With Change From Baseline in Vital Signs |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The safety population included all participants who were randomized and received at least 1 dose of study treatment or sham procedure. |
| Arm/Group Title | Sham Procedure in Part 1 | ISIS 396443 Part 2(Participants on Sham in Part 1) | ISIS 396443 Part 1 & 2 |
|---|---|---|---|
| Arm/Group Description | Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study. | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 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. |
| Measure Participants | 7 | 6 | 14 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
0
0%
|
| Title | Change From Baseline in Head Circumference |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ISIS 396443 Part 2(Participants on Sham in Part 1) | ISIS 396443 Part 1 & 2 |
|---|---|---|
| Arm/Group Description | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 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. |
| Measure Participants | 6 | 14 |
| Baseline |
50.8
(3.83)
|
47.3
(1.51)
|
| Change at Day 15 |
-0.7
(3.34)
|
0.1
(0.36)
|
| Change at Day 29 |
0.0
(2.76)
|
0.3
(0.65)
|
| Change at Day 64 |
0.1
(2.64)
|
0.5
(0.73)
|
| Change at Day 183 |
0.3
(3.10)
|
1.0
(1.12)
|
| Change at Day 302 |
1.0
(3.28)
|
1.6
(1.05)
|
| Change at Day 422 |
0.9
(2.47)
|
2.0
(1.24)
|
| Change at Day 540 |
1.3
(1.97)
|
2.5
(1.24)
|
| Change at Day 659 |
1.5
(2.53)
|
2.6
(1.37)
|
| Change at Day 778 |
2.8
(0.92)
|
|
| Change at Day 898 |
3.5
(1.05)
|
|
| Change at Day 1018 |
3.5
(2.06)
|
|
| Change at Day 1138 |
4.0
(0)
|
| Title | Change From Baseline in Chest Circumference |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ISIS 396443 Part 2(Participants on Sham in Part 1) | ISIS 396443 Part 1 & 2 |
|---|---|---|
| Arm/Group Description | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 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. |
| Measure Participants | 6 | 14 |
| Baseline |
51.3
(5.45)
|
46.9
(3.91)
|
| Change at Day 15 |
-0.2
(3.86)
|
-0.4
(1.53)
|
| Change at Day 29 |
-1.1
(2.70)
|
0.2
(1.39)
|
| Change at Day 64 |
-0.9
(3.50)
|
0.2
(1.92)
|
| Change at Day 183 |
0.2
(3.04)
|
1.4
(2.02)
|
| Change at Day 302 |
1.2
(3.07)
|
1.6
(2.86)
|
| Change at Day 422 |
0.5
(3.72)
|
2.8
(2.73)
|
| Change at Day 540 |
1.8
(2.42)
|
3.8
(3.23)
|
| Change at Day 659 |
2.9
(3.85)
|
5.1
(3.29)
|
| Change at Day 778 |
5.5
(3.52)
|
|
| Change at Day 898 |
7.1
(3.04)
|
|
| Change at Day 1018 |
9.7
(4.92)
|
|
| Change at Day 1138 |
9.1
(0)
|
| Title | Change From Baseline in Arm Circumference |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ISIS 396443 Part 2(Participants on Sham in Part 1) | ISIS 396443 Part 1 & 2 |
|---|---|---|
| Arm/Group Description | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 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. |
| Measure Participants | 6 | 14 |
| Baseline |
16.2
(1.19)
|
14.5
(1.85)
|
| Change at Day 15 |
-0.4
(1.04)
|
0.3
(0.61)
|
| Change at Day 29 |
-0.5
(1.08)
|
-0.1
(0.54)
|
| Change at Day 64 |
-0.3
(0.49)
|
-0.4
(0.89)
|
| Change at Day 183 |
0.0
(0.89)
|
0.0
(0.85)
|
| Change at Day 302 |
-0.6
(0.89)
|
0.2
(1.17)
|
| Change at Day 422 |
-0.6
(1.82)
|
0.5
(1.71)
|
| Change at Day 540 |
-0.2
(2.24)
|
0.5
(1.89)
|
| Change at Day 659 |
0.6
(0.93)
|
0.6
(1.93)
|
| Change at Day 778 |
0.0
(2.18)
|
|
| Change at Day 898 |
0.8
(2.70)
|
|
| Change at Day 1018 |
1.0
(2.02)
|
|
| Change at Day 1138 |
1.5
(0)
|
| Title | Change From Baseline in Weight for Age |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ISIS 396443 Part 2(Participants on Sham in Part 1) | ISIS 396443 Part 1 & 2 |
|---|---|---|
| Arm/Group Description | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 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. |
| Measure Participants | 6 | 14 |
| Baseline |
42.5
(40.87)
|
25.3
(28.41)
|
| Change at Day 15 |
-1.3
(1.41)
|
3.6
(12.12)
|
| Change at Day 29 |
-2.4
(1.61)
|
-1.4
(4.82)
|
| Change at Day 64 |
-2.9
(2.58)
|
0.5
(8.17)
|
| Change at Day 183 |
-3.8
(6.93)
|
-5.9
(8.73)
|
| Change at Day 302 |
-10.1
(13.04)
|
-8.0
(15.42)
|
| Change at Day 422 |
-6.3
(9.45)
|
-7.5
(17.52)
|
| Change at Day 540 |
-7.0
(6.56)
|
-8.1
(17.26)
|
| Change at Day 659 |
-8.5
(17.64)
|
-10.5
(22.23)
|
| Change at Day 778 |
-13.2
(16.95)
|
|
| Change at Day 898 |
-10.5
(24.10)
|
|
| Change at Day 1018 |
-7.0
(34.14)
|
|
| Change at Day 1138 |
0.3
(0)
|
| Title | Change From Baseline in Weight |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ISIS 396443 Part 2(Participants on Sham in Part 1) | ISIS 396443 Part 1 & 2 |
|---|---|---|
| Arm/Group Description | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 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. |
| Measure Participants | 6 | 14 |
| Baseline |
13.0
(2.00)
|
9.5
(1.37)
|
| Change at Day 15 |
-0.1
(0.23)
|
0.2
(0.44)
|
| Change at Day 29 |
-0.1
(0.26)
|
0.1
(0.23)
|
| Change at Day 64 |
0.0
(0.39)
|
0.4
(0.42)
|
| Change at Day 183 |
0.8
(0.61)
|
0.7
(0.48)
|
| Change at Day 302 |
0.7
(1.04)
|
1.3
(0.87)
|
| Change at Day 422 |
1.8
(1.03)
|
1.9
(1.02)
|
| Change at Day 540 |
2.3
(1.33)
|
2.2
(1.17)
|
| Change at Day 659 |
3.1
(1.39)
|
2.8
(1.41)
|
| Change at Day 778 |
3.2
(1.87)
|
|
| Change at Day 898 |
3.9
(2.86)
|
|
| Change at Day 1018 |
4.3
(1.96)
|
|
| Change at Day 1138 |
5.0
(0)
|
| Title | Change From Baseline in Head to Chest Circumference (HCC) Ratio |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ISIS 396443 Part 2(Participants on Sham in Part 1) | ISIS 396443 Part 1 & 2 |
|---|---|---|
| Arm/Group Description | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 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. |
| Measure Participants | 6 | 14 |
| Baseline |
1.0
(0.05)
|
1.0
(0.08)
|
| Change at Day 15 |
0.0
(0.03)
|
0.0
(0.03)
|
| Change at Day 29 |
0.0
(0.04)
|
0.0
(0.04)
|
| Change at Day 64 |
0.0
(0.04)
|
0.0
(0.05)
|
| Change at Day 183 |
0.0
(0.05)
|
0.0
(0.05)
|
| Change at Day 302 |
0.0
(0.03)
|
0.0
(0.06)
|
| Change at Day 422 |
0.0
(0.04)
|
0.0
(0.06)
|
| Change at Day 540 |
0.0
(0.03)
|
0.0
(0.06)
|
| Change at Day 659 |
0.0
(0.03)
|
-0.1
(0.06)
|
| Change at Day 778 |
-0.1
(0.07)
|
|
| Change at Day 898 |
-0.1
(0.06)
|
|
| Change at Day 1018 |
-0.1
(0.10)
|
|
| Change at Day 1138 |
-0.1
(0)
|
| Title | Change From Baseline in Body Length |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ISIS 396443 Part 2(Participants on Sham in Part 1) | ISIS 396443 Part 1 & 2 |
|---|---|---|
| Arm/Group Description | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 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. |
| Measure Participants | 6 | 14 |
| Baseline |
95.0
(9.48)
|
79.9
(5.25)
|
| Change at Day 15 |
-1.6
(3.19)
|
-0.1
(1.81)
|
| Change at Day 29 |
-0.9
(3.49)
|
0.9
(1.66)
|
| Change at Day 64 |
0.5
(4.77)
|
1.8
(2.40)
|
| Change at Day 183 |
3.0
(4.16)
|
5.6
(2.36)
|
| Change at Day 302 |
2.9
(5.76)
|
7.1
(2.70)
|
| Change at Day 422 |
4.2
(5.42)
|
9.3
(3.09)
|
| Change at Day 540 |
4.6
(7.18)
|
11.6
(3.93)
|
| Change at Day 659 |
10.8
(4.12)
|
13.1
(3.79)
|
| Change at Day 778 |
14.8
(3.94)
|
|
| Change at Day 898 |
17.2
(5.62)
|
|
| Change at Day 1018 |
19.0
(6.67)
|
|
| Change at Day 1138 |
15.8
(0)
|
| Title | Number of Participants With Change From Baseline in Neurological Examination Outcomes |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The safety population included all participants who were randomized and received at least 1 dose of study treatment or sham procedure. |
| Arm/Group Title | Sham Procedure in Part 1 | ISIS 396443 Part 2(Participants on Sham in Part 1) | ISIS 396443 Part 1 & 2 |
|---|---|---|---|
| Arm/Group Description | Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study. | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 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. |
| Measure Participants | 7 | 6 | 14 |
| Mental Status |
0
0%
|
1
7.1%
|
3
14.3%
|
| Level of consciousness |
0
0%
|
1
7.1%
|
2
9.5%
|
| Sensory function |
0
0%
|
0
0%
|
0
0%
|
| Motor function |
0
0%
|
0
0%
|
0
0%
|
| Cranial nerve function: Eye Movement |
0
0%
|
0
0%
|
1
4.8%
|
| Cranial nerve function: Vision |
0
0%
|
0
0%
|
1
4.8%
|
| Reflexes |
0
0%
|
0
0%
|
0
0%
|
| Mood |
5
71.4%
|
5
35.7%
|
12
57.1%
|
| Speech/Language |
0
0%
|
1
7.1%
|
1
4.8%
|
| Hearing |
0
0%
|
0
0%
|
0
0%
|
| Title | Number of Participants With Change From Baseline in Activated Partial Thromboplastin Time [aPTT] |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ISIS 396443 Part 2(Participants on Sham in Part 1) | ISIS 396443 Part 1 & 2 |
|---|---|---|
| Arm/Group Description | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 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. |
| Measure Participants | 6 | 14 |
| Shift to Low |
0
0%
|
0
0%
|
| Shift to High |
0
0%
|
0
0%
|
| Title | Number of Participants With Change From Baseline in Partial Thromboplastin Time [PTT] |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ISIS 396443 Part 2(Participants on Sham in Part 1) | ISIS 396443 Part 1 & 2 |
|---|---|---|
| Arm/Group Description | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 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. |
| Measure Participants | 6 | 14 |
| Shift to Low |
0
0%
|
0
0%
|
| Shift to High |
0
0%
|
0
0%
|
| Title | Number of Participants With Change From Baseline in International Normalized Ratio [INR]) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ISIS 396443 Part 2(Participants on Sham in Part 1) | ISIS 396443 Part 1 & 2 |
|---|---|---|
| Arm/Group Description | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 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. |
| Measure Participants | 6 | 14 |
| Shift to Low |
0
0%
|
0
0%
|
| Shift to High |
0
0%
|
0
0%
|
| Title | Number of Participants With Presence of Urine Total Protein Post-baseline |
|---|---|
| Description | Urine total protein was evaluated to assess safety. |
| Time Frame | Part 2: Up to 1080 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| The safety population included all participants who were randomized and received at least 1 dose of study treatment or sham procedure. |
| Arm/Group Title | ISIS 396443 Part 2(Participants on Sham in Part 1) | ISIS 396443 Part 1 & 2 |
|---|---|---|
| Arm/Group Description | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 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. |
| Measure Participants | 6 | 14 |
| Baseline |
0
0%
|
1
7.1%
|
| High/Postive |
2
28.6%
|
8
57.1%
|
| Title | Plasma Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ISIS 396443 Part 2(Participants on Sham in Part 1) |
|---|---|
| Arm/Group Description | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2. |
| Measure Participants | 6 |
| Day 64 |
1.983
(0.7320)
|
| Day 183 |
0.776
(0.3994)
|
| Day 540 |
0.425
(0.2200)
|
| Day 659 |
0.365
(0.1146)
|
| Title | Plasma Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ISIS 396443 Part 1 & 2 |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 14 |
| Day 64 |
2.139
(0.8811)
|
| Day 183 |
1.059
(0.5569)
|
| Day 302 |
0.667
(0.1852)
|
| Day 422 |
0.858
(0.4636)
|
| Day 540 |
0.608
(0.2736)
|
| Day 659 |
0.739
(0.2812)
|
| Day 778 |
0.590
(0.3414)
|
| Day 898 |
0.661
(0.2558)
|
| Day 1018 |
0.329
(0.1020)
|
| Day 1138 |
0.423
(0)
|
| Title | Cerebrospinal Fluid (CSF) Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ISIS 396443 Part 2(Participants on Sham in Part 1) |
|---|---|
| Arm/Group Description | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2. |
| Measure Participants | 6 |
| Day 1 |
NA
(NA)
|
| Day 15 |
3.094
(1.2172)
|
| Day 29 |
4.805
(2.6706)
|
| Day 64 |
4.357
(2.3229)
|
| Day 183 |
4.110
(2.4535)
|
| Day 302 |
5.397
(2.7503)
|
| Day 422 |
6.460
(2.9428)
|
| Day 540 |
8.405
(6.2423)
|
| Title | CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | ISIS 396443 Part 1 & 2 |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 14 |
| Day 1 |
NA
(NA)
|
| Day 15 |
3.925
(2.0525)
|
| Day 29 |
7.273
(4.4786)
|
| Day 64 |
7.176
(2.8487)
|
| Day 183 |
8.226
(3.6450)
|
| Day 302 |
8.968
(3.1188)
|
| Day 422 |
9.251
(4.0631)
|
| Day 540 |
9.026
(2.6864)
|
| Day 659 |
9.785
(3.3725)
|
| Day 778 |
8.632
(2.4131)
|
| Day 898 |
11.321
(8.9351)
|
| Day 1018 |
7.010
(0)
|
| Title | Number of Participants With Plasma Antibodies to ISIS 396443 |
|---|---|
| Description | |
| Time Frame | Part 2: Baseline to Day 596 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The safety population included all participants who were randomized and received at least 1 dose of study treatment or sham procedure. |
| Arm/Group Title | ISIS 396443 Part 2(Participants on Sham in Part 1) | ISIS 396443 Part 1 & 2 |
|---|---|---|
| Arm/Group Description | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 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. |
| Measure Participants | 6 | 14 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
Adverse Events
| Time Frame | From start to end of study (up to 1133 days) | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | The safety population included all participants who were randomized and received at least 1 dose of study treatment or sham procedure. | |||||
| Arm/Group Title | Sham Procedure in Part 1 | ISIS 396443 Part 1 & 2 | ISIS 396443 Part 2(Participants on Sham in Part 1) | |||
| Arm/Group Description | Participants who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study. | 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. | Participants who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2. | |||
All Cause Mortality |
||||||
| Sham Procedure in Part 1 | ISIS 396443 Part 1 & 2 | ISIS 396443 Part 2(Participants on Sham in Part 1) | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | |||
Serious Adverse Events |
||||||
| Sham Procedure in Part 1 | ISIS 396443 Part 1 & 2 | ISIS 396443 Part 2(Participants on Sham in Part 1) | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/7 (42.9%) | 9/14 (64.3%) | 4/6 (66.7%) | |||
| Cardiac disorders | ||||||
| Cardio-respiratory arrest | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | |||
| Sinus bradycardia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Gastrointestinal disorders | ||||||
| Dental caries | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Dysphagia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Vomiting | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| General disorders | ||||||
| Brain death | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | |||
| Infections and infestations | ||||||
| Bronchiolitis | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | |||
| Bronchitis moraxella | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Enterovirus infection | 1/7 (14.3%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Gastroenteritis | 0/7 (0%) | 1/14 (7.1%) | 1/6 (16.7%) | |||
| Gastroenteritis norovirus | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Gastroenteritis viral | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Lower respiratory tract infection | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Parainfluenzae virus infection | 0/7 (0%) | 1/14 (7.1%) | 1/6 (16.7%) | |||
| Pneumonia | 0/7 (0%) | 7/14 (50%) | 3/6 (50%) | |||
| Pneumonia haemophilus | 1/7 (14.3%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Pneumonia moraxella | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Pneumonia pneumococcal | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Pneumonia respiratory syncytial viral | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Respiratory syncytial virus bronchiolitis | 0/7 (0%) | 2/14 (14.3%) | 1/6 (16.7%) | |||
| Respiratory syncytial virus infection | 0/7 (0%) | 1/14 (7.1%) | 1/6 (16.7%) | |||
| Respiratory tract infection | 1/7 (14.3%) | 1/14 (7.1%) | 1/6 (16.7%) | |||
| Rhinovirus infection | 1/7 (14.3%) | 2/14 (14.3%) | 2/6 (33.3%) | |||
| Staphylococcal infection | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Nasopharyngitis | 0/7 (0%) | 1/14 (7.1%) | 1/6 (16.7%) | |||
| Injury, poisoning and procedural complications | ||||||
| Femur fracture | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Metabolism and nutrition disorders | ||||||
| Failure to thrive | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Metabolic acidosis | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Nervous system disorders | ||||||
| Hypoxic-ischaemic encephalopathy | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | |||
| Loss of consciousness | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Acute respiratory failure | 1/7 (14.3%) | 1/14 (7.1%) | 1/6 (16.7%) | |||
| Bronchial secretion retention | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Cough | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Hypoventilation | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Hypoxia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Pneumonia aspiration | 0/7 (0%) | 3/14 (21.4%) | 1/6 (16.7%) | |||
| Respiratory distress | 1/7 (14.3%) | 2/14 (14.3%) | 2/6 (33.3%) | |||
| Respiratory failure | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Sham Procedure in Part 1 | ISIS 396443 Part 1 & 2 | ISIS 396443 Part 2(Participants on Sham in Part 1) | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/7 (85.7%) | 14/14 (100%) | 6/6 (100%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Leukocytosis | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Thrombocytosis | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Cardiac disorders | ||||||
| Bradycardia | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Sinus tachycardia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Tachycardia | 2/7 (28.6%) | 3/14 (21.4%) | 0/6 (0%) | |||
| Congenital, familial and genetic disorders | ||||||
| Congenital nystagmus | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Plagiocephaly | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Ear and labyrinth disorders | ||||||
| Ear pain | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Eye disorders | ||||||
| Myopia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Ocular hyperaemia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Gastrointestinal disorders | ||||||
| Abdominal discomfort | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Abdominal pain upper | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Aphthous ulcer | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | |||
| Constipation | 1/7 (14.3%) | 4/14 (28.6%) | 0/6 (0%) | |||
| Dental caries | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Diarrhoea | 0/7 (0%) | 5/14 (35.7%) | 1/6 (16.7%) | |||
| Dyspepsia | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Dysphagia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Flatulence | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Gastrointestinal haemorrhage | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Gastrooesophageal reflux disease | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Gingival pain | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Lip swelling | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Oral contusion | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Salivary hypersecretion | 0/7 (0%) | 1/14 (7.1%) | 1/6 (16.7%) | |||
| Teething | 2/7 (28.6%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Vomiting | 1/7 (14.3%) | 7/14 (50%) | 2/6 (33.3%) | |||
| General disorders | ||||||
| Asthenia | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Complication associated with device | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Fatigue | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Influenza like illness | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Oedema peripheral | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Pyrexia | 1/7 (14.3%) | 12/14 (85.7%) | 4/6 (66.7%) | |||
| Swelling | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Immune system disorders | ||||||
| Drug hypersensitivity | 1/7 (14.3%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Seasonal allergy | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Infections and infestations | ||||||
| Bronchiolitis | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Bronchitis | 1/7 (14.3%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Cellulitis | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Conjunctivitis | 0/7 (0%) | 4/14 (28.6%) | 0/6 (0%) | |||
| Conjunctivitis bacterial | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Ear infection | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Gastroenteritis | 0/7 (0%) | 5/14 (35.7%) | 0/6 (0%) | |||
| Gastroenteritis adenovirus | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Gastroenteritis norovirus | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Gastroenteritis viral | 0/7 (0%) | 2/14 (14.3%) | 1/6 (16.7%) | |||
| Hand-foot-and-mouth disease | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Influenza | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Lower respiratory tract infection | 0/7 (0%) | 5/14 (35.7%) | 1/6 (16.7%) | |||
| Otitis externa | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Otitis media | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Otitis media acute | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Parainfluenzae virus infection | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Pharyngitis streptococcal | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Pneumonia | 0/7 (0%) | 7/14 (50%) | 2/6 (33.3%) | |||
| Pneumonia haemophilus | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Pneumonia moraxella | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Respiratory syncytial virus infection | 0/7 (0%) | 3/14 (21.4%) | 1/6 (16.7%) | |||
| Respiratory tract infection | 1/7 (14.3%) | 5/14 (35.7%) | 1/6 (16.7%) | |||
| Rhinovirus infection | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Sinusitis | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Stoma site infection | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Upper respiratory tract infection | 2/7 (28.6%) | 9/14 (64.3%) | 3/6 (50%) | |||
| Urinary tract infection | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Vaginal infection | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Viral rash | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Viral upper respiratory tract infection | 1/7 (14.3%) | 5/14 (35.7%) | 1/6 (16.7%) | |||
| Injury, poisoning and procedural complications | ||||||
| Ankle fracture | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Arthropod bite | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Contusion | 1/7 (14.3%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Fall | 0/7 (0%) | 1/14 (7.1%) | 2/6 (33.3%) | |||
| Femur fracture | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Incision site erythema | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Incision site pain | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Joint dislocation | 0/7 (0%) | 3/14 (21.4%) | 0/6 (0%) | |||
| Laceration | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Muscle strain | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | |||
| Procedural pain | 0/7 (0%) | 3/14 (21.4%) | 0/6 (0%) | |||
| Procedural vomiting | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | |||
| Skin abrasion | 0/7 (0%) | 1/14 (7.1%) | 1/6 (16.7%) | |||
| Stoma site haemorrhage | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Stoma site hypergranulation | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Thermal burn | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Traumatic haematoma | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Upper limb fracture | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Vaccination complication | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Investigations | ||||||
| Aspiration bronchial | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Blood urea increased | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Bone density decreased | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Carnitine decreased | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Enterobacter test positive | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Full blood count increased | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Heart rate increased | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Oxygen saturation decreased | 0/7 (0%) | 2/14 (14.3%) | 1/6 (16.7%) | |||
| Pco2 increased | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Urine output decreased | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Urine output increased | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | |||
| Weight decreased | 0/7 (0%) | 2/14 (14.3%) | 1/6 (16.7%) | |||
| Weight increased | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| White blood cell count increased | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Metabolism and nutrition disorders | ||||||
| Decreased appetite | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Dehydration | 0/7 (0%) | 3/14 (21.4%) | 0/6 (0%) | |||
| Failure to thrive | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Feeding disorder | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Hyperchloraemia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Hyperglycaemia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Hypernatraemia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Hypochloraemia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Hypoglycaemia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Hypokalaemia | 1/7 (14.3%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Hyponatraemia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Hypophagia | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Metabolic acidosis | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Weight gain poor | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Back pain | 0/7 (0%) | 2/14 (14.3%) | 1/6 (16.7%) | |||
| Hip deformity | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Joint contracture | 0/7 (0%) | 1/14 (7.1%) | 1/6 (16.7%) | |||
| Joint hyperextension | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Muscle spasms | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Muscle tightness | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Musculoskeletal pain | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Musculoskeletal stiffness | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Myalgia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Osteopenia | 0/7 (0%) | 1/14 (7.1%) | 1/6 (16.7%) | |||
| Pain in extremity | 0/7 (0%) | 6/14 (42.9%) | 2/6 (33.3%) | |||
| Scoliosis | 0/7 (0%) | 4/14 (28.6%) | 0/6 (0%) | |||
| Spinal pain | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Tendinous contracture | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Torticollis | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Nervous system disorders | ||||||
| Cranial nerve disorder | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Dysarthria | 0/7 (0%) | 1/14 (7.1%) | 1/6 (16.7%) | |||
| Headache | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Product Issues | ||||||
| Device extrusion | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Psychiatric disorders | ||||||
| Dysphemia | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Intermittent explosive disorder | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | |||
| Irritability | 1/7 (14.3%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Renal and urinary disorders | ||||||
| Acute kidney injury | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Urinary retention | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Reproductive system and breast disorders | ||||||
| Penile adhesion | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Aspiration | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | |||
| Atelectasis | 0/7 (0%) | 2/14 (14.3%) | 1/6 (16.7%) | |||
| Bronchial secretion retention | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Chronic respiratory failure | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Cough | 1/7 (14.3%) | 11/14 (78.6%) | 3/6 (50%) | |||
| Dysphonia | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Dyspnoea | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Epistaxis | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Hypoventilation | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Hypoxia | 2/7 (28.6%) | 3/14 (21.4%) | 0/6 (0%) | |||
| Increased bronchial secretion | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | |||
| Larynx irritation | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | |||
| Lower respiratory tract congestion | 0/7 (0%) | 1/14 (7.1%) | 2/6 (33.3%) | |||
| Nasal congestion | 0/7 (0%) | 6/14 (42.9%) | 2/6 (33.3%) | |||
| Oropharyngeal pain | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Pneumonia aspiration | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Productive cough | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Pulmonary congestion | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Restrictive pulmonary disease | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Rhinitis allergic | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Rhinorrhoea | 0/7 (0%) | 6/14 (42.9%) | 1/6 (16.7%) | |||
| Sinus congestion | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
| Sleep apnoea syndrome | 1/7 (14.3%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Tachypnoea | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Tonsillar hypertrophy | 0/7 (0%) | 1/14 (7.1%) | 1/6 (16.7%) | |||
| Upper respiratory tract congestion | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Upper-airway cough syndrome | 0/7 (0%) | 1/14 (7.1%) | 1/6 (16.7%) | |||
| Use of accessory respiratory muscles | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Decubitus ulcer | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Dermatitis contact | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Dermatitis diaper | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Dry skin | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Erythema | 2/7 (28.6%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Miliaria | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Petechiae | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Rash | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Rash erythematous | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Rash generalised | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Rash macular | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Rash papular | 0/7 (0%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Skin irritation | 1/7 (14.3%) | 1/14 (7.1%) | 0/6 (0%) | |||
| Urticaria | 0/7 (0%) | 2/14 (14.3%) | 0/6 (0%) | |||
| Vascular disorders | ||||||
| Flushing | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | |||
| Haematoma | 0/7 (0%) | 1/14 (7.1%) | 1/6 (16.7%) | |||
| Hypertension | 1/7 (14.3%) | 0/14 (0%) | 0/6 (0%) | |||
| Hypotension | 0/7 (0%) | 0/14 (0%) | 1/6 (16.7%) | |||
Limitations/Caveats
Despite the early termination of both Parts of the study, the data from this study is of quality and reliable.
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
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.
Results Point of Contact
| Name/Title | Biogen Study Medical Director |
|---|---|
| Organization | Biogen |
| Phone | 866-633-4636 |
| clinicaltrials@biogen.com |
Responsible Party:
Biogen
ClinicalTrials.gov Identifier:
NCT02462759
Other Study ID Numbers:
- 232SM202
- 2014-003657-33
First Posted:
Jun 4, 2015
Last Update Posted:
Feb 17, 2021
Last Verified:
Feb 1, 2021