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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02462759




Registration number
NCT02462759
Ethics application status
Date submitted
14/05/2015
Date registered
4/06/2015
Date last updated
17/02/2021

Titles & IDs
Public title
A Study to Assess the Safety and Tolerability of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy (SMA).
Scientific 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
Secondary ID [1] 0 0
2014-003657-33
Secondary ID [2] 0 0
232SM202
Universal Trial Number (UTN)
Trial acronym
EMBRACE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Spinal Muscular Atrophy 0 0
Condition category
Condition code
Musculoskeletal 0 0 0 0
Other muscular and skeletal disorders
Neurological 0 0 0 0
Other neurological disorders
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above
Renal and Urogenital 0 0 0 0
Kidney disease
Metabolic and Endocrine 0 0 0 0
Other metabolic disorders
Cancer 0 0 0 0
Other cancer types

Intervention/exposure
Study type
Interventional(has expanded access)
Description of intervention(s) / exposure
Treatment: Drugs - Nusinersen
Treatment: Surgery - Sham Procedure

Experimental: Nusinersen - Administered by intrathecal injection.

Sham comparator: Sham Procedure - Small needle prick on the lower back at the location where the IT injection is normally made.


Treatment: Drugs: Nusinersen
Administered by intrathecal injection.

Treatment: Surgery: Sham Procedure
Small needle prick on the lower back at the location where the IT injection is normally made.
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Surgery
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Timepoint [1] 0 0
Part 1 and 2: From first dose/sham procedure to end of study (up to 1080 days)
Primary outcome [2] 0 0
Number of Participants With Change From Baseline in Clinical Laboratory Parameters
Timepoint [2] 0 0
Part 1 and 2: From first dose/sham procedure to end of study (up to 1080 days)
Primary outcome [3] 0 0
Number of Participants With Change From Baseline in Electrocardiograms (ECGs)
Timepoint [3] 0 0
Part 1: Day 2, 29 and 422; Part 2: Day 1 to 596
Primary outcome [4] 0 0
Number of Participants With Change From Baseline in Vital Signs
Timepoint [4] 0 0
Part 1: Day 2, 29 and 422; Part 2: Day 1 to 596
Primary outcome [5] 0 0
Change From Baseline in Head Circumference
Timepoint [5] 0 0
Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
Primary outcome [6] 0 0
Change From Baseline in Chest Circumference
Timepoint [6] 0 0
Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
Primary outcome [7] 0 0
Change From Baseline in Arm Circumference
Timepoint [7] 0 0
Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
Primary outcome [8] 0 0
Change From Baseline in Weight for Age
Timepoint [8] 0 0
Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
Primary outcome [9] 0 0
Change From Baseline in Weight
Timepoint [9] 0 0
Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
Primary outcome [10] 0 0
Change From Baseline in Head to Chest Circumference (HCC) Ratio
Timepoint [10] 0 0
Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
Primary outcome [11] 0 0
Change From Baseline in Body Length
Timepoint [11] 0 0
Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
Primary outcome [12] 0 0
Number of Participants With Change From Baseline in Neurological Examination Outcomes
Timepoint [12] 0 0
Part 1: Baseline to Day 422; Part 2: Baseline to Day 596
Primary outcome [13] 0 0
Number of Participants With Change From Baseline in Activated Partial Thromboplastin Time [aPTT]
Timepoint [13] 0 0
Part 2: Up to 1080 days
Primary outcome [14] 0 0
Number of Participants With Change From Baseline in Partial Thromboplastin Time [PTT]
Timepoint [14] 0 0
Part 2: Up to 1080 days
Primary outcome [15] 0 0
Number of Participants With Change From Baseline in International Normalized Ratio [INR])
Timepoint [15] 0 0
Part 2: Up to 1080 days
Primary outcome [16] 0 0
Number of Participants With Presence of Urine Total Protein Post-baseline
Timepoint [16] 0 0
Part 2: Up to 1080 days
Secondary outcome [1] 0 0
Rate of patients whose Pi reduction is 0.65 mmol/L (2.0 mg/dL)
Timepoint [1] 0 0
8 weeks
Secondary outcome [2] 0 0
Plasma Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study
Timepoint [2] 0 0
Pre-dose on Days 64, 183, 540 and 659
Secondary outcome [3] 0 0
Plasma Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study
Timepoint [3] 0 0
Pre-dose on Days 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
Secondary outcome [4] 0 0
Cerebrospinal Fluid (CSF) Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study
Timepoint [4] 0 0
Pre-dose on Days 15, 29, 64, 183, 302, 422 and 540
Secondary outcome [5] 0 0
CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study
Timepoint [5] 0 0
Pre-dose on Days 15, 29, 64, 183, 302, 422, 540, 659, 778, 898 and 1018
Secondary outcome [6] 0 0
Number of Participants With Plasma Antibodies to ISIS 396443
Timepoint [6] 0 0
Part 2: Baseline to Day 596
Secondary outcome [7] 0 0
Rate of patients whose Pi reaches the goal between 1.13 mmol/L (3.5 mg/dL) and 1.94 mmol/L (6.0 mg/dL)
Timepoint [7] 0 0
8 weeks
Secondary outcome [8] 0 0
Optimum biological dose (OBD)
Timepoint [8] 0 0
6 months
Secondary outcome [9] 0 0
Safety of the repeated dosing of NMP by oral administration - possible toxicities
Timepoint [9] 0 0
6 months
Secondary outcome [10] 0 0
Pharmacokinetic properties of NMP after oral administration
Timepoint [10] 0 0
Predose,0.5,1,2,4,8, 24 hours post dose
Secondary outcome [11] 0 0
Response rate measured using IMWG criteria
Timepoint [11] 0 0
6 months up to 2 years
Secondary outcome [12] 0 0
Time to progression from start of treatment
Timepoint [12] 0 0
up to 3.5 years

Eligibility
Key inclusion criteria
Key

* 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
Minimum age
No limit
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
19/08/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
24/09/2018
Sample size
Target
Accrual to date
Final
21
Recruitment in Australia
Recruitment state(s)
WA,VIC
Recruitment hospital [1] 0 0
LCR Clinical Research - Perth
Recruitment hospital [2] 0 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment postcode(s) [1] 0 0
- Perth
Recruitment postcode(s) [2] 0 0
3002 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Connecticut
Country [3] 0 0
United States of America
State/province [3] 0 0
Maryland
Country [4] 0 0
United States of America
State/province [4] 0 0
Minnesota
Country [5] 0 0
United States of America
State/province [5] 0 0
Texas
Country [6] 0 0
United States of America
State/province [6] 0 0
Washington
Country [7] 0 0
Germany
State/province [7] 0 0
Muenchen

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Biogen
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Melbourne Health
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT02462759
Trial related presentations / publications
Acsadi G, Crawford TO, Muller-Felber W, Shieh PB, Richardson R, Natarajan N, Castro D, Ramirez-Schrempp D, Gambino G, Sun P, Farwell W. Safety and efficacy of nusinersen in spinal muscular atrophy: The EMBRACE study. Muscle Nerve. 2021 May;63(5):668-677. doi: 10.1002/mus.27187. Epub 2021 Feb 16.
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Biogen
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT02462759