Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy

• Register: EUCTR
• Last refreshed on: 5 January 2021
• Main ID: EUCTR2019-002663-10-GB
• Date of registration: 01/09/2020
• Prospective Registration: Yes
• Primary sponsor: Biogen Idec Research Limited
• Public title: Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy
• Scientific title: Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy - Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy
• Date of first enrolment: 17/12/2020
• Target sample size: 152
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2019-002663-10
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: no Parallel group: no Cross over: no Other: yes Other trial design description: Sequential Assignment: Part A - Open Label. Part B - Double Blind. Part C - Open Label If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Part B only - commercial Spinraza Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Brazil, Canada, Chile, Colombia, Estonia, Germany, Greece, Hungary, Ireland, Israel, Italy, Korea, Republic of, Latvia, Lebanon, Mexico, Poland, Russian Federation, Saudi Arabia, Spain, Taiwan, Turkey, United Kingdom, United States

Contacts

• Name: Medical Director
• Affiliation: Biogen Idec Research Limited

• Name: Medical Director
• Affiliation: Biogen Idec Research Limited

Key inclusion & exclusion criteria

Inclusion criteria:
Part A, B and C: - Genetic documentation of 5q SMA (homozygous gene
deletion, mutation, or compound heterozygote)
Part A:
- Onset of clinical signs and symptoms consistent with SMA at > 6 months (> 180 days) of age (i.e., later-onset SMA)
- Age 2 to = 15 years, inclusive, at the time of informed consent
Part B:
- Participants with SMA symptom onset = 6 months (= 180 days) of age (infantile onset) should have age = 7 months (= 210 days) at the time of informed consent
- Participants with SMA symptom onset > 6 months (> 180 days) of age (later onset):
- Age 2 to < 10 years at the time of informed consent
- Can sit independently but has never had the ability to walk independently
- HFMSE score = 10 and = 54 at Screening
Part C:
- Participants = 18 years of age at Screening must be ambulatory
- Currently on nusinersen treatment at the time of Screening, with the first dose being at least 1 year prior to Screening
Are the trial subjects under 18? yes
Number of subjects for this age range: 140
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 12
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0

Exclusion criteria:
Part A, B and C:
- Presence of an untreated or inadequately treated active infection
requiring systemic antiviral or antimicrobial therapy at any time during the Screening period
- Presence of an implanted shunt for the drainage of CSF or of an implanted central nervous system (CNS) catheter
- Hospitalization for surgery, pulmonary event, or nutritional support
within 2 months prior to Screening or planned within 12 months after the participant's first dose
Part A:
- Respiratory insufficiency, defined by the medical necessity for invasive
or noninvasive ventilation for > 6 hours during a 24-hour period, at Screening
- Medical necessity for a gastric feeding tube
- Treatment with an investigational drug given for the treatment of SMA,
biological agent, or device within 30 days or 5 half-lives of the agent,
whichever is longer, prior to Screening or anytime during the study; any prior or current treatment with any survival motor neuron-2 (SMN2)-
splicing modifier or gene therapy; or prior antisense oligonucleotide treatment, or cell transplantation
Part B:
- Participants with SMA symptom onset > 6 months (> 180 days) of age (later onset)
- Respiratory insufficiency, defined by the medical necessity for invasive
or noninvasive ventilation for > 6 hours during a 24-hour period, at Screening
- Medical necessity for a gastric feeding tube
- Treatment with an investigational drug given for the treatment of SMA, biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening or anytime during the study; any prior or current treatment with any survival motor neuron-2 (SMN2)-
splicing modifier or gene therapy; or prior antisense oligonucleotide treatment, or cell transplantation
Part C:
- Concurrent or previous participation and/or administration of nusinersen in another clinical study
NOTE: Other protocol defined Inclusion/Exclusion criteria may apply


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Muscular Atrophy, Spinal
MedDRA version: 20.1 Level: PT Classification code 10041582 Term: Spinal muscular atrophy System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Intervention(s)

Trade Name: Spinraza
Product Name: Spinraza
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Nusinersen
CAS Number: 125894-36-9
Current Sponsor code: ISIS 396443 (BIIB058)
Other descriptive name: NUSINERSEN SODIUM
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2.4-

Product Name: Nursinersen
Product Code: ISIS 396443, BIIB058
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Nursinersen
CAS Number: 125894-36-9
Current Sponsor code: ISIS 396443 (BIIB058)
Other descriptive name: NUSINERSEN SODIUM
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 12.0-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Part B Infantile-onset SMA:
1) Baseline up to Day 183
Part A and C:
2) Screening up to Day 389
3) Screening up to Day 302
4) Screening up to Day 302
5) Screening up to Day 302
6) Baseline up to Day 302
Part C Infantile-onset SMA:
7) Baseline up to Day 302
8) Baseline up to Day 302
9) Baseline up to Day 302
Part A and C Later-onset SMA:
10) Baseline up to Day 302
Part A and C:
11) Baseline up to Day 302
12) Baseline up to Day 302
Part C:
13) Baseline up to Day 302
Part A and C:
14) Baseline up to Day 269
15) Baseline up to Day 269
16) Baseline up to Day 269
17) Baseline up to Day 302
18) Baseline up to Day 302
19) Baseline up to Day 302
20) Baseline up to Day 302

Main Objective: The primary objectives of this study are to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with spinal muscular atrophy (SMA) (Parts A and C); to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with SMA, as measured by change in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) total score (Part B).

Secondary Objective: The secondary objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A, B and C); to examine the effect of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A and C); to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with SMA, to examine the effect of nusinersen administered intrathecally at higher doses compared to the currently approved dose in participants with SMA (Part B).

Primary end point(s): Part B Infantile-onset SMA:
1) Change from Baseline in Children's Hospital of Philadelphia Infant
Test of Neuromuscular Disorders (CHOP INTEND) Total Score
Part A and C:
2) Number of Participants with Adverse Events (AEs) and Serious
Adverse Events (SAEs)
3) Number of Participants with Clinically Significant Shifts from Baseline
in Clinical Laboratory Parameters
4) Number of Participants with Clinically Significant Shifts from Baseline
in Electrocardiograms (ECGs)
5) Number of Participants with Clinically Significant Shifts from Baseline
in Vital Signs
6) Change from Baseline in Body Length/Height
Part C Infantile-onset SMA:
7) Change from Baseline in Head Circumference
8) Change from Baseline in Chest Circumference
9) Change from Baseline in Arm Circumference
Part A and C Later-onset SMA:
10) Change from Baseline in Ulnar Length
Part A and C:
11) Ratio of Weight for Age
12) Ratio of Weight for Length
Part C:
13) Ratio of Head-to-chest Circumference
Part A and C:
14) Change from Baseline in Activated Partial Thromboplastin Time (aPTT)
15) Change from Baseline in Prothrombin Time (PT)
16) Change from Baseline in International Normalized Ratio (INR)
17) Change in Urine Total Protein
18) Change from Baseline in Neurological Examination Outcomes
19) Percentage of Participants with a Postbaseline Platelet Count Below the Lower Limit of Normal on at least 2 Consecutive Measurements
20) Percentage of Participants with a Postbaseline Corrected QT Interval
Using Fridericia's Formula (QTcF) of > 500 millisecond (msec) and an Increase from Baseline to Any Postbaseline Timepoint in QTcF of > 60 msec

Secondary Outcome(s)

Secondary end point(s): Part B Infantile-onset SMA:
1) Percentage of Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestone Responders
Part B Infantile-onset SMA:
2) Change from Baseline in HINE Section 2 Motor Milestones Total Score
3) Time to Permanent Ventilation
4) Time to Death (Overall Survival)
Part A and B Later-onset SMA:
5) Change from Baseline in Hammersmith Functional Motor Scale – Expanded (HFMSE) Score
Part A, B and C Later-onset SMA
6) Change from Baseline in Revised Upper Limb Module (RULM) Score Part A and B Later-onset SMA
7) Number of New WHO Motor Milestones Responders
8) Change from Baseline in Assessment of Caregiver Experience with Neuromuscular Disease (ACEND)
9) Change from Baseline in Pediatric Quality of Life Inventory™ (PedsQL)
Part B:
10) Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
11) Number of Participants with Clinically Significant Shifts from Baseline in Clinical Laboratory Parameters
12) Number of Participants with Clinically Significant Shifts from Baseline in Electrocardiograms (ECGs)
13) Number of Participants with Clinically Significant Shifts from Baseline in Vital Signs
14) Change from Baseline in body length/height
Part B Infantile-onset SMA:
15) Change from Baseline in Head Circumference
16) Change from Baseline in Chest Circumference
17) Change from Baseline in Arm Circumference
Part B Later-onset SMA:
18) Change from baseline in Ulnar Length
Part B:
19) Ratio of Weight for Age
20) Ratio of Weight for Length
21) Ratio of Head-to-chest Circumference
22) Change from Baseline in aPTT
23) Change from Baseline in PT
24) Change from Baseline in INR
25) Change in Urine Total Protein
26) Change from Baseline in Neurological Examination Outcomes
27) Percentage of Participants with a Postbaseline Platelet Count Below
the Lower Limit of Normal on at least 2 Consecutive Measurements
28) Percentage of Participants with a Postbaseline QTcF of > 500
millisecond (msec) and an Increase from Baseline to Any Postbaseline
Timepoint in QTcF of > 60 msec
Part A, B and C:
29) Number of Hospitalizations
30) Duration of Hospitalizations
31) Clinical Global Impression of Change (CGIC)
32) Number of Participants with Serious Respiratory Events
Part B Infantile-onset SMA:
33) Percentage of Time on Ventilation
Parts A, B and C:
34) Ventilator Use
Part B Infantile-onset SMA:
35) Change from Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale
Part C :
36) Change from Baseline in HFMSE Score
37) Number of New WHO Motor Milestone Responders
38) Change from Baseline in ACEND
39) Change from Baseline in PedsQL
40) Change from Baseline in CHOP INTEND Total Score
41) Change from Baseline in HINE Section 2 Motor Milestones Total Score
Parts A and B Later-onset SMA:
42) Change from Baseline in the PASA Scale

Timepoint(s) of evaluation of this end point: 1) Day 302
2) Baseline up to Day 302
3) Screening up to Day 302
4) Screening up to Day 399
5) to 9) - Baseline up to Day 302
10) Screening to day 399
11) Screening to Day 302
12) Day 1 up to Day 302
13) Screening up to Day 302
14) Baseline up to Day 302
15) to 17) Baseline up to Day 302
18) Baseline up to Day 302
19) to 21) Baseline up to Day 302
22) to 24) Baseline up to Day 279
25) Baseline to Day 302
26) to 28) Baseline up to Day 302
29) and 30) Day 1 to Day 279
31) Day 302
32) Screening up to Day 399
33) Screening up to Day 302
34) Screening up to Day 302
35) Baseline up to Day 302
36) to 41) Baseline to up Day 302
42) Baseline up to Day 302

Secondary ID(s)

110011

2019-002663-10-LV

232SM203

NCT04089566

Source(s) of Monetary Support

Biogen Idec Research Limited

Ethics review

Status: Approved
Approval date: 17/12/2020
Contact: