NCT01839656

A Study to Assess the Efficacy, Safety and Pharmacokinetics of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy (SMA)

Completed Phase 2 Results posted Last updated 17 February 2021

What this trial tests

Phase 2 trial testing nusinersen in Spinal Muscular Atrophy in 21 participants. Completed in 21 August 2017.

Timeline

8 May 2013

Primary endpoint
21 August 2017

21 August 2017

Quick facts

Lead sponsor	Biogen
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	21
Start date	8 May 2013
Primary completion	21 August 2017
Estimated completion	21 August 2017
Sites	4 locations across Canada, United States

Drugs / interventions tested

• nusinersen (NUSINERSEN) — full drug profile →

Conditions studied

• Spinal Muscular Atrophy — all drugs for Spinal Muscular Atrophy →

Sponsor

Biogen — full company profile →

Who can join

Adults 21 Days to 210 Days, any sex, with Spinal Muscular Atrophy. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percent of Participants Who Achieved Improvement in Motor Milestones as Assessed by Section 2 of the HINE at the Last Visit Primary · Day 1352 or Early Termination

Section 2 of HINE consists of 8 independent milestone categories. Within each of these categories, participants can progress from complete absence of a motor ability (the lowest level in each category) through multiple milestones (2 to 4 levels in each category) to the highest level within the category. Overall, there are a total of 26 milestones that can be achieved across the 8 categories. Improvement was defined as any of the following: 1. An increase from baseline of 2 milestones or more, or the achievement of pincer grasp in the voluntary grasp category 2. An increase from baseline of 2 m

Group	Value	95% CI
Nusinersen 6 mg	25.0
Nusinersen 12 mg	68.8

Event-free Survival at the End of Study Secondary · Up to Day 1638

Event-free survival was defined as the percent of participants who were alive and did not require permanent ventilatory support (defined as tracheostomy or the need for ≥16 hours ventilation/day continuously for at least 2 weeks in the absence of an acute reversible illness) Event-free survival was estimated using Kaplan-Meier methodology.

Group	Value	95% CI
Nusinersen 6 mg	25.0
Nusinersen 12 mg	62.5

Percent of Participants With Improved Motor Function at the Last Visit as Assessed by the CHOP-INTEND Motor Function Scale Secondary · Day 1352 or Early Termination

The CHOP-INTEND test includes 16 items structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). All item scores range from 0 (worst) to 4 (best). Total scores range from 0 to 64, with higher scores indicating better movement functioning. Improvement was defined as an increase in total CHOP INTEND score ≥4 points from baseline as of the last study visit.

Group	Value	95% CI
Nusinersen 6 mg	25.0
Nusinersen 12 mg	62.5

Change in Neuromuscular Electrophysiology at the Last Visit as Assessed by the Change From Baseline in CMAP Amplitude Secondary · Baseline, Day 1072

CMAP is an electrophysiological technique that can be used to determine the approximate number of motor neurons in a muscle or group of muscles. A positive change from Baseline indicates that the number of motor neurons increased.

Peroneal nerve

Group	Value	95% CI
Nusinersen 6 mg	1.88	± 2.58
Nusinersen 12 mg	2.81	± 1.28

Ulnar nerve

Group	Value	95% CI
Nusinersen 6 mg	0.776	± 1.448
Nusinersen 12 mg	0.685	± 0.415

Number of Participants Experiencing Adverse Events (AEs) and/or Serious Adverse Events (SAEs) Secondary · Up to Day 1352

AE: any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. SAE: any AE that in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening: that is, poses an immediate risk of death at the time of the event; requires in-patient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the abili

Any AE

Group	Value	95% CI
Nusinersen 6 mg	4
Nusinersen 12 mg	16

Any SAE

Group	Value	95% CI
Nusinersen 6 mg	3
Nusinersen 12 mg	13

Concentration of Nusinersen in Cerebrospinal Fluid (CSF) Secondary · Day 1135 (Predose)

The concentration of nusinersen in CSF was measured by using standard laboratory assays.

Group	Value	95% CI
Nusinersen 6 mg	12.2	± 8.60
Nusinersen 12 mg	11.1	± 4.99

PK Parameters of Nusinersen in Plasma: Maximum Concentration (Cmax) Secondary · Day 1 (Predose and 1, 2, and 4 hours [hr] Postdose) and Day 2 (24 hr Postdose )

Cmax is the maximum observed concentration of study drug in plasma.

Group	Value	95% CI
Nusinersen 6 mg	396	± 311
Nusinersen 12 mg	829	± 625

PK Parameters of Nusinersen in Plasma: Time to Reach Cmax (Tmax) Secondary · Day 1 (Predose and 1, 2, and 4 hours [hr] Postdose) and Day 2 (24 hr Postdose )

Tmax is the time at which Cmax occurs.

Group	Value	95% CI
Nusinersen 6 mg	2.09	± 1.35
Nusinersen 12 mg	2.37	± 1.25

PK Parameters of Nusinersen in Plasma: Area Under the Plasma Concentrations Time Curve From the Time of the IT Dose to Four Hours After Dosing (AUC0-4) Secondary · Day 1 (Predose and 1, 2, and 4 hours [hr] Postdose) and Day 2 (24 hr Postdose )

AUC is area under the plasma concentration-time curve from zero time (Predose) to 4 hours after IT administration of study drug. AUC was determined by using the linear trapezoidal rule.

Group	Value	95% CI
Nusinersen 6 mg	894	± 610
Nusinersen 12 mg	2181	± 1488

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to Day 1359. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Nusinersen 6 mg

Serious: 3/4 (75%)

Deaths: 1/4

Nusinersen 12 mg

Serious: 13/16 (81%)

Deaths: 4/16

Serious adverse events (43 terms)

Reaction	System	Nusinersen 6 mg	Nusinersen 12 mg
Respiratory distress	Respiratory, thoracic and mediastinal disorders	—	—
Pneumonia	Infections and infestations	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Rhinovirus infection	Infections and infestations	—	—
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Bronchiolitis	Infections and infestations	—	—
Pneumonia viral	Infections and infestations	—	—
Respiratory syncytial virus bronchiolitis	Infections and infestations	—	—
Pneumonia aspiration	Respiratory, thoracic and mediastinal disorders	—	—
Metapneumovirus infection	Infections and infestations	—	—
Viral infection	Infections and infestations	—	—
Viral upper respiratory tract infection	Infections and infestations	—	—
Apnoea	Respiratory, thoracic and mediastinal disorders	—	—
Atelectasis	Respiratory, thoracic and mediastinal disorders	—	—
Bradycardia	Cardiac disorders	—	—
Cardiac arrest	Cardiac disorders	—	—
Cardio-respiratory arrest	Cardiac disorders	—	—
Cyanosis	Cardiac disorders	—	—
Pneumopericardium	Cardiac disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Adenovirus infection	Infections and infestations	—	—
Corona virus infection	Infections and infestations	—	—
Enterovirus infection	Infections and infestations	—	—
Lower respiratory tract infection viral	Infections and infestations	—	—
Parainfluenzae virus infection	Infections and infestations	—	—

Other adverse events (237 terms — click to expand)

Reaction	System	Nusinersen 6 mg	Nusinersen 12 mg
Pyrexia	General disorders	—	—
Upper respiratory tract infection	Infections and infestations	—	—
Constipation	Gastrointestinal disorders	—	—
Nasopharyngitis	Infections and infestations	—	—
Joint contracture	Musculoskeletal and connective tissue disorders	—	—
Gastrooesophageal reflux disease	Gastrointestinal disorders	—	—
Otitis media	Infections and infestations	—	—
Scoliosis	Musculoskeletal and connective tissue disorders	—	—
Nasal congestion	Respiratory, thoracic and mediastinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Pneumonia	Infections and infestations	—	—
Atelectasis	Respiratory, thoracic and mediastinal disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Increased upper airway secretion	Respiratory, thoracic and mediastinal disorders	—	—
Rash	Skin and subcutaneous tissue disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Pain	General disorders	—	—
Respiratory tract infection	Infections and infestations	—	—
Rhinovirus infection	Infections and infestations	—	—
Viral infection	Infections and infestations	—	—
Hypoxia	Respiratory, thoracic and mediastinal disorders	—	—
Oedema peripheral	General disorders	—	—
Seasonal allergy	Immune system disorders	—	—
Ear infection	Infections and infestations	—	—
Rhinitis	Infections and infestations	—	—
Feeding tube complication	Injury, poisoning and procedural complications	—	—
Joint dislocation	Injury, poisoning and procedural complications	—	—
Human rhinovirus test positive	Investigations	—	—
Kyphosis	Musculoskeletal and connective tissue disorders	—	—
Muscle contractions involuntary	Nervous system disorders	—	—
Anxiety	Psychiatric disorders	—	—
Chronic respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Respiratory distress	Respiratory, thoracic and mediastinal disorders	—	—
Dermatitis diaper	Skin and subcutaneous tissue disorders	—	—
Eczema	Skin and subcutaneous tissue disorders	—	—
Excessive granulation tissue	Skin and subcutaneous tissue disorders	—	—
Skin irritation	Skin and subcutaneous tissue disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Tachycardia	Cardiac disorders	—	—
Abdominal distension	Gastrointestinal disorders	—	—

Most-reported serious reactions: Respiratory distress, Pneumonia, Respiratory failure, Rhinovirus infection, Acute respiratory failure, Bronchiolitis, Pneumonia viral, Respiratory syncytial virus bronchiolitis.

Data from ClinicalTrials.gov NCT01839656 adverse events section.

Sponsor's own description

The primary objective is to examine the clinical efficacy of multiple doses of nusinersen (ISIS 396443) administered intrathecally to participants with Infantile-Onset Spinal Muscular Atrophy (SMA). The secondary objectives are to examine the safety and tolerability of multiple doses of nusinersen administered intrathecally to participants with infantile-onset SMA and to examine the cerebral spinal fluid (CSF) and plasma Pharmacokinetics (PK) of multiple doses of nusinersen administered intrathecally to participants with infantile-onset SMA.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study.
   Finkel RS, Chiriboga CA, Vajsar J, Day JW, et al · · 2016 · cited 743× · PMID 27939059 · DOI 10.1016/s0140-6736(16)31408-8
2. Splice-switching antisense oligonucleotides as therapeutic drugs.
   Havens MA, Hastings ML. · · 2016 · cited 402× · PMID 27288447 · DOI 10.1093/nar/gkw533
3. Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases.
   Schoch KM, Miller TM. · · 2017 · cited 211× · PMID 28641106 · DOI 10.1016/j.neuron.2017.04.010
4. Gene-based therapies for neurodegenerative diseases.
   Sun J, Roy S. · · 2021 · cited 126× · PMID 33526943 · DOI 10.1038/s41593-020-00778-1
5. Adverse Drug Reactions and Toxicity of the Food and Drug Administration-Approved Antisense Oligonucleotide Drugs.
   Alhamadani F, Zhang K, Parikh R, Wu H, et al · · 2022 · cited 101× · PMID 35221289 · DOI 10.1124/dmd.121.000418
6. Antisense oligonucleotides in neurological disorders.
   Wurster CD, Ludolph AC. · · 2018 · cited 100× · PMID 29854003 · DOI 10.1177/1756286418776932
7. Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance.
   Keinath MC, Prior DE, Prior TW. · · 2021 · cited 99× · PMID 33531827 · DOI 10.2147/tacg.s239603
8. Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study.
   Finkel RS, Chiriboga CA, Vajsar J, Day JW, et al · · 2021 · cited 89× · PMID 34089650 · DOI 10.1016/s2352-4642(21)00100-0