NCT02292537: CHERISH

A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Participants With Later-onset Spinal Muscular Atrophy (SMA)

Completed Phase 3 Results posted Last updated 17 February 2021

What this trial tests

Phase 3 trial testing Nusinersen in Spinal Muscular Atrophy in 126 participants. Completed in 20 February 2017.

Timeline

24 November 2014

Primary endpoint
20 February 2017

20 February 2017

Quick facts

Lead sponsor	Biogen
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	126
Start date	24 November 2014
Primary completion	20 February 2017
Estimated completion	20 February 2017
Sites	24 locations across France, Hong Kong, Italy, Japan, Sweden, Germany, South Korea, Canada

Drugs / interventions tested

• Nusinersen (NUSINERSEN) — full drug profile →
• Sham procedure — full drug profile →

Conditions studied

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

Sponsor

Biogen — full company profile →

Who can join

Adults 2 to 12, 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.

Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score at Month 15 Primary · Baseline and Month 15

The HFMSE consists of 33 scored activities used to assess motor function in children with SMA. The scale was originally developed with 20 scored activities and was devised for use in children with SMA Type 2 and Type 3 with limited ambulation to give objective information on motor ability and clinical progression. The expanded scale includes an additional module of 13 items developed to allow for evaluation of ambulatory SMA patients. Participants were asked to do a specific activity (such as rolling) and they were then graded on the quality and execution of that movement on a scale of 0=being

Group	Value	95% CI
Sham Procedure	-1.0	-2.5 – 0.5
Nusinersen	3.9	3.0 – 4.9

Proportion of Participants Who Achieved a 3-Point Increase From Baseline in HFMSE Score at Month 15 Secondary · Baseline and Month 15

The HFMSE consists of 33 scored activities used to assess motor function in children with SMA. The scale was originally developed with 20 scored activities and was devised for use in children with SMA Type 2 and Type 3 with limited ambulation to give objective information on motor ability and clinical progression. The expanded scale includes an additional module of 13 items developed to allow for evaluation of ambulatory SMA patients. Participants were asked to do a specific activity (such as rolling) and they were then graded on the quality and execution of that movement on a scale of 0=being

Group	Value	95% CI
Sham Procedure	26.3	12.40 – 40.22
Nusinersen	56.8	45.62 – 68.05

Proportion of Participants That Achieved Any New Motor Milestone at Month 15 Secondary · Month 15

New motor milestones are defined as sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone and walking alone.

Group	Value	95% CI
Sham Procedure	5.9	0.72 – 19.68
Nusinersen	19.7	10.93 – 31.32

Number of New Motor Milestones Achieved Per Participant Secondary · Month 15

New motor milestones are defined as sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone and walking alone.

Group	Value	95% CI
Sham Procedure	-0.2	± 0.54
Nusinersen	0.2	± 0.51

Change From Baseline in Revised Upper Limb Module (RULM) Test Secondary · Baseline and Month 15

The RULM Test is used in patients with SMA to assess upper limb functional ability items that are reflective of activities of daily living (i.e., raise a can to mouth as if drinking, take a coin and place it in a box, remove the lid of a container). The RULM test has a total of 20 items with an entry item that serves as functional class identification and does not contribute to the total score. The remaining 19 scorable items reflect different functional domains and are graded on a 3-point system with a score of 0 (unable), 1 (able, with modification), and a maximum of 2 (able, no difficulty).

Group	Value	95% CI
Sham Procedure	0.5	-0.6 – 1.6
Nusinersen	4.2	3.4 – 5.0

Proportion of Participants That Achieved Standing Alone Secondary · Month 15

If the participant was unable to achieve standing alone at Baseline but could achieve this at Month 15 then they were considered a responder. If they could not achieve this or if a participant terminated the study prior to the 15-month assessment due to treatment failure or death, then any imputed value was ignored and the participant was considered as a non-responder.

Group	Value	95% CI
Sham Procedure	2.9	0.07 – 15.33
Nusinersen	1.5	0.04 – 8.16

Proportion of Participants That Achieved Walking With Assistance Secondary · Month 15

If the participant was unable to achieve walking with assistance at baseline but could achieve this at Month 15 then they were considered a responder. If they could not achieve this or if a participant terminated the study prior to the 15-month assessment due to treatment failure or death, then any imputed value was ignored and the participant was considered as a non-responder.

Group	Value	95% CI
Sham Procedure	0.0	0.00 – 10.28
Nusinersen	1.5	0.04 – 8.16

Number of Participants That Experienced Adverse Events (AEs) and Serious Adverse Events (SAEs) Secondary · Baseline through Month 15

AEs: any sign, symptom, or diagnosis/disease that is unfavorable or unintended, that is new, or if pre-existing, worsens in participants administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. SAEs: an event that results in death; an event that, in the view of the investigator, places the participant at immediate risk of death; an outcome that results in a congenital anomaly/birth defect diagnosed in a child of a participant; an event that requires or prolongs inpatient hospitalization; an event that results in persistent or significa

AEs

Group	Value	95% CI
Sham Procedure	42
Nusinersen	78

SAEs

Group	Value	95% CI
Sham Procedure	12
Nusinersen	14

Number of Participants With Clinically Significant Vital Sign Abnormalities Secondary · Baseline through Month 15

Vital signs assessed for clinical significance include resting blood pressure, pulse, respiratory rate, and temperature.

Systolic blood pressure <90 mmHg

Group	Value	95% CI
Sham Procedure	33
Nusinersen	80

Systolic blood pressure >140 mmHg

Group	Value	95% CI
Sham Procedure	1
Nusinersen	4

Systolic blood pressure >160 mmHg

Group	Value	95% CI
Sham Procedure	0
Nusinersen	2

Diastolic blood pressure <50 mmHg

Group	Value	95% CI
Sham Procedure	31
Nusinersen	65

Diastolic blood pressure >90 mmHg

Group	Value	95% CI
Sham Procedure	7
Nusinersen	11

Diastolic blood pressure >100 mmHg

Group	Value	95% CI
Sham Procedure	2
Nusinersen	2

Heart rate <60 beats/min

Group	Value	95% CI
Sham Procedure	0
Nusinersen	1

Heart rate >100 beats/min

Group	Value	95% CI
Sham Procedure	42
Nusinersen	84

Number of Participants With Clinically Significant Weight Abnormalities Secondary · Baseline through Month 15

Weight changes assessed from Baseline to Month 15.

Weight decrease of >=7% from baseline

Group	Value	95% CI
Sham Procedure	3
Nusinersen	4

Weight increase of >=7% from baseline

Group	Value	95% CI
Sham Procedure	38
Nusinersen	77

Number of Participants With Clinically Significant Laboratory Parameter Abnormalities Secondary · Baseline through Month 15

Laboratory parameter changes assessed for clinical significance include serum chemistry, hematology, coagulation and urinalysis.

Hematology: Hemoglobin - High

Group	Value	95% CI
Sham Procedure	2
Nusinersen	2

Hematology: Hemoglobin - Low

Group	Value	95% CI
Sham Procedure	7
Nusinersen	15

Hematology: Hematocrit - High

Group	Value	95% CI
Sham Procedure	3
Nusinersen	1

Hematology: Hematocrit - Low

Group	Value	95% CI
Sham Procedure	6
Nusinersen	18

Hematology: Red blood cells - High

Group	Value	95% CI
Sham Procedure	2
Nusinersen	2

Hematology: Red blood cells - Low

Group	Value	95% CI
Sham Procedure	7
Nusinersen	13

Hematology: White blood cells - High

Group	Value	95% CI
Sham Procedure	11
Nusinersen	12

Hematology: White blood cells - Low

Group	Value	95% CI
Sham Procedure	10
Nusinersen	20

Number of Participants With Abnormal, Clinically Relevant Post-Baseline Worsening in Electrocardiogram (ECG) in Results Secondary · Baseline through Month 15

The number of participants with abnormal, clinically relevant worsening, defined as participants with an ECG interpreted as abnormal and clinically relevant, with a comparison with Baseline value is reported.

Group	Value	95% CI
Sham Procedure	2
Nusinersen	0

Adverse events — posted to ClinicalTrials.gov

Time frame: From signing of Informed Consent to the end of the Follow-up period (Month 15). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Sham Procedure

Serious: 12/42 (29%)

Deaths: 0/42

Nusinersen

Serious: 14/84 (17%)

Deaths: 0/84

Serious adverse events (21 terms)

Reaction	System	Sham Procedure	Nusinersen
Pneumonia	Infections and infestations	—	—
Pneumonia viral	Infections and infestations	—	—
Faecaloma	Gastrointestinal disorders	—	—
Gastroenteritis	Infections and infestations	—	—
Influenza	Infections and infestations	—	—
Dehydration	Metabolism and nutrition disorders	—	—
Respiratory distress	Respiratory, thoracic and mediastinal disorders	—	—
Abdominal distension	Gastrointestinal disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Pain	General disorders	—	—
Bacteraemia	Infections and infestations	—	—
Bronchitis	Infections and infestations	—	—
Parainfluenzae virus infection	Infections and infestations	—	—
Pneumonia adenoviral	Infections and infestations	—	—
Pneumonia parainfluenzae viral	Infections and infestations	—	—
Respiratory syncytial virus bronchitis	Infections and infestations	—	—
Respiratory syncytial virus infection	Infections and infestations	—	—
Upper respiratory tract infection	Infections and infestations	—	—
Post lumbar puncture syndrome	Injury, poisoning and procedural complications	—	—
Pneumonia aspiration	Respiratory, thoracic and mediastinal disorders	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—

Other adverse events (25 terms — click to expand)

Reaction	System	Sham Procedure	Nusinersen
Pyrexia	General disorders	—	—
Upper respiratory tract infection	Infections and infestations	—	—
Vomiting	Gastrointestinal disorders	—	—
Headache	Nervous system disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Nasopharyngitis	Infections and infestations	—	—
Gastroenteritis	Infections and infestations	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Gastroenteritis viral	Infections and infestations	—	—
Influenza	Infections and infestations	—	—
Bronchitis	Infections and infestations	—	—
Ear infection	Infections and infestations	—	—
Joint contracture	Musculoskeletal and connective tissue disorders	—	—
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	—	—
Conjunctivitis	Infections and infestations	—	—
Pneumonia	Infections and infestations	—	—
Epistaxis	Respiratory, thoracic and mediastinal disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Otitis media	Infections and infestations	—	—
Upper respiratory tract congestion	Respiratory, thoracic and mediastinal disorders	—	—
Pharyngitis streptococcal	Infections and infestations	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—
Scoliosis	Musculoskeletal and connective tissue disorders	—	—

Most-reported serious reactions: Pneumonia, Pneumonia viral, Faecaloma, Gastroenteritis, Influenza, Dehydration, Respiratory distress, Abdominal distension.

Data from ClinicalTrials.gov NCT02292537 adverse events section.

Sponsor's own description

The primary objective of this study is to examine the clinical efficacy of nusinersen (ISIS 396443) administered intrathecally to participants with later-onset Spinal Muscular Atrophy (SMA). The secondary objective is to examine the safety and tolerability of nusinersen administered intrathecally to participants with later-onset SMA.

Publications & conference data

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

1. Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy.
   Mercuri E, Darras BT, Chiriboga CA, Day JW, et al · · 2018 · cited 1040× · PMID 29443664 · DOI 10.1056/nejmoa1710504
2. RNA-based therapeutics: an overview and prospectus.
   Zhu Y, Zhu L, Wang X, Jin H. · · 2022 · cited 417× · PMID 35871216 · DOI 10.1038/s41419-022-05075-2
3. Splice-switching antisense oligonucleotides as therapeutic drugs.
   Havens MA, Hastings ML. · · 2016 · cited 402× · PMID 27288447 · DOI 10.1093/nar/gkw533
4. Antisense Oligonucleotide Therapies for Neurodegenerative Diseases.
   Bennett CF, Krainer AR, Cleveland DW. · · 2019 · cited 263× · PMID 31283897 · DOI 10.1146/annurev-neuro-070918-050501
5. 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
6. Clinical Evidence Supporting Early Treatment Of Patients With Spinal Muscular Atrophy: Current Perspectives.
   Dangouloff T, Servais L. · · 2019 · cited 149× · PMID 31632042 · DOI 10.2147/tcrm.s172291
7. Gene-based therapies for neurodegenerative diseases.
   Sun J, Roy S. · · 2021 · cited 126× · PMID 33526943 · DOI 10.1038/s41593-020-00778-1
8. Prospective and longitudinal natural history study of patients with Type 2 and 3 spinal muscular atrophy: Baseline data NatHis-SMA study.
   Chabanon A, Seferian AM, Daron A, Péréon Y, et al · · 2018 · cited 122× · PMID 30048507 · DOI 10.1371/journal.pone.0201004