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

A Phase 3, Randomized, Double-blind, Sham-Procedure Controlled Study to Assess the Clinical Efficacy and Safety of ISIS 396443 Administered Intrathecally in Patients With Later-onset Spinal Muscular Atrophy

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02292537

Acronym

CHERISH

Enrollment

126

Registered

2014-11-17

Start date

2014-11-24

Completion date

2017-02-20

Last updated

2021-02-17

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Spinal Muscular Atrophy

Keywords

Spinal Muscular Atrophy, SMA, SMN, SMNRx, ISIS-SMNRx, ISIS-SMN Rx, ISIS 396443, CHERISH, IONIS-SMNRx, IONIS-SMN Rx

Brief summary

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.

Detailed description

This study was conducted and the protocol was registered by Ionis Pharmaceuticals, Inc. In August 2016, sponsorship of the trial was transferred to Biogen.

Interventions

DRUGNusinersen

Administered by intrathecal (IT) lumbar puncture (LP) injection

PROCEDURESham procedure

Small needle prick on the lower back at the location where the IT injection is normally made

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

2 Years to 12 Years

Healthy volunteers

Inclusion criteria

Key Inclusion Criteria: * Parent or guardian has signed informed consent and, if indicated per participant's age and institutional guidelines, participant has signed informed assent * Be medically diagnosed with Spinal Muscular Atrophy (SMA) * Have onset of clinical signs and symptoms consistent with SMA at greater than 6 months of age * Be able to sit independently, but has never had the ability to walk independently * Have Motor Function Score (Hammersmith Functional Motor Scale - Expanded) greater than or equal to 10 and less than or equal to 54 at Screening * Be able to complete all study procedures, measurements and visits and parent or guardian and subject has adequately supportive psychosocial circumstances, in the opinion of the Investigator * Have an estimated life expectancy of greater than 2 years from Screening, in the opinion of the Investigator * Meet age-appropriate institutional criteria for use of anesthesia and sedation, if use is planned for study procedures * For subjects who have reached reproductive maturity, satisfy study contraceptive requirements Key

Exclusion criteria

* Respiratory insufficiency, defined by the medical necessity for invasive or non-invasive ventilation for greater than 6 hours during a 24 hour period, at Screening * Medical necessity for a gastric feeding tube, where the majority of feeds are given by this route, as assessed by the Site Investigator * Severe contractures or severe scoliosis evident on X-ray examination at Screening * Hospitalization for surgery (i.e., scoliosis surgery, other surgery), pulmonary event, or nutritional support within 2 months of Screening or planned during the duration of the study * Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period * History of brain or spinal cord disease, including tumors, or abnormalities by magnetic resonance imaging (MRI) or computed tomography (CT) that would interfere with the LP procedures or cerebrospinal fluid (CSF) circulation * Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system (CNS) catheter * History of bacterial meningitis * Dosing with IONIS-SMN Rx in any previous clinical study * Prior injury (e.g., upper or lower limb fracture) or surgical procedure which impacts the subject's ability to perform any of the outcome measure testing required in the protocol and from which the subject has not fully recovered or achieved a stable baseline * Clinically significant abnormalities in hematology or clinical chemistry parameters or electrocardiogram (ECG), as assessed by the Site Investigator, at the Screening visit that would render the subject unsuitable for inclusion * Treatment with another investigational drug (e.g., oral albuterol or salbutamol, riluzole, carnitine, creatine, sodium phenylbutyrate, et.c), biological agent, or device within 1-month of Screening or 5 half-lives of study agent, whichever is longer. Treatment with valproate or hydroxyurea within 3-months of Screening. Any history of gene therapy, antisense oligonucleotide therapy, or cell transplantation. * Ongoing medical condition that according to the Site Investigator would interfere with the conduct and assessments of the study. Examples are medical disability (e.g., wasting or cachexia, severe anemia, etc.) that would interfere with the assessment of safety or would compromise the ability of the subject to undergo study procedures. NOTE: Other protocol defined Inclusion/

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score at Month 15	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 unable, 1=performed with some compensation, and 2=unaided. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement.

Secondary

Measure	Time frame	Description
Proportion of Participants That Achieved Any New Motor Milestone at Month 15	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.
Number of New Motor Milestones Achieved Per Participant	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.
Change From Baseline in Revised Upper Limb Module (RULM) Test	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). There is only 1 item (item I) that is scored as a can/cannot score, with 1 as the highest score. Scorable items are summed for a total score range of 0-37, with higher scores increased great upper limb function. A positive change from Baseline indicates improvement.
Proportion of Participants That Achieved Standing Alone	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.
Proportion of Participants That Achieved Walking With Assistance	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.
Number of Participants That Experienced Adverse Events (AEs) and Serious Adverse Events (SAEs)	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 significant disability/incapacity. Any other medically important event that, in the opinion of the investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the definition above.
Proportion of Participants Who Achieved a 3-Point Increase From Baseline in HFMSE Score at Month 15	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 unable, 1=performed with some compensation, and 2=unaided. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement.
Number of Participants With Clinically Significant Weight Abnormalities	Baseline through Month 15	Weight changes assessed from Baseline to Month 15.
Number of Participants With Clinically Significant Neurological Examination Abnormalities	Baseline through Month 15	Neurological changes assessed for clinical significance include assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, and reflexes.
Number of Participants With Clinically Significant Physical Examination Abnormalities	Baseline through Month 15	Physical examination changes were assessed for clinical significance.
Number of Participants With Clinically Significant Laboratory Parameter Abnormalities	Baseline through Month 15	Laboratory parameter changes assessed for clinical significance include serum chemistry, hematology, coagulation and urinalysis.
Number of Participants With Abnormal, Clinically Relevant Post-Baseline Worsening in Electrocardiogram (ECG) in Results	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.
Number of Participants Taking Any Concomitant Medication Related to Dosing Procedure or Sham Procedure	Baseline through Month 15	Concomitant medications include prescription and over-the-counter medications administered to participants on or after the first day of study treatment.
Number of Participants With Clinically Significant Vital Sign Abnormalities	Baseline through Month 15	Vital signs assessed for clinical significance include resting blood pressure, pulse, respiratory rate, and temperature.

Countries

Canada, France, Germany, Hong Kong, Italy, Japan, South Korea, Spain, Sweden, United States

Participant flow

Pre-assignment details

After parental informed consent was obtained and prior to any treatment, participants entered a Screening Period of up to 21 days to determine their eligibility for the study. Of the 179 participants screened, 53 were screening failures.

Participants by arm

Arm	Count
Sham Procedure Sham comparator on Days 1, 29, 85 and 274.	42
Nusinersen Nusinersen 12 mg solution via intrathecal (IT) injection on Days 1, 29, 85 and 274.	84
Total	126

Baseline characteristics

Characteristic	Sham Procedure	Nusinersen	Total
Age, Continuous	3.4 years STANDARD_DEVIATION 1.61	3.8 years STANDARD_DEVIATION 1.63	3.6 years STANDARD_DEVIATION 1.63
Hammersmith Functional Motor Scale - Expanded (HFMSE) Score	19.9 scores on a scale STANDARD_DEVIATION 7.23	22.4 scores on a scale STANDARD_DEVIATION 8.33	21.6 scores on a scale STANDARD_DEVIATION 8.03
Race/Ethnicity, Customized Asian	7 Participants	16 Participants	23 Participants
Race/Ethnicity, Customized Black	1 Participants	1 Participants	2 Participants
Race/Ethnicity, Customized Hispanic or Latino	0 Participants	4 Participants	4 Participants
Race/Ethnicity, Customized Multiple	4 Participants	3 Participants	7 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	42 Participants	80 Participants	122 Participants
Race/Ethnicity, Customized White	30 Participants	64 Participants	94 Participants
Sex: Female, Male Female	21 Participants	46 Participants	67 Participants
Sex: Female, Male Male	21 Participants	38 Participants	59 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 42	0 / 84
other Total, other adverse events	42 / 42	75 / 84
serious Total, serious adverse events	12 / 42	14 / 84

Outcome results

Primary

Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score at 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 unable, 1=performed with some compensation, and 2=unaided. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement.

Time frame: Baseline and Month 15

Population: ITT Set: All participants who were randomized and received at least 1 dose of study drug/sham procedure. Missing postbaseline HFMSE data were imputed using the multiple imputation method.

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Sham Procedure	Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score at Month 15	-1.0 scores on a scale
Nusinersen	Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score at Month 15	3.9 scores on a scale

p-value: 1e-795% CI: [3.1, 6.7]ANCOVA

Secondary

Change From Baseline in Revised Upper Limb Module (RULM) Test

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). There is only 1 item (item I) that is scored as a can/cannot score, with 1 as the highest score. Scorable items are summed for a total score range of 0-37, with higher scores increased great upper limb function. A positive change from Baseline indicates improvement.

Time frame: Baseline and Month 15

Population: ITT Set: All participants who were randomized and received at least 1 dose of study drug/sham procedure. Missing postbaseline data were imputed using multiple imputation.

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Sham Procedure	Change From Baseline in Revised Upper Limb Module (RULM) Test	0.5 scores on a scale
Nusinersen	Change From Baseline in Revised Upper Limb Module (RULM) Test	4.2 scores on a scale

95% CI: [2.3, 5]

Secondary

Number of New Motor Milestones Achieved Per Participant

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

Time frame: Month 15

Population: Efficacy Set: All participants with a Day 456 Visit and all participants with a time difference of at least 463 days (456 days plus a 7-day window) between the date of first dose and the date for the final analysis. Based on imputed data where there was missing data.

Arm	Measure	Value (MEAN)	Dispersion
Sham Procedure	Number of New Motor Milestones Achieved Per Participant	-0.2 milestones achieved	Standard Deviation 0.54
Nusinersen	Number of New Motor Milestones Achieved Per Participant	0.2 milestones achieved	Standard Deviation 0.51

95% CI: [0.2, 0.7]

Secondary

Number of Participants Taking Any Concomitant Medication Related to Dosing Procedure or Sham Procedure

Concomitant medications include prescription and over-the-counter medications administered to participants on or after the first day of study treatment.