The primary objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with spinal muscular atrophy (SMA), as measured by change in Children's Hospital of Philadelphia…
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Brief title
Condition
- Musculoskeletal and connective tissue deformities (incl intervertebral disc disorders)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part B Infantile-onset SMA:
1) Change from Baseline in Children's Hospital of Philadelphia Infant Test of
Neuromuscular Disorders (CHOP INTEND)
Secondary outcome
Part B Infantile-onset SMA:
1) Percentage HINE Section 2 Motor Milestone Responders
2) Change from Baseline in HINE Section 2 Motor Milestones Total Score
3) Time to Death or Permanent Ventilation
4) Time to Death (Overall Survival)
15) Change from Baseline in Head Circumference
16) Change from Baseline in Chest Circumference
17) Change from Baseline in Arm Circumference
33) Percentage of Time on Ventilation
35) Change from Baseline in the Parent Assessment of Swallowing Ability (PASA)
Scale
Part B Later-onset SMA:
5) Change from Baseline in Hammersmith Functional Motor Scale - Expanded
(HFMSE) Score
6) Change from Baseline in Revised Upper Limb Module (RULM) Score
7) Total number of New WHO Motor Milestones
8) Change from Baseline in Assessment of Caregiver Experience with
Neuromuscular Disease (ACEND)
9) Change from Baseline in Pediatric Quality of Life Inventory* (PedsQL)
18) Change from baseline in Ulnar Length
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
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
29) Number of Hospitalizations
30) Duration of Hospitalizations
31) Clinical Global Impression of Change (CGIC)
32) Number of Participants with Serious Respiratory Events
34) Ventilator Use
Background summary
SMA is an autosomal recessive neuromuscular disease characterized by
degeneration of the motor neurons in the anterior horn of the spinal cord,
resulting in atrophy of the voluntary muscles of the limbs and trunk. With an
incidence of 8.5 to 10.3 per 100,000 live births, it is the most common
monogenetic cause of infant mortality and a major cause of childhood morbidity
due to weakness in the US.
Efficacy and safety results across the nusinersen clinical development program
have demonstrated an overall positive benefit-risk profile of nusinersen across
a broad range of SMA phenotypes and patient populations. Nusinersen is approved
in the US, Europe, and other countries and regions for the treatment of SMA in
pediatric and adult patients at a recommended dosage of 12 mg administered in 3
loading doses at 14-day intervals, a fourth loading dose 30 days after the
third dose, and maintenance doses every 4 months thereafter.
Pharmacokinetic (PK) and pharmacodynamic (PD) analyses indicate that nusinersen
drug exposure higher than that achieved with 12 mg in patients with SMA may
produce an even greater benefit in motor function. Additionally, PK modeling
and simulations identified dosing regimens that achieve higher drug exposure
more rapidly. Therefore, this study is being conducted to investigate the
efficacy, safety, tolerability, and PK of a 50/28-mg dose of nusinersen (50-mg
loading dose/28-mg maintenance dose) and a dosing regimen targeted to achieve
higher drug exposure more rapidly.
Study objective
The primary objectives of this study are to examine the clinical efficacy of
nusinersen administered intrathecally at higher doses to participants with
spinal muscular atrophy (SMA), as measured by change in Children's Hospital of
Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) total score
(Part B)
Study design
This is a global, phase II, escalating dose and randomized-controlled study of
Nusinersen (BIIB058) in participants with Spinal Muscular Atrophy.
Intervention
Participants will be assigned to either a control group (1/3) or a higher dose
group (2/3):
- Control Group: Children in this group receive the approved dose and dosing
schedule of the study drug. Your child will receive 6 study drug injections.
This will include 4 loading doses of 12 mg study drug, followed by 2
maintenance doses of 12 mg study drug once every 4 months.
- Higher Dose group: Children in this group receive 4 study drug injections.
This will include 2 loading doses of 50 mg study drug followed by 2 maintenance
doses of 28 mg study drug once every 4 months.
The study drug will be administered intrathecally.
Study burden and risks
Participation in the study will last up to 11-14 months: 21 days of screening,
279 days of treatment and 23-120 days of follow-up. Participants have to
visits the study site up to 9-10 times.
In addition to section E6, subjects will be subjected to: questions regarding
medical history, use of concomitant medications/procedures and adverse events;
urine sampling; measurement of vital signs; physical examination; neurological
examination; assessment of movement abilities; SARS CoV-2 test; record of
ventilator use in a diary, parental assessment of swallowing and patient
reported outcomes questionnaires.
Subjects will be expected to not take part in other medical studies, keep their
appointments for visits, follow instructions from the study team, keep a
patient card with them at all times. Also, subjects and parents will be asked
not to talk about which group they/their child might be in.
The study drug may have following side effects: constipation, upper respiratory
tract infection, pneumonia (infection of the lungs), nasopharyngitis (common
cold), teething and respiratory tract infection (infections of the nose,
sinuses, throat, or lungs), pyrexia (fever), headache, vomiting (throwing up)
and back pain.
The following side effects are rare and can be serious:
• Serious infection such as meningitis after a lumbar puncture (LP)
• Meningitis not caused by a bacterial infection
• Hydrocephalus (a build up of too much fluid around the brain)
• Hypersensitivity (an allergic or allergic-like reaction that may include
swelling, rash, or itching)
Nusinersen (Spinraza) 12 mg has a positive benefit-risk profile, with more than
4 years of postmarketing experience and more than 11,000 patients treated. The
safety profile to date does not preclude study of higher doses in any
population.
Anticipating a potential enhancement of benefit with the dosing regimens
proposed for Study 232SM203, substantiated by PK/PD modeling described in
Section 3.1.2, the safety of the loading period for Study 232SM203 is supported
by a nonclinical study conducted in monkeys (Study P058-17-03). In this study,
the no-observed-adverse-effect level (NOAEL) was 15 mg (human equivalent dose
of 150 mg). As such, dosing for Study 232SM203 has a safety margin of at least
4.5-fold for cumulative doses during the loading period and a 3-fold margin for
a single loading dose of 50 mg.
The safety of long-term exposure during the Study 232SM203 maintenance period
is supported by a 53-week monkey study (Study 396443-AS06). Monkeys received a
cumulative dose of 3.9, 13, and 52 mg at each dose level (0.3, 1, and 4 mg per
dose, respectively) during the 52-week treatment duration. The overall NOAEL
was determined to be 4 mg. Tissue concentrations measured in monkeys from the
53-week toxicology study at the NOAEL (4 mg) were compared to the estimated
tissue concentrations in patients with SMA. The exposure-based safety margin is
at least 1.4-fold based on exposure in the spinal cord (safety margins are
higher for other tissues).
Innovation House, Norden Road 70
Maidenhead SL6 4AY
GB
Innovation House, Norden Road 70
Maidenhead SL6 4AY
GB
Listed location countries
Age
Inclusion criteria
Part B
- Genetic documentation of 5q SMA (homozygous gene deletion, mutation, or
compound heterozygote)
- Participants with SMA symptom onset <= 6 months (<= 180 days) of age (infantile
onset) should have age > 1 week to <= 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
Exclusion criteria
Part B:
- 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
- Treatment with an investigational drug including but not limited to 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
- 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
- Participants with SMA symptom onset <= 6 months (<= 180 days) of age (infantile
onset): Signs or symptoms of SMA present at birth or within the first week
after birth
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-002663-10-NL |
| ClinicalTrials.gov | NCT04089566 |
| CCMO | NL79273.000.22 |