Primary-Assess the efficacy of apitegromab compared with placebo using the HFMSE in patients 2 through 12 years oldKey secondary-Assess the efficacy of apitegromab compared with placebo based on the number of patients with clinical improvement in…
ID
Source
Brief title
Condition
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change from Baseline in HFMSE total score at 12 months
Secondary outcome
-Proportion of patients with >=3-point change from Baseline in the HFMSE total
score at 12 months
-Change from Baseline in RULM total score at 12 months
-Change from Baseline in number of WHO motor development milestones attained at
12 months
Background summary
SMA is a whole-body disease (Wirth 2020). Although the SMN-targeted therapies,
which include gene therapy (onasemnogene abeparvovec-xioi [ZOLGENSMA®]) and the
SMN upregulator (also referred to as SMN corrector) therapies nusinersen and
risdiplam, approved for the treatment of SMA have been shown to significantly
improve clinical outcomes by preventing or reducing the decline in motor
function, patients may continue to suffer from substantial motor functional
impairment because SMN-targeted therapies focus on SMN-dependent pathways and
do not directly impact skeletal muscle to reverse the atrophy that has already
taken place (Mercuri 2018, Mercuri 2020).
Consequently, there remains an unmet medical need for a complementary
therapeutic strategy, namely muscle-directed therapy, that may address muscle
atrophy and thereby improve motor function in patients with SMA. Through its
novel mechanism of action as a selective inhibitor of
myostatin activation, apitegromab (SRK-015) has the potential to produce a
clinically meaningful effect on motor function in a broad population of
patients with SMA who are being treated with background SMN upregulator
therapies (e.g., nusinersen [SPINRAZA®] or risdiplam [EVRYSDI®]) (SPINRAZA Food
and Drug Administration [FDA] Prescribing Information [PI] 2020, SPINRAZA
Summary of Product Characteristics [SmPC] 2022, EVRYSDI FDA PI 2022, EVRYSDI
SmPC 2022).
Study objective
Primary
-Assess the efficacy of apitegromab compared with placebo using the HFMSE in
patients 2 through 12 years old
Key secondary
-Assess the efficacy of apitegromab compared with placebo based on the number
of patients with clinical improvement in patients 2 through 12 years old
-Assess the efficacy of apitegromab compared with placebo by measuring changes
in upper limb function using the Revised Upper Limb Module (RULM) in patients 2
through 12 years old
-Assess the efficacy of apitegromab compared with placebo by measuring changes
in number of World Health Organization (WHO) motor development milestones in
patients 2 through 12 years old
Study design
This Phase 3 trial will be conducted at approximately 55 to 60 trial sites
globally to evaluate the safety and efficacy of apitegromab compared with
placebo as an adjunctive therapy to nusinersen or risdiplam in nonambulatory
patients with later-onset SMA. In the Main Efficacy Population, 2 dose levels
of apitegromab will be evaluated to further assess the lowest efficacious dose
level. Patients will be randomized to receive apitegromab
(10 mg/kg or 20 mg/kg) or matching placebo by intravenous (IV) infusion. The
trial will include Screening, Treatment, and Safety Follow-up Periods.
Intervention
• For the Main Efficacy Population, approximately 156 patients who are 2
through 12 years old at Screening will be randomized 1:1:1 double-blind to
receive apitegromab 10 mg/kg, apitegromab 20 mg/kg, or placebo every 4 weeks
during the 52-week Treatment Period. Randomization for the Main Efficacy
Population will be stratified by type of background therapy (i.e., nusinersen
or risdiplam) and age at initiation of SMN upregulator therapy (>=5 and <5).
• For the Exploratory Subpopulation, a maximum of 48 patients who are 13
through 21 years old at Screening will be randomized 2:1 double-blind to
receive apitegromab 20 mg/kg or placebo every 4 weeks during the 52-week
Treatment Period. Randomization for the Exploratory Subpopulation will be
stratified by type of background therapy (i.e., nusinersen or risdiplam).
Study burden and risks
-The study lasts a total of approximately 76 weeks for patients.
-Additional hospital visits, additional physical tests, including a pregnancy
test.
-A total of approximately 150ml of blood is taken. This amount is not a problem
(for comparison: a blood donation means that 500 ml of blood is taken each
time). Possible side effects of blood tests include fainting, soreness and
tenderness at the injection site and, in rare cases, infection.
-If the study drug does not work for the patient, he/she may see an increase in
his/her disease symptoms.
Binney Street, 3rd Floor 301
Cambridge MA 02142
US
Binney Street, 3rd Floor 301
Cambridge MA 02142
US
Listed location countries
Age
Inclusion criteria
1. Informed consent document signed by the patient if the patient is legally an
adult. If the patient is legally a minor, informed consent document signed by
the patient's parent or legal guardian and patient's oral or written assent
obtained, if applicable and in accordance with the regulatory and legal
requirements of the participating location.
2. Males and females 2 through 21 years old at Screening
3. Estimated life expectancy >2 years from Screening
4. Documented diagnosis of 5q SMA
5. Diagnosed with later-onset SMA (i.e., Type 2 and Type 3 SMA) before
receiving an approved SMN upregulator therapy (i.e., either nusinersen or
risdiplam). Patients who never had the ability to walk independently will be
classified as Type 2. Patients who previously had the ability to walk unaided
will be classified as Type 3.
6. Must be nonambulatory at Screening. Nonambulatory patients must be able to
sit independently (sits up straight with head erect for at least 10 seconds;
does not use arms or hands to balance body or support position) per WHO motor
milestones at Screening
7. Receiving one background therapy for SMA (i.e., either nusinersen or
risdiplam) for the time period specified below and anticipated to remain on
that same treatment throughout the trial
a. If receiving the SMN upregulator therapy nusinersen, must have completed at
least 10 months of dosing (i.e., completed the loading regimen and at least 2
maintenance doses) before Screening
b. If receiving the SMN upregulator therapy risdiplam, must have completed at
least 6 months of dosing before Screening
8. Motor Function Score (HFMSE) >=10 and <=45 at the Screening Visit
9. No physical limitations that would prevent the patient from undergoing motor
function outcome measures throughout the trial
10. Able to receive study drug infusions and provide blood samples through the
use of a peripheral IV or a long-term IV access device that the patient has
placed for reasons independent from the trial (i.e., for background medical
care and not for the purpose of receiving apitegromab in the trial), throughout
the trial
11. Able to adhere to the requirements of the protocol, including travel to the
trial site and completing all trial procedures and trial visits
12. Females of childbearing potential must have a negative pregnancy test at
Screening and agree to use at least 1 acceptable method of contraception
throughout the trial and for 20 weeks after the last dose of study drug. Female
patients who are expected to have reached reproductive maturity by the end of
the trial must agree to adhere to
trial-specific contraception requirements.
Exclusion criteria
1. Received ZOLGENSMA® (onasemnogene abeparvovec-xioi) at any time
2. Previous treatment with apitegromab
3. Prior history of severe hypersensitivity reaction or intolerance to SMN
upregulator therapies
4. Prior history of a hypersensitivity reaction to a mAb or recombinant protein
bearing an Fc domain (e.g., a soluble receptor-Fc fusion protein),
apitegromab, or excipients of apitegromab
5. Require invasive ventilation or tracheostomy
6. Nutritional status that was not stable over the past 6 months and is not
anticipated to be stable throughout the trial or medical necessity for
a gastric/nasogastric feeding tube, where the majority of feeds are given by
this route, as assessed by the Investigator
7. Major orthopedic or other interventional procedure, including spine or hip
surgery, considered to have the potential to substantially limit the
ability of the patient to be evaluated on any motor function outcome measures,
within 6 months before Screening or anticipated during the trial
8. Treatment with other investigational drugs in a clinical trial within 3
months or 5 half-lives, whichever is longer, before Screening
9. Use of valproic acid or hydroxyurea within 90 days before Screening
10. Use of therapies with potentially significant muscle effects (e.g.,
androgens, insulin like growth factor, growth hormone, systemic betaagonist,
botulinum toxin, or muscle relaxants or muscle-enhancing supplements) or
potentially significant neuromuscular effects (e.g.,
acetylcholinesterase inhibitors) other than approved SMN upregulator therapy
within 60 days before Screening
11. Use of systemic corticosteroids within 60 days before Screening. Inhaled or
topical steroids are allowed.
12. Any acute or comorbid condition interfering with the well-being of the
patient within 7 days before Screening, including active systemic
infection, the need for acute treatment, or inpatient observation due to any
reason
13. Severe contractures (National Cancer Institute [NCI] Common Terminology
Criteria for Adverse Events [CTCAE]) or scoliosis (general
guideline for Grade 3) at Screening. Based on clinical judgment, any
contractures or scoliosis present must be stable over the past 6 months,
anticipated to be stable throughout the trial, and not prevent the patient from
being evaluated on any motor function outcome measures
throughout the trial.
14. Use of chronic daytime noninvasive ventilatory support for >16 hours daily
in the 2 weeks before dosing, or anticipated to regularly
receive such daytime ventilator support chronically throughout the trial
15. Pregnant or breastfeeding
16. Any other condition or clinically significant laboratory result or ECG
value that, in the opinion of the Investigator, may compromise safety or
compliance, would preclude the patient from successful completion of the trial,
or interfere with the interpretation of the results
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 | EUCTR2021-005314-34-NL |
| CCMO | NL80453.028.22 |