Objectives for both the Treatment Period and Extension Period:Primary Objectives: - To assess safety and tolerability of the study medicine in patients with later onset (e.g., Type 2 and Type 3) spinal muscular atrophy (SMA)- To assess the efficacy…
ID
Source
Brief title
Condition
- Musculoskeletal and connective tissue disorders congenital
- Musculoskeletal and connective tissue disorders congenital
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy:
Cohort 1 (Ambulatory Type 3 Patients):
Primary Efficacy Endpoint:
- Change from Baseline in the RHS total score at Day 364 (Visit 15)
Cohort 2 (Type 2 and nonambulatory Type 3 patients) and Cohort 3 (Type 2
patients):
Primary Efficacy Endpoint:
- Change from Baseline in HFMSE total score at Day 364 (Visit 15)
Safety:
Safety will be evaluated based on occurrence of or changes in the following
parameters:
- Treatment-emergent adverse events (TEAEs) and SAEs
- Vital signs, including blood pressure, heart rate, body temperature, and
respiratory rate
- Height and weight
- Physical examinations
- Laboratory assessments (hematology, serum chemistry, coagulation, urinalysis)
- 12 lead electrocardiogram (ECG)
- Concomitant medications Safety assessments may be revised if any important
safety signals emerge from any ongoing clinical studies (including this study).
Secondary outcome
Cohort 1 (Ambulatory Type 3 Patients)
Secondary Efficacy Endpoints:
- Change from Baseline in the RHS total score at other prespecified timepoints
- Proportion of patients achieving various magnitudes of change in RHS score
from Baseline
- Change from Baseline in 6 Minute Walk Test (6MWT)
- Change from Baseline in 30 Second sit to stand
- Change from Baseline in 10 Meter Walk/Run (from the RHS)
- Change from Baseline in timed rise from floor (from the RHS)
Tertiary Endpoints:
- Change from Baseline in Pediatric Evaluation of Disability Inventory Computer
Adaptive Test (PEDI CAT)
- Change from Baseline in Patient-reported Outcomes Measurement Information
System (PROMIS) Fatigue Questionnaire
Cohort 2 (Type 2 and nonambulatory Type 3 Patients) and Cohort 3 (Type 2
Patients) :
Secondary Efficacy Endpoints:
- Change from Baseline in HFMSE total score at other prespecified timepoints
- Proportion of patients achieving various magnitudes of change in HFMSE score
from Baseline
- Change from Baseline in Revised Upper Limb Module (RULM) total score
- Change from Baseline in number of WHO motor development milestones attained
- Proportion of patients achieving various magnitudes of change in RULM score
from Baseline
- Proportion of patients who attain a new WHO motor development milestone
relative to Baseline
Tertiary Endpoints:
- Change from Baseline in Time to limitation on Endurance Shuttle Nine Hole Peg
Test (ESNHPT) or Endurance Shuttle Box and Block Test (ESBBT)
- Change from Baseline in PEDI-CAT
- Change from Baseline in PROMIS Fatigue Questionnaire
Additional Tertiary Endpoint for Cohort 3:
- Time to therapeutic effect (described in the Statistical Analysis Plan [SAP])
as compared between low and high dose of the study medicine arms
Background summary
Later-Onset Spinal Muscular Atrophy (SMA) is an inherited disease of the motor
nerves (the nerves that send signals from your brain to the muscles) causing
muscle weakness. The study medicine is being developed towards the goal of
treating diseases of muscle atrophy. Muscle atrophy is a condition in which
muscles are smaller and weaker than normal, such as in SMA. There are currently
no approved muscle-directed therapies for the treatment of SMA.
The study medicine is a protein that acts upon a muscle protein called
myostatin. Myostatin is one of the factors that control the size and function
of muscles. Results from animal research studies show that the study medicine
may block myostatin and might cause muscles to grow larger and larger. The
study medicine increased muscle size in healthy mice, rats, and monkeys. In two
animal experiments of mice with SMA, treatment with the study medicine led to
increases in muscle size and strength. These results show that the study
medicine might have potential in treating diseases of muscle atrophy like SMA
in humans.
SRK-015 has not been administrated to children prior to this research study. It
has also not been administrated to any children or adults with SMA prior to
this study.
Study objective
Objectives for both the Treatment Period and Extension Period:
Primary Objectives:
- To assess safety and tolerability of the study medicine in patients with
later onset (e.g., Type 2 and Type 3) spinal muscular atrophy (SMA)
- To assess the efficacy of the study medicine by assessing changes in motor
function outcome measures in 3 separate predefined cohorts
Secondary Objectives:
- To characterize the pharmacokinetics (PK) of the study medicine
- To evaluate the pharmacodynamic (PD) effects of the study medicine
- To evaluate time to therapeutic effect between low and high dose of the study
medicine in a predefined cohort (Cohort 3)
- To evaluate the immunogenicity of the study medicine
- To evaluate the effect of the study medicine on quality of life
Study design
This study will be conducted in approximately 20 study sites across the United
States and Europe to evaluate the safety and efficacy of the study medicine in
later-onset SMA patients (e.g., patients with Type 2 and Type 3 SMA) age 2
through 21 years old. Patients may receive the study medicine on top of an
approved SMA treatment or may receive it as monotherapy. Approximately 55 male
and female patients with later onset SMA will be enrolled across 3 separate
parallel subpopulations subsequently described as cohorts. Patients will
receive the study medicine every 4 weeks during the 52-week Treatment Period,
with patients in Cohorts 1 and 2 directly assigned high dose (20 mg/kg) of the
study medicine and patients in Cohort 3 randomized 1:1 double blind between low
dose (2 mg/kg) and high dose (20 mg/kg) of the study medicine.
Intervention
Treatment Period:
High dose of the study medicine will be 20 mg/kg and low dose will be 2 mg/kg.
Doses will be diluted in normal saline and administered via IV over 2 hours +
10-minute window. If there are no acute reactions following the first two
doses for a patient, and if the Investigator determines that it would be safe
to do so, the infusion duration can be changed to less than two hours but no
shorter than 1 hour. Total study participation for an individual patient will
consist of approximately 4 weeks for Screening, 52 weeks of study visits, if
the patient does not enroll into the Extension Period A, 12 weeks Safety
Follow-up for a total duration of approximately 68 weeks (approximately 16
months).
Extension Period A:
Patient will receive the study medicine by IV infusion in the same manner in
which he/she received the study medicine during his/her participation in the
Treatment Period. Total study participation for an individual patient who
completes both Treatment and Extension Period A will consist of approximately 4
weeks for Screening, 104 weeks of study visits, and 12 weeks Safety Follow-up
for a total duration of approximately 120 weeks (approximately 28 months).
Extension Period B:
Patient will receive the study medicine by IV infusion in the same manner in
which he/she received the study medicine during his/her participation in the
Extension Period A. Total study participation for an individual patient who
completes the Treatment Period and Extension Periods A and B will consist of
approximately 4 weeks for Screening, 156 weeks of study visits, and 12 weeks of
Safety Follow-up for a total duration of approximately 172 weeks (approximately
40 months).
Extension Period C:
Patient will receive the study medicine by IV infusion in the same manner in
which he/she received the study medicine during his/her participation in the
Extension Period B. Total study participation for an individual patient who
completes the Treatment Period and Extension Periods A, B, and C will consist
of approximately 4 weeks for Screening, 208 weeks of study visits, and 12 weeks
of Safety Follow-up for a total duration of approximately 224 weeks
(approximately 52 months).
Study burden and risks
Participation of this study (without enrollment in the Extenstion Period A, B
and C) will comprise approximately 16 months. The total duration of study
participation including all Extension Periods (A, B and C) will be
approximately 52 months. During this study the following procedures will be
performed: Physical exam, vital signs check (including heart rate, blood
pressure, temperature and breathing rate), ECG, several motor function tests,
completion of questionnaires, blood and urine tests (incl. pregnancy test if
applicable), and treatment with the study medicine.
Consequences of these procedures could include: When taking blood samples the
subject may feel pain or be light-headed. Additional bleeding, temporary
discomfort, bruising, and infections (rare) could occur when drawing blood.
During an ECG subjects may experience temporary discomfort (e.g. pulling
hair/skin during the removal of sensors), subjects might develop minor skin
irritation from the ECG patch adhesive. Concerning the examination of motor
functions there is a risk that subjects could fall down/over when attempting to
complete exercises. Regarding the study medicine, 58 healthy individuals have
received the study medicine in a previous clinical trial. The most common
adverse effects observed in this research study were headache (26%), pyrexia
(fever, 24%), sinus infection (22%), nasopharyngitis (common cold, 22%), cough
(22%), vomiting (16%), rash (16%), nausea (14%), fall (14%), scoliosis (12%),
nasal congestion (10%) and dizziness (10%). The majority of these adverse
events were considered mild or moderate in severity.
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Listed location countries
Age
Inclusion criteria
1. Age 5 through 21 years old at the time of screening for Cohorts 1 and 2; Age
2 years old at the time of screening for Cohort 3
2. Estimated life expectancy >2 years from screening
3. 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 patients parent or legal guardian and patients oral or written assent
obtained, if applicable and in accordance with the regulatory and legal
requirements of the participating location
4. Documented diagnosis of 5q SMA
5. Diagnosed as later onset (e.g., Type 2 or Type 3) SMA prior to receiving any
treatment with therapy approved for SMA
6. Non ambulatory 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 World Health Organization (WHO) motor milestones
definition at screening. 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.
7. Ambulatory patients must have the ability to independently ambulate without
aids or orthotics over 10 meters at screening
8. For Cohort 1, Revised Hammersmith Scale (RHS) score no greater than 63 at
screening
9. For Cohorts 2 and 3, Hammersmith Functional Motor Scale Expanded (HFMSE)
score no less than 10 at screening
10. Receiving the same background SMA therapy (e.g., on an approved survival
motor neuron (SMN) upregulator therapy such as nusinersen, or not on any SMA
therapy) for at least 6 months prior to screening and anticipated to remain on
that therapy throughout the duration of the study a. If receiving the SMN
upregulator therapy nusinersen, must have completed the loading regimen and
initiated maintenance dosing (i.e., completed at least one maintenance dose)
with at least 4 weeks after the first maintenance dose having elapsed prior to
screening
11. Nutritional status stable over the past 6 months and anticipated to be
stable throughout the duration of the study
12. Have no physical limitations that would prevent the patient from undergoing
motor function outcome measures throughout the duration of the study
13. Able to receive study drug infusions and provide blood samples through the
use of a peripheral intravenous (IV) or a long-term IV access device that the
patient has placed for reasons independent from the study (i.e., for background
medical care and not for the purpose of receiving SRK-015 in the study),
throughout the duration of the study
14. Able to adhere to the requirements of the protocol, including travel to the
study center and completing all study procedures and study visits
15. For patients who are expected to have reached reproductive maturity by the
end of the study, adhere to study specific contraception requirements
a. Females of childbearing potential (see Section 10.1.7.4 for definition)
must have a negative pregnancy test at screening and agree to employ highly
effective contraceptive
measures (failure rate of 1% or less per year when used consistently and
correctly) for the duration of the study and for 18 weeks following the last
dose of study drug. Effective
contraception methods are restricted to combined (estrogen and progestogen
containing) hormonal contraception associated with inhibition of ovulation
(oral,
intravaginal, transdermal), progestogen-only hormonal contraception
associated with inhibition of ovulation (oral, injectable, implantable),
intrauterine device (IUD), intrauterine
hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized
partner, or sexual abstinence. In the context of this guidance, sexual
abstinence is considered a highly effective
method only if defined as refraining from hetrosexual intercourse during
the entire period of risk associated with the study treatments. The reliability
of sexual abstinence needs to be
evaluated in relation to the duration of the clincial trial and the
preferred and lifestyle of the patient.
b. Male patients with female partners of childbearing potential must be
abstinent or agree to employ the use of a condom with or without spermicide
throughout the duration of the
study and for 18 weeks following the last dose of study drug.
Exclusion criteria
1. Use of tracheostomy with positive pressure
2. Use of chronic daytime non invasive ventilatory support for >16 hours daily
in the 2 weeks prior to dosing, or anticipated to regularly receive such
daytime ventilator support chronically over the duration of the study
3. Any acute or comorbid condition interfering with the well being of the
patient within 14 days of screening, including active systemic infection, the
need for acute treatment or inpatient observation due to any reason
4. Severe scoliosis and/or contractures at screening. Based on clinical
judgment, any scoliosis or contractures present must be stable over the past 6
months, anticipated to be stable for the duration of the study and not prevent
the patient from being evaluated on any functional outcome measures throughout
the duration of the study.
5. Pregnant or breastfeeding
6. 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 functional outcome measures, within 6 months
prior to screening, or anticipated for the duration of the study
7. Prior history of a hypersensitivity reaction to a monoclonal antibody (mAb)
or recombinant protein bearing an Fc domain (such as a soluble receptor-Fc
fusion protein), SRK-015, or excipients of SRK-015
8. Use of systemic corticosteroids within 60 days prior to screening. Inhaled
or topical steroids are allowed.
9. Treatment with investigational drugs within 3 months or 5 half-lives,
whichever is longer prior to screening
10. Use of therapies with potentially significant muscle effects (such as
androgens, insulin-like growth factor, growth hormone, systemic beta-agonist,
botulinum toxin, or muscle relaxants or muscle-enhancing supplements) or
potentially significant neuromuscular effects (such as acetylcholinesterase
inhibitors) other than approved SMN upregulator therapy within 60 days prior to
screening.
11. Use of valproic acid within 60 days prior to screening.
12. Patient has any other condition, which in the opinion of the Investigator
may compromise safety or compliance, would preclude the patient from successful
completion of the study, 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 | EUCTR2018-004383-65-NL |
| ClinicalTrials.gov | NCT03921528 |
| CCMO | NL69360.041.19 |