| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Spinal Muscular Atrophy (SMA) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Spinal Muscular Atrophy (SMA) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041582 |
| E.1.2 | Term | Spinal muscular atrophy |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the efficacy of taldefgrobep alfa in participants who are already taking a stable dose
of nusinersen or risdiplam or have a history of onasemnogene abeparvovec-xioi, compared to
placebo, measured by change in the 32 item Motor Function Measure (MFM-32) total score
between Baseline and Week 48 |
|
| E.2.2 | Secondary objectives of the trial |
- To compare the efficacy of taldefgrobep alfa to placebo using the Revised Upper Limb
Module (RULM).
-To compare the efficacy of taldefgrobep alfa to placebo using the Revised Hammersmith
Scale (RHS).
-To assess the safety and tolerability of taldefgrobep alfa as reflected by new or worsening lab
abnormalities, treatment-related adverse events (AEs), serious AEs, and AEs leading to
discontinuation.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed Written Informed Consent
a. Written informed consent/assent must be obtained from the participant in accordance
with requirements of the study center’s institutional review board (IRB) or ethics
committee, prior to the initiation of any protocol-required procedures.
b. As applicable according to age, the participant is able to understand the Informed Assent
Form (IAF) and the participant’s parent(s)/legal representative(s) (according to local
regulations) are/is able to read and understand the Informed Consent Form (ICF).
c. The participant has signed the IAF and the participant’s parent(s)/legal representative(s)
(according to local regulations) have/has signed the ICF prior to the conduct of any
study-specific procedures, as applicable according to age.
d. The participant and the participant’s parent(s)/legal representative(s) (as required
according to local regulations) are/is willing and able to attend protocol-specified study
appointments within the specified time windows.
e. The participant must be able to understand and follow instructions and be willing to
complete all assessments under supervision of legal representative(s) as required by the
protocol.
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2. Participants must agree to provide all requested demographic information (i.e. gender, race).
3. Target Population
a. Male and female participants 4 years to 21 years of age at the time of Screening.
b. Spinal Muscular Atrophy confirmed by genetic diagnosis of 5q-autosomal recessive
SMA as well as SMN2 copy number (genetic diagnosis and SMN2 copy number
confirmed with documentation either prior to enrollment from previous testing or
confirmed during during study)
c. Ambulant or non-ambulant
i. Ambulant defined as:
(1) Able to walk/run 10 meters in 30 seconds at screening
Participants who are unable to meet ambulatory criteria may still be enrolled if
they meet other criteria but would be considered non-ambulant
ii. Non-ambulant defined as all of the following:
(1) Unable to able to walk/run 10 meters in 30 seconds at screening;
(2) 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); and
(3) RULM entry item A score of 2.
d. Treated with an SMA disease-modifying therapy and anticipated to remain on that same
treatment regimen and dose throughout the trial, including the following:
i. a stable regimen of nusinersen for 6 months prior to Screening;
ii. a stable regimen of risdiplam, for 6 months prior to Screening; and/or
iii. a single dose of onasemnogene abeparvovec, received at least 2 years prior to
Screening.
e. MFM32 Total Score <90% out of 100% (achieved by a total mark raw score of ≤86 out
of 96) at Screening
f. Be able to complete all study procedures, measurements (including functional
assessments) and visits and parent or guardian and participant has adequately supportive
psychosocial circumstances, in the judgment of the Investigator
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g. Have an estimated life expectancy of greater than 2 years from Screening, in the
judgment of the Investigator
h. Must have reliable caregiver to accompany participant to study visits, with the
consistency of caregiver completing the caregiver assessments at Baseline, Week 24 and
Week 48/Early Discontinuation, when possible. Caregiver must be able to read,
understand, and speak local language fluently to ensure comprehension of informed
consent and protocol-specified assessments. Caregiver must also have frequent contact
with participant and be willing to monitor the participant’s health and concomitant
medications throughout the study
i. Participants should maintain their regular physical therapy and occupational therapy
programs and keeping the schedule as stable as possible throughout the trial.
4. Women of Childbearing Potential
a. For participants who have reached reproductive maturity, satisfy study contraceptive
requirements
b. WOCBP must have a negative serum pregnancy test at Screening and a negative urine
pregnancy test within approximately 24 hours prior to dosing at Baseline/Randomization.
They must also comply with measures to prevent pregnancy and restrictions on egg
donation (Section 4.5).
5. Men of Childbearing Potential
a. They must also comply with measures to prevent pregnancy and restrictions on sperm
donation (Section 4.6) |
|
| E.4 | Principal exclusion criteria |
1. Participation in any other investigational clinical trial while participating in this clinical trial
with the exception of registry and natural history studies
regarding investigational drug trials.
2. Receiving or have received previous administration of anti-myostatin therapies
3. Weight <15 kg
4. Medical History and Concurrent Diseases
a. Respiratory insufficiency, defined by the medical necessity for invasive or non-invasive
ventilation for daytime treatment while awake (use overnight or during daytime naps is
acceptable)
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b. Hospitalization for a pulmonary event within the last 2 months or planned hospitalization
at the time of screening
c. History of spinal fusion within 6 months prior to screening. Note: MAGEC rod nonsurgical adjustments are allowed during the study.
d. 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 participant from being evaluated
on any functional outcome measures throughout the duration of the study
e. Past surgery for scoliosis or hip fixation in the 6 months preceding screening or planned
during the study.
f. Immobilization, surgical procedures, fracture, or trauma to the upper or lower limbs
within 90 days prior to screening
g. Presence of an untreated or inadequately treated active infection requiring systemic
antiviral or antimicrobial therapy at any time during the screening period
h. Presence of an implanted shunt for the drainage of CSF or an implanted central nervous
system (CNS) catheter
i. History of bacterial meningitis
j. Treatment with another investigational drug within 90 days prior to Screening or 5 halflives (whichever is longer). If treatment was with a currently approved medication, this
timeframe is not applicable. If the participant is in a study for an approved medication
that does not include procedures that could impact blinding (such as drawing blood for
biomarkers), this can be assessed on a case by case basis.
k. 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 participant to undergo study procedures.
l. The participant has reported current use of, or has tested positive at the Screening visit
for, drugs of abuse (amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine,
methadone, opiates, MDMA, methamphetamines, oxycodone, phencyclidine (PCP).
Detectable levels of these compounds are exclusionary with the following exception:
i. Participants who are positive for amphetamines, and who are prescribed an
amphetamine for an approved indication (e.g. ADHD) will be allowed into the study
at the Investigator’s discretion. This determination by the Investigator must be well
documented in the participant’s source medical records. The stimulant dose must be
stable from 3 months prior to baseline until the end of treatment visit occurs.
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m. The participant has a history of cancer.
n. Unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular system diseases as
considered to be clinically significant by the Investigator.
o. History of spinal contusion in the 6 months preceding screening
Any major illness within one month before the screening examination or any febrile illness
within one week prior to screening and up to first dose administration.
6. All vaccines should not be given within 2 weeks of the first dose.
7. The participant has a history of intolerance to venipuncture and/or difficult venipuncture
access.
8. ECG and laboratory test findings:
a. Clinically significant abnormality identified on the medical or laboratory evaluation. A
participant with a clinical abnormality or laboratory parameters outside the reference
range may be included only if the investigator considers the finding not clinically
significant, that it will not introduce additional risk factors, nor interfere with the study
procedures
Ascertained or presumptive hypersensitivity (e.g., anaphylactic reaction) to taldefgrobep alfa,
or to the constituents of its formulation.
10. For WOCBP, positive serum Beta-hCG which is indicative of pregnancy (and not false
positive) at Screening or a positive urine pregnancy test at Baseline.
11. Breastfeeding
12. Prisoners or participants who are involuntarily incarcerated.
13. Participants who are compulsorily detained for treatment of either a psychiatric or physical
(e.g., infectious disease) illness.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Change from baseline in the MFM-32 at Week 48
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Double blind phase: Baseline, visit 5, visit 6, visit 7, visit 8
|
|
| E.5.2 | Secondary end point(s) |
- Change from baseline in the RULM at Week 48
- Change from baseline in the RHS at Week 48
- Frequency of unique subjects with: new or worsening lab abnormalities, treatment related
adverse events, serious adverse events, and adverse events leading to discontinuation.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Double blind phase:
RULM: Baseline, visit 5, visit 6, visit 7, visit 8
RHS: Baseline, visit 5, visit 6, visit 7, visit 8 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Double-blind with Open label follow-up |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 18 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 18 |
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