Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04690998 |
| Other study ID # |
2020-54 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
July 13, 2021 |
| Est. completion date |
July 13, 2025 |
Study information
| Verified date |
July 2023 |
| Source |
Assistance Publique Hopitaux De Marseille |
| Contact |
Shahram Attarian, Pr |
| Phone |
33491386579 |
| Email |
shahram.attarian[@]ap-hm.fr |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The "SMOB" project intends to contribute to fill the gap with reliable and operational
outcome measures for type III and IV SMA. In analysing the reliability in imaging (spinal and
muscular), electrophysiology analysis (MUNIX), and evaluate the evolution of respiratory
function for 50 patients' cohort. The investigators would also take the opportunity to
collect biologic samples in order to investigate genetic markers and to assess quality of
life of patients by QoL-gNMD questionnaire. The investigators aim to build a database that
will allow us to evaluate the effectiveness of a new therapy for adult SMA patients by
studying the natural history of the disease. The investigators have distributed the various
expertise in Work Package where several centers are involved.
This study is original in that it evaluates the parameters of qMRI and MUNIX in correlation
with blood biomarkers. To our knowledge, there are no quantitative MRI (spinal and muscular)
biomarkers and/or electrophysiological (MUNIX technique) highlighted for tracking the
progression of the adult form of SMA type III and IV. This pilot study would allow
identification of predictive markers of the disease progression, and to have validated,
sensitive to change and relevant measurement tools that could be used as endpoints in future
therapeutic trials.
Description:
Spinal muscular atrophy is an autosomal recessive neurodegenerative disease characterized by
degeneration of spinal cord motor neurons, atrophy of skeletal muscles, and generalized
weakness. It is caused by homozygous disruption of the survival motor neuron 1 (SMN1) gene by
deletion, conversion, or mutation. Spinal muscular atrophy (SMA) is a genetic disease that
affects mostly children but also some adults. Motor neuron loss often results in severe
muscle weakness causing affected infants to die before reaching 2 years of age. There are
types I, II, and III that affect children, and Type IV that affects adults. The prevalence of
this rare disease is around 1/30 000 births.The disease is characterized by a slowly
progressive muscle weakness over many years in patients with a milder form.
SMA is caused by the loss of SMN1 and the retention of at least 1 copy of a highly homologous
SMN2. An alternative splicing event in the pre-mRNA arising from SMN2 results in the
production of low levels of functional SMN protein. Onset and severity of disease, and
therefore type, correlate mainly with SMN2 copy number (and theoretically with SMN protein
level) providing a molecular basis for the classification of the different subtypes of SMA.
Type III patients have 3-4 copies, and patients with type 4 usually have 4 copies or more.
About 30% of patients have type III SMA, which is associated with onset between ages 18
months and adulthood. By definition standing or walking without support is achieved, although
many patients lose these abilities later with disease progression (Zerres.K et al 1995).
Patients usually present with symptoms of falls, difficulty climbing stairs, and other
features of proximal weakness and respiratory deficit. Abnormal gait characteristics are
common in order to compensate for weakness, and many patients are able to continue ambulation
despite severe weakness. Foot deformity may be seen in ambulatory patients. Lifespan is
normal in SMA type III. Some classifications of SMA include an additional disease subtype at
the mild end of the continuum. In this case, patients may be classified as having type IV
SMA. Patients with type IV, representing less than 5% of SMA, are ambulatory and have the
mildest form of SMA. The presentation is very similar to type III and is distinguished solely
on later onset during adulthood (Zerres K. et al 1995, Piepers S. et al 2008). Though onset
of type IV is not clearly defined, it is often considered to be at age 30 or later. The
remarkably slow rate of progression of late onset SMA types IIIb and IV underlines that more
sensitive tools are needed to monitor muscle strength in clinical trials.
Documenting functional status in SMA is important, since all patients show limitations in
daily functioning and the preservation or improvement is the goal for pharmacological
intervention. Regardless, precisely designed supportive, rehabilitative, and palliative care
can partly reduce the disease burden and alter the natural history. Treatment is designed to
address the primary and secondary effects of muscle weakness and should include management of
pulmonary complications, nutritional and gastrointestinal support, orthopedic care,
rehabilitative interventions, and end-of-life care. Standards of care for SMA are
established, but there is need for improved and more specific directives in this regard (Wang
CH et al 2007). It is important to understand the expected natural history of SMA to
anticipate and stratify risk, to monitor function with appropriate measures, to determine the
appropriate treatment options, and to delivery timely intervention. Proactive care and
treatment decision-making by the treatment team and family are of utmost importance.
Preclinical progress in the SMA field has been rapid since the identification of SMN1 as the
responsible gene in 1995 and by the creation of the first mouse model in 2000 (Hsieh-Li HM et
al, 2000).
Several clinical therapeutic trials have been performed in SMA without success. The first
very successful therapies in murine models of SMA were published in 2010 using gene therapy
to replace the SMN1 gene (Foust KD et al, 2010). Later a phase 1 trial was conducted using
systemic delivered AAV9 gene therapy to replace SMN1 in infants with SMA type I. A single
intravenous infusion of adeno-associated viral vector containing DNA coding for SMN resulted
in longer survival, superior achievement of motor milestones, and better motor function than
in historical cohorts (Mendell. R et al, 2017). More recently, development of antisense
oligonucleotide therapies that can modify SMN2 splicing to include exon 7 and produce
increased amounts of full length SMN protein has shown promising results. Nusinersen is an
antisense oligonucleotide. It has been developed for the treatment of spinal muscular atrophy
(SMA). In the CHERISH trial, among children with later onset SMA, significant improvement in
motor function was observed with Nusinersen treatment as compared with a sham procedure.
Persons with later-onset SMA and their caregivers indicated that stabilization of their
current state would meet their therapeutic expectations and represent a clinically meaningful
response. In this trial, as in the ENDEAR trial for infantile-onset SMA (most likely to be
classified as SMA type 1), they found that Nusinersen had the capacity to produce meaningful
changes in the clinical course of SMA. In this trial, more than half the children in the
Nusinersen group had an increase from baseline to month 15 in the Hammersmith Functional
Motor Scale-Expanded (HFMSE) score of at least 3 points (i.e., a clinically meaningful
improvement), which is uncommon among children with later-onset SMA (Mercuri E. et al, 2018).
This trial had some limitations, no adult form of SMA was considered. In the trial, 16% of
the enrolled children were 6 years of age or older. The results reported are consistent with
the results of previous open-label studies that enrolled children up to 15 years of age. The
studies showed that Nusinersen had positive effects in populations of children with SMA type
II or III that were broader and more heterogeneous than the population enrolled in this
trial. That is why it is important to explore the Nusinersen effects on type III and IV and
allow adult patients to benefit from this new therapy. For that it is essential to have
efficient biomarkers for evaluation of efficiency of Nusinersen as it remains somewhat
controversial given its high price and its highly invasive administration. In this
therapeutic evaluation context, the choice of outcome measures had a great importance.
Moreover, although advances have been made on SMA pathogenesis, there still are unknown
factors that could explain the variability of the disease's severity among patients.
The "NH-SMA" project intends to contribute to fill the gap with reliable and operational
outcome measures for type III and IV SMA. In analysing the reliability in imaging (spinal and
muscular), electrophysiology analysis (MUNIX), and evaluate the evolution of respiratory
function for 50 patients' cohort. The investigators would also take the opportunity to
collect biologic samples in order to investigate genetic markers and to assess quality of
life of patients by QoL-gNMD questionnaire. The investigators aim to build a database that
will allow us to evaluate the effectiveness of a new therapy for adult SMA patients by
studying the natural history of the disease. The investigators have distributed the various
expertise in Work Package where several centers are involved.
This study is original in that it evaluates the parameters of qMRI and MUNIX in correlation
with blood biomarkers. To our knowledge, there are no quantitative MRI (spinal and muscular)
biomarkers and/or electrophysiological (MUNIX technique) highlighted for tracking the
progression of the adult form of SMA type III and IV. This pilot study would allow
identification of predictive markers of the disease progression, and to have validated,
sensitive to change and relevant measurement tools that could be used as endpoints in future
therapeutic trials.
The primary objective is to identify potential markers (clinical, biological, genetic,
imaging) of the health status evolution The health evolution will be assessed at 6, 12, 18
and 24-month post-inclusion. The primary point is the 24-month follow-up. The other points
will be retained as secondary points.
The health status evolution will be assessed using
- Clinical examination :
- MFM-32 (gold standard, Motor Function Measure), RULM (Revised Upper Limb Module) HFMSE
(Hammersmith Functional Motor Scale Expanded), SMAFRS (spinal muscular atrophy
functional rating scale)
- Muscle strength assessment (QMT)
- gait speed, 30s sit to stand, climb 4 stairs
- Evaluation of Respiratory Functions
- Quality of life, pain, and fatigue assessment: QoL-NMD-V1, EVA, EVN, FSS
- Imagery: Muscular, spinal and cranial MRI
- Electrophysiological examination
- Biological and biochemical analyses: blood test samples, NF dosage, genetics,
proteomics, biobanking The main analyses currently used to determine the patient status
are the clinical examination, especially the MFM-32 score, which is the gold standard,
the RULM and the evaluation of the respiratory functions. The other analyses will bring
supplementary data. Their comparison to the usual analyses will allow us to see if it is
possible to detect more subtle changes in the patient status.
The secondary objectives are to identify potential markers (clinical, biological, genetic,
imaging) of the treatment response in the subgroup of patients who will be treated The
treatment response will be assessed at 6, 12, 18 and 24- month post-inclusion.
The treatment response will be assessed This study is a multicenter, prospective study, to
follow for 24 months a cohort of 100 patients aged from 18 to 70 and suffering from type III
and IV SMA.
The choice of a prospective study is most likely to fulfill the objectives. Five evaluation
visits are planned at D0, M6, M12, M18 and M24. Two years follow-up is necessary because of
the variability and the rate of progression of this chronic disease. This period is also
appropriated to better estimate the clinically meaningful difference of the outcome measures
studied. Thus, a 24 month- follow-up will be conducted with a visit every one year. An
inter-visit questionnaire will be completed by phone once a year between 2 visits, to have a
more regular follow-up of the disease evolution and to minimize the number of patients lost
to follow-up.
100 patients will be included. The investigators estimate than 70 will be able to walk
independently and 30 in wheelchairs. About 40 type III patients will be treated with
Nusinersen during the 2 years follow-up and won't be evaluated for natural history of SMA.
The sample size will allow to approximate pertinent odd ratios regarding the primary (health
status evolution) and the secondary (treatment response) objectives.
The study will assess markers of 1) health status evolution; 2) treatment response.
The health status evolution will be assessed at 6, 12, 18, and 24-month post-inclusion. The
health status will be measured from many parameters (Clinical examination, Imagery,
Electrophysiological examination Biological and biochemical analyses) The treatment response
will be assessed in the subgroup of treated patients, at 6- 12- 18- and 24-month
post-inclusion. The response treatment will be assessed through the improvement of clinical
scores, and quality of life Predictive biomarkers of disease progression of type III and IV
SMA will be evaluated from the baseline to the end of the study
It is expected that this study will help to identify quantitative reliable markers that will
allow a better understanding of the disease progression and a better management and patient
follow-up.
