Amyotrophic Lateral Sclerosis
Conditions
Keywords
Neural Stem Cells, ALS, Biomarkers, ICV Surgery
Brief summary
A Not for Profit Phase II Study to Evaluate Safety, Efficacy and Biomarkers secondary endpoints of Human Neural Stem cell intracerebroventricular transplantation in amyotrophic lateral sclerosis patients: a randomized, placebo controlled, triple blind study. This is an approximate 24-months study (PHASE B) consisting, per patient, of a 30-day screening period, 12-month enrollment and follow up period. A preliminary 3+3 dose-escalation open-label phase (PHASE A) will be performed in order to test the toxicity of the two proposed cell doses. The study will be stopped when all the subjects included in the treatment period complete the study visits. The study uses an ATMP, for that reason all the patients follow up will be prosecuted long life.
Detailed description
Phase A: Open, monocentric safety, dose-finding study: The hNSCs will be produced by the UPTA (Unità Produttiva per Terapie Avanzate) of Casa Sollievo della Sofferenza according to GMP guidelines and injected using an Ommaya reservoir which will be removed immediately after the transplant procedure. The reservoir consists of an indwelling ventricular catheter with a dome-shaped collapsible silicone reservoir port positioned under the scalp. The distal end of the catheter is surgically positioned into the ipsilateral ventricle and connected to the reservoir. Six patients affected by ALS will be consecutively enrolled after pre- and screening visits. Thereafter, the first three patients will receive 20 million of hNSCs. If none of the three patients will present a serious adverse event classified as related to the study treatment, the dose level will be escalated up to 40 million of hNSCs for the next and last cohort of three patients. An Independent Data Safety Monitoring Board (DSMB) will oversee the safety of the Study Subjects on an ongoing basis, will review all safety data and issue a final recommendation at the end of this phase. Phase B: randomized, controlled vs placebo, in three arms, with two different doses of 20 and 40 \*10\^6 cells transplanted using an Ommaya reservoir. The reservoir will be placed to all recruited patients in a first surgical session, after randomization half of the subjects will receive the drug product (further randomized for doses) and half the placebo. After three months, patients that already received cells will also be infused with placebo while the others will be randomized and transplanted with one of the two cell doses previously mentioned. This secondary randomization will be performed to provide experimental treatment to all patients and is not intended as a second stage of a cross-over study. In the second surgical session the Ommaya reservoir will be removed and patients will be monitored for 3 months after that.
Interventions
PROCEDUREhuman Neural Stem Cells (hNSC)
The patient is placed on a regular operating room table with or without rigid head fixation. Procedure will be performed whether under general anesthesia or sedation and local anesthesia. Image guidance will be registered using the frameless stereotactic AxiEM system. Image guidance will be used to perform ventricular cannulation with the catheter passed over an electromagnetic-tipped stylet, which is recognized and tracked by the navigation system. The correct placement of the catheter is verified by the egress of CSF. Finally the electromagnetic stylet will be removed and a Rickam reservoir connect to ventricular catheter. Operative time will be about 30 minute. A post-operative CT scan will be obtained in all patients to confirm the catheter position.
PROCEDURESaline (Placebo)
The patient is placed on a regular operating room table with or without rigid head fixation. Procedure will be performed whether under general anesthesia or sedation and local anesthesia. Image guidance will be registered using the frameless stereotactic AxiEM system. Image guidance will be used to perform ventricular cannulation with the catheter passed over an electromagnetic-tipped stylet, which is recognized and tracked by the navigation system. The correct placement of the catheter is verified by the egress of CSF. Finally the electromagnetic stylet will be removed and a Rickam reservoir connect to ventricular catheter. Operative time will be about 30 minute. A post-operative CT scan will be obtained in all patients to confirm the catheter position.
Sponsors
Ministry of Health, Italy
Casa Sollievo della Sofferenza IRCCS
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
In order to blind also the statistician that will analyse the results the protocol has been designed as a triple-blinded protocol. This means that both the researchers, which include neurologist, neurosurgeon and biologist, as well as the patients and the statisticians are unaware of whether the participant received the treatment or the placebo (only IMP Manufacturer QP is unblinded since release the cell drug to the use in the surgery room)
Intervention model description
This is an approximate 24-months triple-blinded, randomized, controlled vs placebo, in three arms study (PHASE B). A preliminary 3+3 dose-escalation open-label phase (PHASE A) will be performed in order to test the toxicity of the two proposed cell doses. In the phase B three arms will be: 1) hNSCs 20 milion cells 2) hNSCs 40 milion cells 3) Saline (comparator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Patient provides written informed consent, informed consent signature collection prior to any study procedure (patient has good acceptance and understanding of the informed consent); 2. Definite, probable diagnosis according to the revised El Escorial criteria; 3. Age: 18-65 years; 4. FVC \>70%; 5. Onset ≤ 24 months; 6. Patients with an ALSFRS-R score of at least 26; overall, including a score of at least 2 on each of the 1-9 ALSFRS-R individual component items and of at least 3 of the 10-12 individual components items; 7. Evidence of fast progression of the disease. We exclude slow progressors at the time of screening defined as Patient with an ALSFRS-R total score progression between onset of the disease and screening of \< 0.3 per month. We document the fast progression of the disease defined as ALSFRS-R total score decrease of ≥ 1 point per month during a 12 week run-in period between screening and randomization; 8. Patient should be on a stable dose of Riluzole for \> 30 days from pre-screening visit or not taking riluzole at all, nor plan to begin riluzole during the study period; 9. Patient is medically able to tolerate transient immunosuppression regimen; 10. Presence of a willing and able caregiver who understands the need to attend all follow-up visits, even if mobility declines.
Exclusion criteria
1. Psychiatric disease or other neurological diseases different from ALS; 2. Evidence of any concurrent illness or treatments limiting the safety to participate or any condition that the neurosurgeon feels may pose complications for the surgery; 3. Cancer within the previous 10 years; 4. Immunosuppressive therapy within 12 weeks of screening; active autoimmune disease or infection (including hepatitis B, hepatitis C, or HIV); 5. Cognitive impairment; 6. Contraindications to perform MRI scans, CSF withdrawal and Skin biopsy; 7. Patient unable to understand informed consent form; 8. Pregnancy and breast feeding; 9. Patient has been treated previously with any stem cell or somatic cells therapy; 10. Patient has participated in another clinical treatment trial or received other experimental medications outside of a clinical trial within 1 month prior to start of this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety of treatment | From date of enrollment until 12 month. | safety assessed with respect to the incidence of treatment-emergent AEs (TEAEs) and serious AEs (SAEs) over the whole study period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Biological Endpoints | Samples for biological endpoints will be taken at treatment, 1, 3, and 6 months after treatment | To evaluate the biological activity of hNSC treatment by measuring the levels of selected pharmacodynamics biomarkers in CSF and serum. Data will be statistically assessed for significance by either Student t test or analysis of variance as applicable. A p value of less than 0.05 will be considered statistically significant. Candidate markers include: lNf, GFAP, NF1, VEGF, Osteopontin, CXCL13, Cystatina, MCP-1 BDNF, YKL-40, IL-6, TNF-a, IL-17, TDP43 TAU In parallel to the clinical evaluation of hNSCs efficacy we will also develop patient-specific cell models in order to individuate molecular and cellular mechanisms supporting the putative therapeutic action of hNSCs treatment. These models will be derived from blood or skin cells of the patients recruited in the trial in order to produce iPS cells, then differentiated in NSCs. disease |
Countries
Italy
Contacts
Primary ContactMassimo Carella, PhD
Backup ContactCTO Clinical Trial Office
Outcome results
None listed