Neural Stem Cell Treatment for Amyotrophic Lateral Sclerosis (STEMALS) (STEMALS)

Neural Stem Cell Treatment for Amyotrophic Lateral Sclerosis: A Multicenter, Randomized Placebo Controlled and Biological Endpoints Clinical Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Procedure: human Neural Stem Cells (hNSC); Procedure: Saline (Placebo)

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.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Massimo Carella, PhD; Phone Number: +390882835928; Email: m.carella@operapadrepio.it
• Study Contact Backup: Name: CTO Clinical Trial Office; Phone Number: +390882410997; Email: clinicaltrialoffice@operapadrepio.it

Study Locations

• Italy
  • Novara, Italy, 28100
    • Recruiting
    • Centro SLA Azienda Ospedaliera Università Maggiore della Carità
    • Contact: Letizia Mazzini, MD; Phone Number: +39 0321 3733962; Email: ambulatorio.sla@maggioreosp.novara.it
  • Padua, Italy, 35128
    • Not yet recruiting
    • Azienda Ospedaliera di Padova
    • Contact: Gianni Sorarù, MD; Phone Number: +39049-8213645/646; Email: cl.neurologica@aopd.veneto.it
  • Palermo, Italy, 90129
    • Not yet recruiting
    • Azienza Ospedaliera Universitaria - Policlinico "P. Giaccone" Università degli Studi di Palermo
    • Contact: Vincenzo La Bella, MD; Phone Number: +39 091 6555158; Email: info@centroslapalermo.it
  • Foggia
    • San Giovanni Rotondo, Foggia, Italy, 71013
      • Not yet recruiting
      • Casa Sollievo Della Sofferenza IRCCS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: hNSC 20*10^6; Inoculation of 20*10^6 neural stem cells into the right lateral ventricle through a silicone catheter	Procedure: human 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.; Other Names: Injection of human neural stem cells into brain lateral ventricle
Experimental: hNSC 40*10^6; Inoculation of 40*10^6 neural stem cells into the right lateral ventricle through a silicone catheter	Procedure: human 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.; Other Names: Injection of human neural stem cells into brain lateral ventricle
Placebo Comparator: Saline Solution (placebo); Inoculation of saline (placebo) into the right lateral ventricle through a silicone catheter 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 (period of time considered the minimum for a correct clinical evaluation that does not risk having to exclude patients treated with placebo from subsequent treatment with cells due to excessive physical decline), 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	Procedure: Saline (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.; Other Names: Injection of saline into brain lateral ventricle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of treatment	safety assessed with respect to the incidence of treatment-emergent AEs (TEAEs) and serious AEs (SAEs) over the whole study period	From date of enrollment until 12 month.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biological Endpoints	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	Samples for biological endpoints will be taken at treatment, 1, 3, and 6 months after treatment

Collaborators and Investigators

• Sponsor: Casa Sollievo della Sofferenza IRCCS
• Collaborators: Ministry of Health, Italy
• Investigators: Study Director: Angelo L Vescovi, PhD, Scientific Director Fondazione IRCCS "Casa Sollievo della Sofferenza"

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2024
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): September 1, 2027

Study Registration Dates

• First Submitted: March 18, 2024
• First Submitted That Met QC Criteria: March 27, 2024
• First Posted (Actual): April 3, 2024

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: ALS; Biomarkers; Neural Stem Cells; ICV Surgery
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: hNSCALSII

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No