<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03282760</url>
  </required_header>
  <id_info>
    <org_study_id>NSC SPMS</org_study_id>
    <secondary_id>2015-004855-37</secondary_id>
    <nct_id>NCT03282760</nct_id>
  </id_info>
  <brief_title>Safety Study of Human Neural Stem Cells Injections for Secondary Progressive Multiple Sclerosis Patients</brief_title>
  <acronym>NSC-SPMS</acronym>
  <official_title>A Phase I Multicenter Study of Allogenic, Intracerebroventricular Human Neural Stem Cells Transplantation for the Experimental Treatment of Secondary Progressive Multiple Sclerosis Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Casa Sollievo della Sofferenza IRCCS</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Associazione Revert ONLUS</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Neurocenter of Southern Switzerland</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Fondazione Cellule Staminali</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Casa Sollievo della Sofferenza IRCCS</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This will be a phase I, open, multicenter, international study performed by 3 participating&#xD;
      centres across two countries (Italy and Switzerland). Fifteen to 24 patients affected by SPMS&#xD;
      will be enrolled, according to a &quot;standard&quot; phase I design over 18 months. All patients will&#xD;
      enter a 3 months run in phase. Thereafter they will receive one of four different doses of&#xD;
      allogenic hNSCs (dose A=5 millions hNSCs; dose B=10 millions hNSCs; dose C=16 millions hNSCs;&#xD;
      dose D=24 millions hNSCs). Following hNSCs injection, all SPMS patients will receive&#xD;
      immunosuppression with tacrolimus for 6 months. Patients will be clinically followed monthly&#xD;
      for 1 year and then every 6 months for the 5 years following the study completion (possibly&#xD;
      all life long).&#xD;
&#xD;
      MRI assessments will be performed monthly for the first 6 months and then every 3 months for&#xD;
      5 years following the study completion.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 9, 2017</start_date>
  <completion_date type="Actual">May 29, 2021</completion_date>
  <primary_completion_date type="Actual">May 29, 2021</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>Fifteen to 24 patients affected by SPMS will be enrolled, according to a &quot;standard&quot; phase I design over 18 months. All patients will enter a 3 months run in phase. Thereafter they will receive one of four different doses of allogenic hNSCs (dose A=5 millions hNSCs; dose B=10 millionshNSCs; dose C=16 millions hNSCs; dose D=24 millions hNSCs).</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of Treatment Emergent AE</measure>
    <time_frame>1 year</time_frame>
    <description>To Evaluate the Feasibility, Safety and Tolerability of intracerebroventricular injection of allogenic hNSCs</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percentage of Mortality in treated patients</measure>
    <time_frame>1 year</time_frame>
    <description>Percentage of subjects (%) with death due to procedure (mortality correlated to treatment)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Functional disability</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>this will be measured by the change of the Expanded Disability Scale (EDSS-disability score about pyramidal, cereberral, brainstem, sensory, bowel and bladder, visual, cerebral Functional Systems) during the study period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Functional disability</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>this will be measured by the change of the the Multiple Sclerosis Functional Composite (MSFC-scores about upper extremity function, ambulation and cognitive function) during the study period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Activity of Cognitive function</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>This will be measured as the mean change of the score of the RAO Brief Repeatable Battery of Neuropsychological Test, during the study period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapses Rate</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>Relapses will be measured by the change in EDSS scale</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapses Rate</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>Relapses will be measured by the Imaging evaluations</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MS Biomarkers</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>Investigation of potential candidate biomarkers able to monitor disease activity and predict clinical course in MS (Neurofilaments)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Alteration in Neurophysiological parameters</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>Assessed by Evoked Potentials.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Secondary-progressive Multiple Sclerosis</condition>
  <arm_group>
    <arm_group_label>Human Neural Stem Cells Suspension</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intraventricular injections of Allogenic human Neural Stem Cells (hNSCs) in four different dosages (5, 10,16 or 24 millions)</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Human Neural Stem Cells</intervention_name>
    <description>Allogenic human Neural Stem Cells (hNSCs) in four different dosages (5, 10, 16 or 24 millions). hNSCs are produced by the Laboratorio Cellule Staminali of Terni according to GMP guidelines and are obtained from brain specimens of several fetal human donors from spontaneous miscarriages occurred after the 8th week after conception.</description>
    <arm_group_label>Human Neural Stem Cells Suspension</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. SPMS with progressive accumulation of disability after initial relapsing course, with&#xD;
             or without disease activity (Lublin et al. 2014).&#xD;
&#xD;
          2. EDSS ≥ 6.5 and ≤ 8&#xD;
&#xD;
          3. EDSS progression over the 2 years prior to study start of ≥ 1.0 point for patients&#xD;
             with EDSS =6.5 at the time of inclusion , and of ≥ 0.5 points for patients with EDSS &gt;&#xD;
             6.5 at the time of inclusion&#xD;
&#xD;
          4. Age ≥ 18 and ≤ 60 years&#xD;
&#xD;
          5. Failure of best medical treatment as judged by the treating neurologist and declared&#xD;
             absence of therapeutic alternatives&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Neurological conditions other than MS.&#xD;
&#xD;
          2. Psychiatric disorders, severe cognitive decline and personality and relational&#xD;
             disorders.&#xD;
&#xD;
          3. History or known presence of significant systemic, infectious, oncologic or metabolic&#xD;
             disorders.&#xD;
&#xD;
          4. Presence of any other autoimmune disease.&#xD;
&#xD;
          5. Chronic infections (HBV, HCV, HIV, tuberculosis).&#xD;
&#xD;
          6. Inability to perform MRI scans.&#xD;
&#xD;
          7. Immunomodulant/immunosuppressive treatments in the last 6 months before inclusion.&#xD;
&#xD;
          8. Current participation to other experimental studies.&#xD;
&#xD;
          9. Inability to provide informed consent.&#xD;
&#xD;
         10. Any contra-indication to lumbar puncture and the surgical procedure (e.g. use of&#xD;
             anticoagulants)&#xD;
&#xD;
         11. Pregnancy and breast feeding.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Angelo L Vescovi, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Casa Sollievo della Sofferenza IRCCS</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Casa Sollievo della Sofferenza - IRCCS</name>
      <address>
        <city>San Giovanni Rotondo</city>
        <state>Foggia</state>
        <zip>71013</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliera Santa Maria di Terni</name>
      <address>
        <city>Terni</city>
        <zip>05100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Neurocentro della Svizzera Italiana, Istituto di Neurosienze cliniche della svizzera italiana, Centro sclerosi Multipla</name>
      <address>
        <city>Lugano</city>
        <zip>6900</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
    <country>Switzerland</country>
  </location_countries>
  <reference>
    <citation>Gelati M, Profico D, Projetti-Pensi M, Muzi G, Sgaravizzi G, Vescovi AL. Culturing and expansion of &quot;clinical grade&quot; precursors cells from the fetal human central nervous system. Methods Mol Biol. 2013;1059:65-77. doi: 10.1007/978-1-62703-574-3_6.</citation>
    <PMID>23934834</PMID>
  </reference>
  <reference>
    <citation>Mazzini L, Gelati M, Profico DC, Sgaravizzi G, Projetti Pensi M, Muzi G, Ricciolini C, Rota Nodari L, Carletti S, Giorgi C, Spera C, Domenico F, Bersano E, Petruzzelli F, Cisari C, Maglione A, Sarnelli MF, Stecco A, Querin G, Masiero S, Cantello R, Ferrari D, Zalfa C, Binda E, Visioli A, Trombetta D, Novelli A, Torres B, Bernardini L, Carriero A, Prandi P, Servo S, Cerino A, Cima V, Gaiani A, Nasuelli N, Massara M, Glass J, Soraru G, Boulis NM, Vescovi AL. Human neural stem cell transplantation in ALS: initial results from a phase I trial. J Transl Med. 2015 Jan 27;13:17. doi: 10.1186/s12967-014-0371-2.</citation>
    <PMID>25889343</PMID>
  </reference>
  <reference>
    <citation>Pluchino S, Gritti A, Blezer E, Amadio S, Brambilla E, Borsellino G, Cossetti C, Del Carro U, Comi G, 't Hart B, Vescovi A, Martino G. Human neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates. Ann Neurol. 2009 Sep;66(3):343-54. doi: 10.1002/ana.21745.</citation>
    <PMID>19798728</PMID>
  </reference>
  <reference>
    <citation>Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, Galli R, Del Carro U, Amadio S, Bergami A, Furlan R, Comi G, Vescovi AL, Martino G. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature. 2003 Apr 17;422(6933):688-94. doi: 10.1038/nature01552.</citation>
    <PMID>12700753</PMID>
  </reference>
  <reference>
    <citation>Ferrari D, Zalfa C, Nodari LR, Gelati M, Carlessi L, Delia D, Vescovi AL, De Filippis L. Differential pathotropism of non-immortalized and immortalized human neural stem cell lines in a focal demyelination model. Cell Mol Life Sci. 2012 Apr;69(7):1193-210. doi: 10.1007/s00018-011-0873-5. Epub 2011 Nov 11.</citation>
    <PMID>22076651</PMID>
  </reference>
  <verification_date>July 2021</verification_date>
  <study_first_submitted>August 9, 2017</study_first_submitted>
  <study_first_submitted_qc>September 12, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 14, 2017</study_first_posted>
  <last_update_submitted>July 9, 2021</last_update_submitted>
  <last_update_submitted_qc>July 9, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">July 12, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Cell Transplantation</keyword>
  <keyword>Neural Stem Cells</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Multiple Sclerosis</mesh_term>
    <mesh_term>Multiple Sclerosis, Chronic Progressive</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>All IPD that underlie results in a publication</ipd_description>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03282760
org study id: NSC SPMS
secondary id: 2015-004855-37
nct id: NCT03282760
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This will be a phase I, open, multicenter, international study performed by 3 participating
      centres across two countries (Italy and Switzerland). Fifteen to 24 patients affected by SPMS
      will be enrolled, according to a "standard" phase I design over 18 months. All patients will
      enter a 3 months run in phase. Thereafter they will receive one of four different doses of
      allogenic hNSCs (dose A=5 millions hNSCs; dose B=10 millions hNSCs; dose C=16 millions hNSCs;
      dose D=24 millions hNSCs). Following hNSCs injection, all SPMS patients will receive
      immunosuppression with tacrolimus for 6 months. Patients will be clinically followed monthly
      for 1 year and then every 6 months for the 5 years following the study completion (possibly
      all life long).

      MRI assessments will be performed monthly for the first 6 months and then every 3 months for
      5 years following the study completion.
allocation: N/A
intervention model: Sequential Assignment
intervention model description: Fifteen to 24 patients affected by SPMS will be enrolled, according to a "standard" phase I design over 18 months. All patients will enter a 3 months run in phase. Thereafter they will receive one of four different doses of allogenic hNSCs (dose A=5 millions hNSCs; dose B=10 millionshNSCs; dose C=16 millions hNSCs; dose D=24 millions hNSCs).
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of Treatment Emergent AE
time frame: 1 year
description: To Evaluate the Feasibility, Safety and Tolerability of intracerebroventricular injection of allogenic hNSCs
measure: Percentage of Mortality in treated patients
time frame: 1 year
description: Percentage of subjects (%) with death due to procedure (mortality correlated to treatment)
measure: Change in Functional disability
time frame: Up to 1 year
description: this will be measured by the change of the Expanded Disability Scale (EDSS-disability score about pyramidal, cereberral, brainstem, sensory, bowel and bladder, visual, cerebral Functional Systems) during the study period.
measure: Change in Functional disability
time frame: Up to 1 year
description: this will be measured by the change of the the Multiple Sclerosis Functional Composite (MSFC-scores about upper extremity function, ambulation and cognitive function) during the study period.
measure: Activity of Cognitive function
time frame: Up to 1 year
description: This will be measured as the mean change of the score of the RAO Brief Repeatable Battery of Neuropsychological Test, during the study period.
measure: Relapses Rate
time frame: Up to 1 year
description: Relapses will be measured by the change in EDSS scale
measure: Relapses Rate
time frame: Up to 1 year
description: Relapses will be measured by the Imaging evaluations
measure: MS Biomarkers
time frame: Up to 1 year
description: Investigation of potential candidate biomarkers able to monitor disease activity and predict clinical course in MS (Neurofilaments)
measure: Alteration in Neurophysiological parameters
time frame: Up to 1 year
description: Assessed by Evoked Potentials.
arm group label: Human Neural Stem Cells Suspension
arm group type: Experimental
description: Intraventricular injections of Allogenic human Neural Stem Cells (hNSCs) in four different dosages (5, 10,16 or 24 millions)
intervention type: Biological
intervention name: Human Neural Stem Cells
description: Allogenic human Neural Stem Cells (hNSCs) in four different dosages (5, 10, 16 or 24 millions). hNSCs are produced by the Laboratorio Cellule Staminali of Terni according to GMP guidelines and are obtained from brain specimens of several fetal human donors from spontaneous miscarriages occurred after the 8th week after conception.
arm group label: Human Neural Stem Cells Suspension
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Angelo L Vescovi, PhD
role: Study Director
affiliation: Casa Sollievo della Sofferenza IRCCS
facility: 
facility: 
facility: 
country: Italy
country: Switzerland
citation: Gelati M, Profico D, Projetti-Pensi M, Muzi G, Sgaravizzi G, Vescovi AL. Culturing and expansion of "clinical grade" precursors cells from the fetal human central nervous system. Methods Mol Biol. 2013;1059:65-77. doi: 10.1007/978-1-62703-574-3_6.
PMID: 23934834
citation: Mazzini L, Gelati M, Profico DC, Sgaravizzi G, Projetti Pensi M, Muzi G, Ricciolini C, Rota Nodari L, Carletti S, Giorgi C, Spera C, Domenico F, Bersano E, Petruzzelli F, Cisari C, Maglione A, Sarnelli MF, Stecco A, Querin G, Masiero S, Cantello R, Ferrari D, Zalfa C, Binda E, Visioli A, Trombetta D, Novelli A, Torres B, Bernardini L, Carriero A, Prandi P, Servo S, Cerino A, Cima V, Gaiani A, Nasuelli N, Massara M, Glass J, Soraru G, Boulis NM, Vescovi AL. Human neural stem cell transplantation in ALS: initial results from a phase I trial. J Transl Med. 2015 Jan 27;13:17. doi: 10.1186/s12967-014-0371-2.
PMID: 25889343
citation: Pluchino S, Gritti A, Blezer E, Amadio S, Brambilla E, Borsellino G, Cossetti C, Del Carro U, Comi G, 't Hart B, Vescovi A, Martino G. Human neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates. Ann Neurol. 2009 Sep;66(3):343-54. doi: 10.1002/ana.21745.
PMID: 19798728
citation: Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, Galli R, Del Carro U, Amadio S, Bergami A, Furlan R, Comi G, Vescovi AL, Martino G. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature. 2003 Apr 17;422(6933):688-94. doi: 10.1038/nature01552.
PMID: 12700753
citation: Ferrari D, Zalfa C, Nodari LR, Gelati M, Carlessi L, Delia D, Vescovi AL, De Filippis L. Differential pathotropism of non-immortalized and immortalized human neural stem cell lines in a focal demyelination model. Cell Mol Life Sci. 2012 Apr;69(7):1193-210. doi: 10.1007/s00018-011-0873-5. Epub 2011 Nov 11.
PMID: 22076651
responsible party type: Sponsor
mesh term: Neoplasm Metastasis
mesh term: Multiple Sclerosis
mesh term: Multiple Sclerosis, Chronic Progressive
mesh term: Sclerosis
sharing ipd: Yes
ipd description: All IPD that underlie results in a publication
ipd info type: Clinical Study Report (CSR)