<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/NCT03247218</url>
  </required_header>
  <id_info>
    <org_study_id>071-17 EMC</org_study_id>
    <nct_id>NCT03247218</nct_id>
  </id_info>
  <brief_title>A Phase - IIa - IIb, Trial to Study the Safety, Tolerability and Efficacy of Memantine as a Long-term Treatment of SCD</brief_title>
  <acronym>MeMAGEN</acronym>
  <official_title>A Phase - IIa - IIb, Open Label, Single Center Trial to Study the Safety, Tolerability and Efficacy of Memantine Teva® as Supportive Long-term Treatment in Symptomatic Sickle Cell Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>HaEmek Medical Center, Israel</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>HaEmek Medical Center, Israel</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Symptomatic sickle cell disease (SCD) is worldwide the most frequent cause for hereditary&#xD;
      hemolytic anemia with recurrent pain crises. Hemolysis, vaso- occlusive and pain crises are&#xD;
      hallmarks of this disease and are causative for an important socio-economic burden worldwide,&#xD;
      especially in Africa.&#xD;
&#xD;
      Aside from allogenic stem cell transplantation, which is rarely available and very expensive,&#xD;
      at present there is no curative treatment for patients with SCD. The current standard of care&#xD;
      includes treatment with Hydroxyurea and symptomatic care such as transfusions,&#xD;
      antibiotic/analgesic treatment. Recent findings allowed the investigators to come up with a&#xD;
      novel pharmacological target for prophylactic treatment of this group of patients. The&#xD;
      investigators showed that N-methyl D-aspartate receptors (NMDARs) are substantially&#xD;
      up-regulated in circulating red blood cells (RBCs) of SCD patients. Ca2+ uptake via these&#xD;
      non-selective cation channels has major impact on RBC hydration and facilitates&#xD;
      polymerization of deoxygenated hemoglobin S variant in RBCs of patients. In vitro&#xD;
      observations shows that inhibition of NMDARs with Memantine caused re-hydration and largely&#xD;
      prevented hypoxia-induced sickling in RBCs. A pilot trial MemSID (NCT02615847) was conducted&#xD;
      in August 2015-March 2017 at the Hematology Division of University Hospital Zurich. A small&#xD;
      cohort of adult SCD patients was treated with 20 mg Memantine daily to test safety,&#xD;
      tolerability and efficacy of this drug and to assess the effect of Memantine on hemolytic&#xD;
      activity and RBC stability. Pilot data reveal safety and an impressive therapeutic potential&#xD;
      of Memantine in treating SCD patients. Due to a small number of SCD patients in Switzerland,&#xD;
      an extended trial including larger number of adult and adolescent patients will be performed&#xD;
      at the Pediatric Hematology Unit of the Emek Medical Center in Afula, Israel&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background and Rationale: Symptomatic sickle cell disease (SCD) is worldwide the most&#xD;
      frequent cause for hereditary hemolytic anemia with recurrent pain crises. Hemolysis, vaso-&#xD;
      occlusive and pain crises are hallmarks of this disease and are causative for an important&#xD;
      socio-economic burden worldwide, especially in Africa.&#xD;
&#xD;
      Aside from allogenic stem cell transplantation, which is rarely available and very expensive,&#xD;
      at present there is no curative treatment for patients with SCD. The current standard of care&#xD;
      includes treatment with Hydroxyurea and symptomatic care such as transfusions,&#xD;
      antibiotic/analgesic treatment. Recent findings allowed the investigators to come up with a&#xD;
      novel pharmacological target for prophylactic treatment of this group of patients. N-methyl&#xD;
      D-aspartate receptors (NMDARs) are substantially up-regulated in circulating red blood cells&#xD;
      (RBCs) of SCD patients. Ca2+ uptake via these non-selective cation channels has major impact&#xD;
      on RBC hydration and facilitates polymerization of deoxygenated hemoglobin S variant in RBCs&#xD;
      of patients. In vitro inhibition of NMDARs with Memantine caused re-hydration and largely&#xD;
      prevented hypoxia-induced sickling in RBCs. A pilot trial MemSID (NCT02615847) was conducted&#xD;
      in August 2015-March 2017 at the Hematology Division of University Hospital Zurich. A small&#xD;
      cohort of adult SCD patients was treated with 20 mg Memantine daily to test safety,&#xD;
      tolerability and efficacy of this drug and to assess the effect of Memantine on hemolytic&#xD;
      activity and RBC stability. Pilot data reveal safety and an impressive therapeutic potential&#xD;
      of Memantine in treating SCD patients. Due to a small number of SCD patients in Switzerland,&#xD;
      an extended trial including larger number of adult and adolescent patients will be performed&#xD;
      at the Pediatric Hematology Unit of the Emek Medical Center in Afula, Israel.&#xD;
&#xD;
      Objective(s): Primary objective:&#xD;
&#xD;
      To evaluate the safety, tolerability and efficacy of low doses of Memantine Teva® treatment&#xD;
      in adult and adolescent patients with symptomatic SCD.&#xD;
&#xD;
      Secondary objective:&#xD;
&#xD;
      To asses and evaluate the long-term effects of Memantine Teva® on the clinical and laboratory&#xD;
      parameters in adult and adolescent patients with symptomatic SCD.&#xD;
&#xD;
      The following laboratory parameters will be assessed and evaluated:&#xD;
&#xD;
        -  Complete blood count.&#xD;
&#xD;
        -  Hemolytic activity (reticulocytes, indirect bilirubin and LDH).&#xD;
&#xD;
        -  Iron status (ferritin, serum iron, transferrin and transferrin saturation).&#xD;
&#xD;
        -  Fetal hemoglobin levels Additional parameters related to red cell volume, density,&#xD;
           membrane stability, adherablilty, inflammatory markers and metabolic activity will be&#xD;
           detected by the external laboratory (Red Cell Research Group, University of Zurich)&#xD;
           Study design: It is a single center and open label study.&#xD;
&#xD;
      Laboratory analysis including hematology, coagulation and chemistry test will be performed&#xD;
      and urine samples will be also analyzed. In addition, at each visit a physical examination&#xD;
      and measurement of vital signs will be performed.&#xD;
&#xD;
      The number of total admissions, hospital days and emergency consultations will be recorded.&#xD;
      The amount and type of analgesic medication given. The amount of RBC transfusions, the number&#xD;
      of days that antibiotics were prescribed will be also recorded.&#xD;
&#xD;
      At screening and at the end of the study SCD specific assessments will be performed, which&#xD;
      include cardiologic examination (ECG, ECHO), abdominal sonography, ophthalmological&#xD;
      examination, lung function testing and neuroangiologic examination.&#xD;
&#xD;
      The impact on working ability assessed by the number of days with inability to work. For the&#xD;
      impact on work ability and social life activities a questionnaire of quality of life will be&#xD;
      filled out by the patient once a month.&#xD;
&#xD;
      - Evaluation of Cognitive function will be also performed at screening and at the end of the&#xD;
      study Study Product / Intervention: Memantine Teva® is a low-moderate affinity,&#xD;
      uncompetitive, NMDAR antagonist and is licensed in Switzerland and in Israel for the&#xD;
      treatment of Alzheimer disease.&#xD;
&#xD;
      Memantine Teva® film-coated tablets (Memantine hydrochloride) is produced by Teva Pharma AG&#xD;
      and will be provided as 5 mg, 10 mg, and 20 mg tablets packed in blister.&#xD;
&#xD;
      The study drug will be taken once a day per os, during Number of Participants with Rationale:&#xD;
      In this study 40 patients with SCD will be included. Twenty patients aged 18 years or older&#xD;
      (cohort 1) and twenty patients 10 - 17 years old (cohort 2).&#xD;
&#xD;
      Study Duration: The study lasts 15 month per patient.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">February 2, 2018</start_date>
  <completion_date type="Anticipated">December 31, 2020</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>a single center and open label study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Assessment of Incidence and severity of Memantine treatment-related Adverse Events (AE), including clinically significant abnormal laboratory values in adult and adolescent patients with symptomatic SCD.</measure>
    <time_frame>one year</time_frame>
    <description>The following laboratory parameters will be assessed and evaluated:&#xD;
Complete blood count.&#xD;
Hemolytic activity (reticulocytes, indirect bilirubin and LDH).&#xD;
Iron status (ferritin, serum iron, transferrin and transferrin saturation).&#xD;
Fetal hemoglobin levels&#xD;
Red cell volume, density, membrane stability, adherablilty, inflammatory markers and metabolic activity.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Assessment of Clinical Improvement during Memantine treatment compared to a pre-screening data obtained from patients clinical files in adult and adolescent patients with symptomatic SCD.</measure>
    <time_frame>one year</time_frame>
    <description>Clinical improvements will be assessed by&#xD;
Number of hospital days.&#xD;
Number of emergency consultations&#xD;
Impact on working ability (the number of days with inability to work)&#xD;
The amount and type of analgesic medication received by the patient.&#xD;
The amount of RBC transfusions received by the patient.&#xD;
The number of days that antibiotics were prescribed.&#xD;
A questionnaire on quality of life.&#xD;
Evaluation of Cognitive function.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Sickle Cell Disease</condition>
  <arm_group>
    <arm_group_label>Single group of patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>In this study 40 patients with SCD will be included. Twenty patients aged 18 years or older (cohort 1) and twenty patients 10 - 17 years old (cohort 2).&#xD;
All the patients will receive Memantine Teva® film-coated tablets (Memantine hydrochloride) produced by Teva Pharma AG and will be provided as 5 mg, 10 mg, and 20 mg tablets packed in blister.&#xD;
The study drug will be taken once a day per os, during one year.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Memantine Hydrochloride</intervention_name>
    <description>a low-moderate affinity, uncompetitive, NMDAR antagonist</description>
    <arm_group_label>Single group of patients</arm_group_label>
    <other_name>Memantine TEVA</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Documented symptomatic sickle cell disease (HbSS or HbS/beta thalassemia)&#xD;
&#xD;
          -  Age 18 years or older (cohort 1) and 10 - 17 years old (cohort 2)&#xD;
&#xD;
          -  Able and willing to provide written informed consent and to comply with the study&#xD;
             protocol procedures Willing to use two effective methods of contraception during study&#xD;
             treatment until 6 months after stop of study treatment. Effective contraception&#xD;
             methods are considered oral, injectable, implantative contraceptives or intrauterine&#xD;
             contraceptive devices combined with use of condom.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of transfusion during last three months before Screening&#xD;
&#xD;
          -  Patients with active bacterial, viral or fungal infection requiring systemic treatment&#xD;
&#xD;
          -  Patients with known infection with human immunodeficiency virus (HIV) of human T cell&#xD;
             leukemia virus 1 (HTLV-1)&#xD;
&#xD;
          -  Inadequate renal function: creatinine clearance &lt; 30ml/min&#xD;
&#xD;
          -  Inadequate liver function: NCICTC Grade 3 liver function tests (AST, ALT &gt; 5x upper&#xD;
             limit of normal (ULN))&#xD;
&#xD;
          -  Patients with Chronic Active Hepatitis - HCV or HBV&#xD;
&#xD;
          -  History of malignancy&#xD;
&#xD;
          -  Women who are pregnant or breast feeding&#xD;
&#xD;
          -  Known epileptic disease and under treatment with anticonvulsive drugs&#xD;
&#xD;
          -  The receipt of any investigational product within 30 days prior to this trial&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>10 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ariel Koren, Professor</last_name>
    <role>Principal Investigator</role>
    <affiliation>Emek Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Ariel Koren, Professor</last_name>
    <phone>9726495615</phone>
    <phone_ext>5615</phone_ext>
    <email>koren_a@clalit.org.il</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Anna H Shuman, B.sc</last_name>
    <phone>9726494044</phone>
    <phone_ext>4044</phone_ext>
    <email>annami31@clalit.org.il</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Emek Medical Centre</name>
      <address>
        <city>Afula</city>
        <zip>18101</zip>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ariel Koren, MD</last_name>
      <phone>972-4-6495615</phone>
      <phone_ext>5615</phone_ext>
      <email>koren_a@clalit.org.il</email>
    </contact>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>August 1, 2017</study_first_submitted>
  <study_first_submitted_qc>August 8, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 11, 2017</study_first_posted>
  <last_update_submitted>October 30, 2019</last_update_submitted>
  <last_update_submitted_qc>October 30, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">November 1, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>HaEmek Medical Center, Israel</investigator_affiliation>
    <investigator_full_name>Dr Koren Ariel</investigator_full_name>
    <investigator_title>Head of Pediatric Hematology Unit</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia, Sickle Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Memantine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT03247218
org study id: 071-17 EMC
nct id: NCT03247218
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Symptomatic sickle cell disease (SCD) is worldwide the most frequent cause for hereditary
      hemolytic anemia with recurrent pain crises. Hemolysis, vaso- occlusive and pain crises are
      hallmarks of this disease and are causative for an important socio-economic burden worldwide,
      especially in Africa.

      Aside from allogenic stem cell transplantation, which is rarely available and very expensive,
      at present there is no curative treatment for patients with SCD. The current standard of care
      includes treatment with Hydroxyurea and symptomatic care such as transfusions,
      antibiotic/analgesic treatment. Recent findings allowed the investigators to come up with a
      novel pharmacological target for prophylactic treatment of this group of patients. The
      investigators showed that N-methyl D-aspartate receptors (NMDARs) are substantially
      up-regulated in circulating red blood cells (RBCs) of SCD patients. Ca2+ uptake via these
      non-selective cation channels has major impact on RBC hydration and facilitates
      polymerization of deoxygenated hemoglobin S variant in RBCs of patients. In vitro
      observations shows that inhibition of NMDARs with Memantine caused re-hydration and largely
      prevented hypoxia-induced sickling in RBCs. A pilot trial MemSID (NCT02615847) was conducted
      in August 2015-March 2017 at the Hematology Division of University Hospital Zurich. A small
      cohort of adult SCD patients was treated with 20 mg Memantine daily to test safety,
      tolerability and efficacy of this drug and to assess the effect of Memantine on hemolytic
      activity and RBC stability. Pilot data reveal safety and an impressive therapeutic potential
      of Memantine in treating SCD patients. Due to a small number of SCD patients in Switzerland,
      an extended trial including larger number of adult and adolescent patients will be performed
      at the Pediatric Hematology Unit of the Emek Medical Center in Afula, Israel
Background and Rationale: Symptomatic sickle cell disease (SCD) is worldwide the most
      frequent cause for hereditary hemolytic anemia with recurrent pain crises. Hemolysis, vaso-
      occlusive and pain crises are hallmarks of this disease and are causative for an important
      socio-economic burden worldwide, especially in Africa.

      Aside from allogenic stem cell transplantation, which is rarely available and very expensive,
      at present there is no curative treatment for patients with SCD. The current standard of care
      includes treatment with Hydroxyurea and symptomatic care such as transfusions,
      antibiotic/analgesic treatment. Recent findings allowed the investigators to come up with a
      novel pharmacological target for prophylactic treatment of this group of patients. N-methyl
      D-aspartate receptors (NMDARs) are substantially up-regulated in circulating red blood cells
      (RBCs) of SCD patients. Ca2+ uptake via these non-selective cation channels has major impact
      on RBC hydration and facilitates polymerization of deoxygenated hemoglobin S variant in RBCs
      of patients. In vitro inhibition of NMDARs with Memantine caused re-hydration and largely
      prevented hypoxia-induced sickling in RBCs. A pilot trial MemSID (NCT02615847) was conducted
      in August 2015-March 2017 at the Hematology Division of University Hospital Zurich. A small
      cohort of adult SCD patients was treated with 20 mg Memantine daily to test safety,
      tolerability and efficacy of this drug and to assess the effect of Memantine on hemolytic
      activity and RBC stability. Pilot data reveal safety and an impressive therapeutic potential
      of Memantine in treating SCD patients. Due to a small number of SCD patients in Switzerland,
      an extended trial including larger number of adult and adolescent patients will be performed
      at the Pediatric Hematology Unit of the Emek Medical Center in Afula, Israel.

      Objective(s): Primary objective:

      To evaluate the safety, tolerability and efficacy of low doses of Memantine Teva® treatment
      in adult and adolescent patients with symptomatic SCD.

      Secondary objective:

      To asses and evaluate the long-term effects of Memantine Teva® on the clinical and laboratory
      parameters in adult and adolescent patients with symptomatic SCD.

      The following laboratory parameters will be assessed and evaluated:

        -  Complete blood count.

        -  Hemolytic activity (reticulocytes, indirect bilirubin and LDH).

        -  Iron status (ferritin, serum iron, transferrin and transferrin saturation).

        -  Fetal hemoglobin levels Additional parameters related to red cell volume, density,
           membrane stability, adherablilty, inflammatory markers and metabolic activity will be
           detected by the external laboratory (Red Cell Research Group, University of Zurich)
           Study design: It is a single center and open label study.

      Laboratory analysis including hematology, coagulation and chemistry test will be performed
      and urine samples will be also analyzed. In addition, at each visit a physical examination
      and measurement of vital signs will be performed.

      The number of total admissions, hospital days and emergency consultations will be recorded.
      The amount and type of analgesic medication given. The amount of RBC transfusions, the number
      of days that antibiotics were prescribed will be also recorded.

      At screening and at the end of the study SCD specific assessments will be performed, which
      include cardiologic examination (ECG, ECHO), abdominal sonography, ophthalmological
      examination, lung function testing and neuroangiologic examination.

      The impact on working ability assessed by the number of days with inability to work. For the
      impact on work ability and social life activities a questionnaire of quality of life will be
      filled out by the patient once a month.

      - Evaluation of Cognitive function will be also performed at screening and at the end of the
      study Study Product / Intervention: Memantine Teva® is a low-moderate affinity,
      uncompetitive, NMDAR antagonist and is licensed in Switzerland and in Israel for the
      treatment of Alzheimer disease.

      Memantine Teva® film-coated tablets (Memantine hydrochloride) is produced by Teva Pharma AG
      and will be provided as 5 mg, 10 mg, and 20 mg tablets packed in blister.

      The study drug will be taken once a day per os, during Number of Participants with Rationale:
      In this study 40 patients with SCD will be included. Twenty patients aged 18 years or older
      (cohort 1) and twenty patients 10 - 17 years old (cohort 2).

      Study Duration: The study lasts 15 month per patient.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: a single center and open label study
primary purpose: Treatment
masking: None (Open Label)
measure: Assessment of Incidence and severity of Memantine treatment-related Adverse Events (AE), including clinically significant abnormal laboratory values in adult and adolescent patients with symptomatic SCD.
time frame: one year
description: The following laboratory parameters will be assessed and evaluated:
Complete blood count.
Hemolytic activity (reticulocytes, indirect bilirubin and LDH).
Iron status (ferritin, serum iron, transferrin and transferrin saturation).
Fetal hemoglobin levels
Red cell volume, density, membrane stability, adherablilty, inflammatory markers and metabolic activity.
measure: Assessment of Clinical Improvement during Memantine treatment compared to a pre-screening data obtained from patients clinical files in adult and adolescent patients with symptomatic SCD.
time frame: one year
description: Clinical improvements will be assessed by
Number of hospital days.
Number of emergency consultations
Impact on working ability (the number of days with inability to work)
The amount and type of analgesic medication received by the patient.
The amount of RBC transfusions received by the patient.
The number of days that antibiotics were prescribed.
A questionnaire on quality of life.
Evaluation of Cognitive function.
arm group label: Single group of patients
arm group type: Experimental
description: In this study 40 patients with SCD will be included. Twenty patients aged 18 years or older (cohort 1) and twenty patients 10 - 17 years old (cohort 2).
All the patients will receive Memantine Teva® film-coated tablets (Memantine hydrochloride) produced by Teva Pharma AG and will be provided as 5 mg, 10 mg, and 20 mg tablets packed in blister.
The study drug will be taken once a day per os, during one year.
intervention type: Drug
intervention name: Memantine Hydrochloride
description: a low-moderate affinity, uncompetitive, NMDAR antagonist
arm group label: Single group of patients
other name: Memantine TEVA
criteria: 
gender: All
minimum age: 10 Years
maximum age: N/A
healthy volunteers: No
last name: Ariel Koren, Professor
role: Principal Investigator
affiliation: Emek Medical Center
last name: Ariel Koren, Professor
phone: 9726495615
phone ext: 5615
email: koren_a@clalit.org.il
last name: Anna H Shuman, B.sc
phone: 9726494044
phone ext: 4044
email: annami31@clalit.org.il
facility: 
status: Recruiting
contact: 
country: Israel
responsible party type: Principal Investigator
investigator affiliation: HaEmek Medical Center, Israel
investigator full name: Dr Koren Ariel
investigator title: Head of Pediatric Hematology Unit
mesh term: Anemia, Sickle Cell
mesh term: Memantine
sharing ipd: No