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History of Changes for Study: NCT03247218
A Phase - IIa - IIb, Open Label Trial to Study the Safety, Tolerability and Efficacy of Memantine as a Long-term Treatment of SCD (MeMAGEN)
Latest version (submitted October 30, 2019) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 August 8, 2017 None (earliest Version on record)
2 August 21, 2017 Outcome Measures, Study Description, Study Status and Study Identification
3 October 30, 2019 Recruitment Status, Study Status, Contacts/Locations and Oversight
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Study NCT03247218
Submitted Date:  August 8, 2017 (v1)

Open or close this module Study Identification
Unique Protocol ID: 071-17 EMC
Brief Title: A Phase - IIa - IIb, Open Label Trial to Study the Safety, Tolerability and Efficacy of Memantine as a Long-term Treatment of SCD (MeMAGEN)
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
Secondary IDs:
Open or close this module Study Status
Record Verification: August 2017
Overall Status: Not yet recruiting
Study Start: January 1, 2018
Primary Completion: December 1, 2019 [Anticipated]
Study Completion: June 30, 2020 [Anticipated]
First Submitted: August 1, 2017
First Submitted that
Met QC Criteria:
August 8, 2017
First Posted: August 11, 2017 [Actual]
Last Update Submitted that
Met QC Criteria:
August 8, 2017
Last Update Posted: August 11, 2017 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: HaEmek Medical Center, Israel
Responsible Party: Principal Investigator
Investigator: Dr Koren Ariel
Official Title: Head of Pediatric Hematology Unit
Affiliation: HaEmek Medical Center, Israel
Collaborators:
Open or close this module Oversight
U.S. FDA-regulated Drug: No
U.S. FDA-regulated Device: No
Data Monitoring: Yes
Open or close this module Study Description
Brief Summary:

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. Our recent findings allowed us to come up with a novel pharmacological target for prophylactic treatment of this group of patients. We 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 we observed 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

Detailed Description:

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. Our recent findings allowed us to come up with a novel pharmacological target for prophylactic treatment of this group of patients. We 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 we observed 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.

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.

Open or close this module Conditions
Conditions: Sickle Cell Disease
Keywords:
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 2
Interventional Study Model: Single Group Assignment
a single center and open label study
Number of Arms: 1
Masking: None (Open Label)
Allocation: N/A
Enrollment: 40 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Experimental: Single group of patients

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.

Drug: Memantine Hydrochloride
a low-moderate affinity, uncompetitive, NMDAR antagonist
Other Names:
  • Memantine TEVA
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Primary Outcome
[ Time Frame: one year ]

Incidence and severity of Memantine treatment-related Adverse Events (AE), including clinically significant abnormal laboratory values 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(
Secondary Outcome Measures:
1. Secondary Outcome
[ Time Frame: one year ]

Clinical improvements are assessed by

  • Number of hospital days and emergency consultations
  • Impact on working ability (the number of days with inability to work,
  • The amount and type of analgesic medication
  • The amount of RBC transfusions
  • The number of days that antibiotics were prescribed
  • A questionnaire on quality of life
  • Evaluation of Cognitive function
Open or close this module Eligibility
Minimum Age: 10 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

  • Documented symptomatic sickle cell disease (HbSS or HbS/beta thalassemia)
  • Age 18 years or older (cohort 1) and 10 - 17 years old (cohort 2)
  • Able and willing to provide written informed consent and to comply with the study protocol procedures Willing to use two effective methods of contraception during study treatment until 6 months after stop of study treatment. Effective contraception methods are considered oral, injectable, implantative contraceptives or intrauterine contraceptive devices combined with use of condom.

Exclusion Criteria:

  • History of transfusion during last three months before Screening
  • Patients with active bacterial, viral or fungal infection requiring systemic treatment
  • Patients with known infection with human immunodeficiency virus (HIV) of human T cell leukemia virus 1 (HTLV-1)
  • Inadequate renal function: creatinine clearance < 30ml/min
  • Inadequate liver function: NCICTC Grade 3 liver function tests (AST, ALT > 5x upper limit of normal (ULN))
  • Patients with Chronic Active Hepatitis - HCV or HBV
  • History of malignancy
  • Women who are pregnant or breast feeding
  • Known epileptic disease and under treatment with anticonvulsive drugs
  • The receipt of any investigational product within 30 days prior to this trial
Open or close this module Contacts/Locations
Central Contact Person: Ariel Koren, Professor
Telephone: 9726495615 Ext. 5615
Email: koren_a@clalit.org.il
Central Contact Backup: Anna H Shuman, B.sc
Telephone: 9726494044 Ext. 4044
Email: annami31@clalit.org.il
Study Officials: Ariel Koren, Professor
Principal Investigator
Emek Medical Center
Locations:
Open or close this module IPDSharing
Plan to Share IPD: No
Open or close this module References
Citations:
Links:
Available IPD/Information:

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