Red Blood Cell Exchange Transfusion as a Novel Treatment for GLUT1 Deficiency Syndrome
Primary Purpose
Glucose Transporter Type 1 Deficiency Syndrome, GLUT1DS1
Status
Active
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Red Blood Cell Transfusion
Sponsored by
About this trial
This is an interventional treatment trial for Glucose Transporter Type 1 Deficiency Syndrome focused on measuring G1D, Glucose transporter
Eligibility Criteria
Inclusion Criteria:
- Male or Female
- Age 16 years to 64 years old.
- Diagnosed with genetically-confirmed glucose transporter type 1 disorder
- Patients not currently receiving dietary therapy, including ketogenic diet or other dietary therapy, due to failure of these diets to achieve seizure remission or due to patient preference, including compliance or tolerance issues. Patients currently on Modified Atkins Diet (MAD) and / or taking Medium Chain Triglyceride (MCT) oil are allowed.
Exclusion Criteria:
- Currently on the ketogenic diet or taking triheptanoin (C7) oil
- No genetic confirmation of G1D diagnosis
- Unable to return for follow up visits
- Weak peripheral veins, such that IV placement is contraindicated (required for transfusion)
- Serious chronic medical conditions, such as congestive heart failure, renal failure, liver failure, or any other medical conditions that preclude large volume transfusions.
- Patients currently pregnant or breast-feeding are excluded from participating in this research. Patients who plan on getting pregnant during this research or who are unwilling to use birth control, including abstinence, during the course of this research are also excluded due to safety concerns for the fetus.
Sites / Locations
- UT Southwestern
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Red Blood Cell Transfusion
Arm Description
Patients will undergo isovolemic hemodilution-red cell exchange (IHD- RBCx) with up to 10 units of red cell antigens (Rh group, Kell, Duffy, Kidd blood group antigens) matched normal donor red cells to replace a target of 70% of the patient's red cells with donor red cells.
Outcomes
Primary Outcome Measures
Change in electroencephalogram (EEG)
Change in number of seizures recorded
Secondary Outcome Measures
Change in neuropsychological receptive language test battery
Change in standard scores obtained from the Peabody Picture Vocabulary Test.
Change in neuropsychological expressive language test battery
Change in standard scores obtained from the Expressive Vocabulary Test.
Change in neuropsychological attention scores
Change in T-scores obtained on the Connors Continuous Performance Test. Minimum T score is less than 30. Maximum T score is 90. Higher T scores for Hit Reaction Time domain indicate slower reaction time while lower scores indicate faster reaction time. For all other domains (detectability, omissions, commissions, perseverations), higher T scores indicated elevated performance while lower T scores indicate lower performance.
Changes in biochemical assay
Number of participants with erythrocyte Glut1 levels that have increased by over 40% from baseline.
Change in General Medical & Neurological Examination
Change in score of standardized clinical physical exam, which has 12 domains scored either normal or abnormal. Minimum total score is 0. Maximum total score is 76. Lower scores are considered more abnormal. Higher scores indicate a more normal exam and and better outcomes than lower scores.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04137692
Brief Title
Red Blood Cell Exchange Transfusion as a Novel Treatment for GLUT1 Deficiency Syndrome
Official Title
Red Blood Cell Exchange Transfusion as a Novel Treatment for GLUT1 Deficiency Syndrome
Study Type
Interventional
2. Study Status
Record Verification Date
December 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 9, 2020 (Actual)
Primary Completion Date
October 2023 (Anticipated)
Study Completion Date
October 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Juan Pascual
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This proposal is an investigator-initiated, single-site proof of concept trial. Five patients will undergo isovolemic hemodilution-red cell exchange (IHD- RBCx) with up to 10 units of red cell antigens (Rh group, Kell, Duffy, Kidd blood group antigens) matched normal donor red cells to replace a target of 70% of the patient's red cells with donor red cells. The procedure will be performed as an outpatient according to protocols established for sickle cell anemia patients. One of the investigators is an expert on RBCx and will oversee the transfusion. Subjects will be assessed before and after transfusion, and at two months post transfusion. Outcome measures include neurological exam, electroencephalography (EEG), neuropsychological testing, and biochemical assays.
Detailed Description
As the transporter responsible for basal levels of glucose flux, Glucose transporter 1 (GLUT1) is expressed at low levels in most tissues. In contrast, GLUT1 is very highly expressed on human erythrocytes. Human erythrocytes possess up to 5x105 copies of GLUT1 in their membranes representing almost 5% of total membrane protein. This allows erythrocytes to catalyze glucose transfer at rates three orders of magnitude greater than their capacity to utilize it. It has been proposed that human erythrocytes function in glucose storage, especially when the serum carrying capacity for glucose becomes limiting. If this hypothesis could be validated experimentally, it would be of fundamental importance to the understanding of human physiology.
This proposal also has the potential to uncover a novel therapeutic option for patients with Glucose Transporter Type 1 Deficiency (G1D). Currently, the only treatment for G1D is the ketogenic diet. While the ketogenic diet improves seizures in a fraction of patients, its effects on neurodevelopment and long-term health are poor, so better treatment options for G1D are needed. Because of the hypoglycorrachia (i.e. low cerebrospinal fluid glucose) of G1D patients, the endothelial cells of the blood-brain barrier microvessels have long been assumed to be the primary site of disease pathogenesis. However, most G1D patients also have deficits in GLUT1 levels and glucose uptake in their erythrocytes and a potential contribution of this compartment to disease pathogenesis is likely. GLUT1 deficient mice are not amenable to test the hypothesis because they do not fully recapitulate the clinical presentation of G1D patients and because they exhibit metabolic adaption to G1D. Red blood cell exchange (RBCx) is a safe and cost effective treatment to prevent strokes and vascular abnormalities in patients with sickle cell anemia. RBCx has the potential to dramatically alter the treatment of G1D patients.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glucose Transporter Type 1 Deficiency Syndrome, GLUT1DS1
Keywords
G1D, Glucose transporter
7. Study Design
Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
5 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Red Blood Cell Transfusion
Arm Type
Experimental
Arm Description
Patients will undergo isovolemic hemodilution-red cell exchange (IHD- RBCx) with up to 10 units of red cell antigens (Rh group, Kell, Duffy, Kidd blood group antigens) matched normal donor red cells to replace a target of 70% of the patient's red cells with donor red cells.
Intervention Type
Other
Intervention Name(s)
Red Blood Cell Transfusion
Intervention Description
The procedure will be performed as an outpatient according to protocols established for sickle cell anemia patients. Two IVs are placed for the purposes of transfusion, one for draw and one for return. Patients will undergo isovolemic hemodilution-red cell exchange (IHD- RBCx) with up to 10 units of red cell antigens (Rh group, Kell, Duffy, Kidd blood group antigens) matched normal donor red cells to replace a target of 70% of the patient's red cells with donor red cells.Total time of procedure: approximately 150 minutes.
Primary Outcome Measure Information:
Title
Change in electroencephalogram (EEG)
Description
Change in number of seizures recorded
Time Frame
Baseline, during transfusion, and 60 days after transfusion
Secondary Outcome Measure Information:
Title
Change in neuropsychological receptive language test battery
Description
Change in standard scores obtained from the Peabody Picture Vocabulary Test.
Time Frame
Baseline, immediately after transfusion, and 60 days after transfusion
Title
Change in neuropsychological expressive language test battery
Description
Change in standard scores obtained from the Expressive Vocabulary Test.
Time Frame
Baseline, immediately after transfusion, and 60 days after transfusion
Title
Change in neuropsychological attention scores
Description
Change in T-scores obtained on the Connors Continuous Performance Test. Minimum T score is less than 30. Maximum T score is 90. Higher T scores for Hit Reaction Time domain indicate slower reaction time while lower scores indicate faster reaction time. For all other domains (detectability, omissions, commissions, perseverations), higher T scores indicated elevated performance while lower T scores indicate lower performance.
Time Frame
Baseline, immediately after transfusion, and 60 days after transfusion
Title
Changes in biochemical assay
Description
Number of participants with erythrocyte Glut1 levels that have increased by over 40% from baseline.
Time Frame
Baseline, immediately after transfusion, and 60 days after transfusion
Title
Change in General Medical & Neurological Examination
Description
Change in score of standardized clinical physical exam, which has 12 domains scored either normal or abnormal. Minimum total score is 0. Maximum total score is 76. Lower scores are considered more abnormal. Higher scores indicate a more normal exam and and better outcomes than lower scores.
Time Frame
Baseline and 60 days after transfusion
10. Eligibility
Sex
All
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
64 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male or Female
Age 16 years to 64 years old.
Diagnosed with genetically-confirmed glucose transporter type 1 disorder
Patients not currently receiving dietary therapy, including ketogenic diet or other dietary therapy, due to failure of these diets to achieve seizure remission or due to patient preference, including compliance or tolerance issues. Patients currently on Modified Atkins Diet (MAD) and / or taking Medium Chain Triglyceride (MCT) oil are allowed.
Exclusion Criteria:
Currently on the ketogenic diet or taking triheptanoin (C7) oil
No genetic confirmation of G1D diagnosis
Unable to return for follow up visits
Weak peripheral veins, such that IV placement is contraindicated (required for transfusion)
Serious chronic medical conditions, such as congestive heart failure, renal failure, liver failure, or any other medical conditions that preclude large volume transfusions.
Patients currently pregnant or breast-feeding are excluded from participating in this research. Patients who plan on getting pregnant during this research or who are unwilling to use birth control, including abstinence, during the course of this research are also excluded due to safety concerns for the fetus.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Juan Pascual, MD, PhD
Organizational Affiliation
UT Southwestern Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
UT Southwestern
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
25982116
Citation
Lee EE, Ma J, Sacharidou A, Mi W, Salato VK, Nguyen N, Jiang Y, Pascual JM, North PE, Shaul PW, Mettlen M, Wang RC. A Protein Kinase C Phosphorylation Motif in GLUT1 Affects Glucose Transport and is Mutated in GLUT1 Deficiency Syndrome. Mol Cell. 2015 Jun 4;58(5):845-53. doi: 10.1016/j.molcel.2015.04.015. Epub 2015 May 14.
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Red Blood Cell Exchange Transfusion as a Novel Treatment for GLUT1 Deficiency Syndrome
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