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Lack of funding
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| Name | Class |
|---|---|
| Seattle Children's Hospital | OTHER |
| Children's Hospital of Philadelphia | OTHER |
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Objective 1 (Primary): To determine the efficacy of acetazolamide in improving ataxia in patients with PMM2-CDG.
Objective 2 (Secondary): To evaluate for any adverse events related to longer term acetazolamide administration.
Objective 3 (Secondary): To examine the effect of acetazolamide on PMM2 biomarkers including carbohydrate deficient transferrin results, electrolytes (Na, K, Cl, CO2), VBG (pH, pCO2, PO2, CO2, Base excess), liver function tests (AST, ALT, GGT, indirect and direct bilirubin, total protein, albumin, alkaline phosphatase), kidney function tests (BUN, Creatinine, Urinalysis, urine calcium/creatinine ratio, urine protein/creatinine ratio), growth (height, weight, head circumference), vital signs (blood pressure, respiratory rate, heart rate), PROMIS scores, dysarthria using the PATA score, and NPCRS score.
Objective 4 (Secondary): To explore characteristics of individuals with PMM2-CDG who do not respond to acetazolamide.
This study is double-blind, placebo-controlled, 1:1 randomized clinical therapeutic trial of acetazolamide for the treatment of ataxia in patients with PMM2-CDG. Clinical history and screening data will be reviewed to determine subject eligibility. Potential subjects who have a molecularly and/or biochemical confirmed diagnosis of PMM2-CDG will be consented. Baseline data will be collected prior to randomization and at treatment initiation. Subjects who meet all inclusion criteria and none of the exclusion criteria will be enrolled into the study. Each subject who meets all the inclusion and none of the exclusion criteria will then be randomized to placebo or acetazolamide. They will be administered weight-dependent doses of acetazolamide or an equivalent volume of placebo twice daily by mouth. Initial dose of acetazolamide is 8 mg/kg/day if subjects are taking the liquid formulation, or as per Table 1b if they are taking the capsule formulation. If taking the liquid formulation, the dose of study drug will be increased by 7 mg/kg/day to a maximum of 22 mg/kg/day (not to exceed 1000 mg/day) if well tolerated with no treatment related SAEs or abnormal pH. If the pH is <7.32, the dose will be reduced by 7 mg/kg/day. The dose will be adjusted similarly according to Table 1b if taking the capsule formulation. Subjects will be randomized after Visit 1, will initiate blinded therapy within the first week, and will continue on prescribed/adjusted blinded treatment until Visit 4. Of note, the concentration of the liquid formulation and the amount of milligrams of acetazolamide per capsule will stay constant, and the volume or number of capsules will be adjusted based on tolerance as assessed by symptoms and laboratories. If an individual is randomized to the placebo arm, the initial volume will be equivalent to 7 mg/kg/day or the initial number of capsules as per Table 1, and volume or number of capsules will also be adjusted based on symptoms and laboratory values each time dose adjustment is planned. Open label period will then begin after Visit 4 up to Visit 9 (see Figure 1 and Table 3). As both the subject and investigator do not know if the subject received placebo or acetazolamide, the dose of acetazolamide will be started at Visit 4 at 8 mg/kg/day and titrated upwards in the same manner in Visits 5 and 6 (remote) as in Visits 2 and 3 (remote). Subjects will have the option to withdraw from the study any time after Visit 4 if they do not wish to proceed onto or continue with the open label phase.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Acetazolamide | Experimental | Acetazolamide administered via capsule or liquid suspension. Capsule would be 250 mg oral capsules encapsulated by gelatin capsule and filled with lactose to match placebo. Liquid suspension would be 25 mg/mL oral suspension but adding 125 mg Acetazolamide tablets to suspending agent Ora-blend |
|
| Placebo | Placebo Comparator | Placebo administered via capsule or liquid suspension. Capsule would be a gelatin capsule filled with lactose powder to match Acetazolamide. Liquid suspension would be Ora-blend. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Placebo | Drug | administered orally or enterally |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Efficacy of Acetazolamide on Ataxia Measured Via Miniature International Cooperative Ataxia Rating Scale (Mini-ICARS) | To achieve this goal, we compared the change of Mini-ICARS score from baseline to after six months of treatment between the placebo and active treatment groups. Minimal score is 0, maximum score is 100, higher score indicates greater impairment. Each subscale has an ordinal scale with a 0 indicating normal and the higher score indicating greater impairment or that the patient was unable to complete the task. | baseline-6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Abnormal Blood pH Value | Blood pH level was assessed through venous blood gas test. The number of participants who experience a drug related adverse event related to abnormal blood pH value. | through study completion, approximately 2 years |
| Electrolyte Balance Testing |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Eva Morava-Kozicz, MD, PhD | Mayo Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic | Rochester | Minnesota | 55905 | United States | ||
| Children's Hospital of Philadelphia |
De-identified data may be shared amongst member of the consortium FCDGC and with the NIH.
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| ID | Title | Description |
|---|---|---|
| FG000 | Acetazolamide | Acetazolamide was administered via capsule or liquid suspension. Capsule was 250 mg oral capsules encapsulated by gelatin capsule and filled with lactose to match placebo. Liquid suspension was 25 mg/mL oral suspension but adding 125 mg Acetazolamide tablets to suspending agent Ora-blend Acetazolamide: administered orally or enterally |
| FG001 | Placebo | Placebo was administered via capsule or liquid suspension. Capsule was a gelatin capsule filled with lactose powder to match Acetazolamide. Liquid suspension was a Ora-blend. Placebo: administered orally or enterally |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Acetazolamide | Acetazolamide was administered via capsule or liquid suspension. Capsule was 250 mg oral capsules encapsulated by gelatin capsule and filled with lactose to match placebo. Liquid suspension was 25 mg/mL oral suspension but adding 125 mg Acetazolamide tablets to suspending agent Ora-blend Acetazolamide: administered orally or enterally |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Efficacy of Acetazolamide on Ataxia Measured Via Miniature International Cooperative Ataxia Rating Scale (Mini-ICARS) | To achieve this goal, we compared the change of Mini-ICARS score from baseline to after six months of treatment between the placebo and active treatment groups. Minimal score is 0, maximum score is 100, higher score indicates greater impairment. Each subscale has an ordinal scale with a 0 indicating normal and the higher score indicating greater impairment or that the patient was unable to complete the task. | Data was not collected nor analyzed for two subjects in the Acetazolamide arm and one subject in the Placebo arm | Posted | Mean | Standard Deviation | score on a scale | baseline-6 months |
|
Adverse Events were collected from baseline to end of study, approximately 3 years
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Acetazolamide | Acetazolamide was administered via capsule or liquid suspension. Capsule was 250 mg oral capsules encapsulated by gelatin capsule and filled with lactose to match placebo. Liquid suspension was 25 mg/mL oral suspension but adding 125 mg Acetazolamide tablets to suspending agent Ora-blend Acetazolamide: administered orally or enterally |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dehydration | Metabolism and nutrition disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal Pain | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Eva Morava-Kozicz, M.D., Ph.D. | Mayo Clinic | 507-266-9140 | Morava-Kozicz.Eva@mayo.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 26, 2024 | Jan 9, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| C535739 | Congenital disorder of glycosylation type 1A |
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| ID | Term |
|---|---|
| D005780 | Gelatin |
| D007785 | Lactose |
| D000086 | Acetazolamide |
| ID | Term |
|---|---|
| D012596 | Scleroproteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D004187 | Disaccharides |
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Randomized, double blind, placebo controlled, with optional extension period
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Double blind
| Acetazolamide | Drug | administered orally or enterally |
|
|
Electrolyte balance was assessed through combination testing on concentration of potassium, sodium, chloride, bicarbonate, magnesium, calcium, and phosphate. The number of participants who experience a drug related adverse event related to abnormal electrolyte balance. |
| through study completion, approximately 2 years |
| Urine Calcium Excretion Testing | Urine calcium excretion is measured by mg excreted per day. The number of participants who experience a drug related adverse event related to abnormal excretion of calcium. | through study completion, approximately 2 years |
| Examine Effect of Acetazolamide on PMM2 Biomarker Carbohydrate Deficient Transferrin | Number of patients with abnormal ratio result will be recorded to understand the effect acetazolamide has on this biomarker | 6 months |
| Change in Patient Reported Outcomes Measurement Information System (PROMIS) Score | PROMIS = Physical activity 10-items from 1(no days) to 5(6-7 days), Strength impact 12-item from 1(no days) to 5(6-7 days), Fatigue 23-item from 1(never) to 5(almost always), Mobility 23-item from 1(not able to do) to 5(with no trouble), Pain interference 13-item from 1(never) to 5(almost always), Upper extremity coordination 29-item from 1(not able to do) to 5(with no trouble), Global Health 9-item from 1(poor) to 5( excellent), Parent Proxy Mobility 8-item from 1(not able to do) to 5(with no trouble), Anxiety 8-item from 1(never) to 5(almost always), Depresson 8-item from 1(never) to 5(almost always), Parent Proxy Fatigue 8-item from 1(never) to 5(almost always), Peer relationships 8-item from 1(never) to 5(almost always), Parent proxy pain interference 8-item from 1(never) to 5(almost always), Pain intensity 1-item from 0(no pain) to 10(worst pain). Total scores range from 168 - 845. Lower scores indicate worse health, higher scores indicate better health | baseline, 6 months |
| Change in Dysarthria as Measured by the PATA Score | PATA test measures the number of times a patient can say the word "PATA" in a 10 second time period. Number of "PATA"s spoken in 10 seconds indicates level of dysarthria. The higher the score the less dysarthria, the lower the score more dysarthria. | baseline, 6 months |
| Change in Nijmegen Pediatric CDG Rating Scale (NPCRS) | The NPCRS is a scale that evaluates the patient's current function, system specific involvement, and current clinical assessment. Total scores range from 0 - 82. A mild score is 0-14, moderate score is 15-25, and severe is a score >26. | baseline, 6 months |
| Philadelphia |
| Pennsylvania |
| 19104 |
| United States |
| Seattle Children's Hospital | Seattle | Washington | 98105 | United States |
| Physician Decision |
|
| Withdrawal by Subject |
|
| BG001 |
| Placebo |
Placebo was administered via capsule or liquid suspension. Capsule was a gelatin capsule filled with lactose powder to match Acetazolamide. Liquid suspension was a Ora-blend. Placebo: administered orally or enterally |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Placebo | Placebo was administered via capsule or liquid suspension. Capsule was a gelatin capsule filled with lactose powder to match Acetazolamide. Liquid suspension was a Ora-blend. Placebo: administered orally or enterally |
|
|
|
| Secondary | Abnormal Blood pH Value | Blood pH level was assessed through venous blood gas test. The number of participants who experience a drug related adverse event related to abnormal blood pH value. | Posted | Count of Participants | Participants | through study completion, approximately 2 years |
|
|
|
|
| Secondary | Electrolyte Balance Testing | Electrolyte balance was assessed through combination testing on concentration of potassium, sodium, chloride, bicarbonate, magnesium, calcium, and phosphate. The number of participants who experience a drug related adverse event related to abnormal electrolyte balance. | Posted | Count of Participants | Participants | through study completion, approximately 2 years |
|
|
|
|
| Secondary | Urine Calcium Excretion Testing | Urine calcium excretion is measured by mg excreted per day. The number of participants who experience a drug related adverse event related to abnormal excretion of calcium. | Posted | Count of Participants | Participants | through study completion, approximately 2 years |
|
|
|
|
| Secondary | Examine Effect of Acetazolamide on PMM2 Biomarker Carbohydrate Deficient Transferrin | Number of patients with abnormal ratio result will be recorded to understand the effect acetazolamide has on this biomarker | Data was not collected nor analyzed for this outcome measure. Data collection for this outcome never occurred. PMM2 biomarker carbohydrate deficient transferrin was not collected for any subjects. The test was never collected for any subjects. | Posted | 6 months |
|
|
| Secondary | Change in Patient Reported Outcomes Measurement Information System (PROMIS) Score | PROMIS = Physical activity 10-items from 1(no days) to 5(6-7 days), Strength impact 12-item from 1(no days) to 5(6-7 days), Fatigue 23-item from 1(never) to 5(almost always), Mobility 23-item from 1(not able to do) to 5(with no trouble), Pain interference 13-item from 1(never) to 5(almost always), Upper extremity coordination 29-item from 1(not able to do) to 5(with no trouble), Global Health 9-item from 1(poor) to 5( excellent), Parent Proxy Mobility 8-item from 1(not able to do) to 5(with no trouble), Anxiety 8-item from 1(never) to 5(almost always), Depresson 8-item from 1(never) to 5(almost always), Parent Proxy Fatigue 8-item from 1(never) to 5(almost always), Peer relationships 8-item from 1(never) to 5(almost always), Parent proxy pain interference 8-item from 1(never) to 5(almost always), Pain intensity 1-item from 0(no pain) to 10(worst pain). Total scores range from 168 - 845. Lower scores indicate worse health, higher scores indicate better health | Data was not collected nor analyzed for seven subjects in the Acetazolamide arm and four subjects in the Placebo arm | Posted | Mean | Standard Deviation | score on a scale | baseline, 6 months |
|
|
|
| Secondary | Change in Dysarthria as Measured by the PATA Score | PATA test measures the number of times a patient can say the word "PATA" in a 10 second time period. Number of "PATA"s spoken in 10 seconds indicates level of dysarthria. The higher the score the less dysarthria, the lower the score more dysarthria. | Data was not collected nor analyzed for four participants in the Acetazolamide arm and three participants in the Placebo arm | Posted | Mean | Standard Deviation | words/10 sec | baseline, 6 months |
|
|
|
|
| Secondary | Change in Nijmegen Pediatric CDG Rating Scale (NPCRS) | The NPCRS is a scale that evaluates the patient's current function, system specific involvement, and current clinical assessment. Total scores range from 0 - 82. A mild score is 0-14, moderate score is 15-25, and severe is a score >26. | Data was not collected nor analyzed for three participants in the Acetazolamide arm and one participant in the Placebo arm | Posted | Mean | Standard Deviation | score on a scale | baseline, 6 months |
|
|
|
|
| 0 |
| 13 |
| 1 |
| 13 |
| 9 |
| 13 |
| EG001 | Placebo | Placebo was administered via capsule or liquid suspension. Capsule was a gelatin capsule filled with lactose powder to match Acetazolamide. Liquid suspension was a Ora-blend. Placebo: administered orally or enterally | 0 | 12 | 3 | 12 | 8 | 12 |
| Fever | General disorders | Systematic Assessment |
|
| Sepsis | Infections and infestations | Systematic Assessment |
|
| Thromboembolic Event | Vascular disorders | Systematic Assessment |
|
| Acute Kidney Injury | Renal and urinary disorders | Systematic Assessment |
|
| Acidosis | Metabolism and nutrition disorders | Systematic Assessment |
|
| Alanine Aminotransferase Increased | Investigations | Systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Ataxia | Nervous system disorders | Systematic Assessment |
|
| Atelectasis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Back Pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Bloating | Gastrointestinal disorders | Systematic Assessment |
|
| Blood and Lymphatic System Disorders - Other | Blood and lymphatic system disorders | Systematic Assessment |
|
| Anorexia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Dizziness | Nervous system disorders | Systematic Assessment |
|
| Ear and Labyrinth Disorders - Other | Ear and labyrinth disorders | Systematic Assessment |
|
| Eye Disorders - Other | Eye disorders | Systematic Assessment |
|
| Eye Pain | Eye disorders | Systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Fatigue | General disorders | Systematic Assessment |
|
| Fever | General disorders | Systematic Assessment |
|
| Flank Pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Gastritis | Gastrointestinal disorders | Systematic Assessment |
|
| Gastrointestinal Disorders - Other | Gastrointestinal disorders | Systematic Assessment |
|
| General Disorders and Administration Site Conditions - Other | General disorders | Systematic Assessment |
|
| Headache | Nervous system disorders | Systematic Assessment |
|
| Hypersomnia | Nervous system disorders | Systematic Assessment |
|
| Immune System Disorders - Other | Immune system disorders | Systematic Assessment |
|
| Infections and Infestations - Other | Infections and infestations | Systematic Assessment |
|
| Investigations - Other | Investigations | Systematic Assessment |
|
| Lethargy | Nervous system disorders | Systematic Assessment |
|
| Malaise | General disorders | Systematic Assessment |
|
| Metabolism and Nutrition Disorders - Other | Metabolism and nutrition disorders | Systematic Assessment |
|
| Musculoskeletal and Connective Tissue Disorder - Other | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Nasal Congestion | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Nausea | General disorders | Systematic Assessment |
|
| Nervous System Disorders - Other | Nervous system disorders | Systematic Assessment |
|
| Otitis Media | Ear and labyrinth disorders | Systematic Assessment |
|
| Pharyngitis | Infections and infestations | Systematic Assessment |
|
| Rash Acneiform | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Renal and Urinary Disorders - Other | Renal and urinary disorders | Systematic Assessment |
|
| Respiratory, Thoracic and Mediastinal Disorders - Other | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Scoliosis | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Seizure | Nervous system disorders | Systematic Assessment |
|
| Sinusitis | Infections and infestations | Systematic Assessment |
|
| Skin and Subcutaneous Tissue Disorders - Other | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Somnolence | Nervous system disorders | Systematic Assessment |
|
| Stomach Pain | Gastrointestinal disorders | Systematic Assessment |
|
| Tremor | Nervous system disorders | Systematic Assessment |
|
| Upper Respiratory Infection | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Urinary Frequency | Renal and urinary disorders | Systematic Assessment |
|
| Urinary Incontinence | Renal and urinary disorders | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Systematic Assessment |
|
| Edema Limbs | General disorders | Systematic Assessment |
|
| Rhinitis Infective | Infections and infestations | Systematic Assessment |
|
| Non-Cardiac Chest Pain | General disorders | Systematic Assessment |
|
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| D009844 |
| Oligosaccharides |
| D011134 | Polysaccharides |
| D002241 | Carbohydrates |
| D000073893 | Sugars |
| D013830 | Thiadiazoles |
| D013844 | Thiazoles |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |