Acetazolamide Efficacy in Ataxia in PMM2-CDG

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Randomized, Double-blind, Placebo-controlled Study Evaluating Acetazolamide Efficacy in Ataxia in PMM2-CDG

Conditions
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Pmm2-CDG, CDG1A

Intervention / Treatment
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* Drug: Placebo
* Drug: Acetazolamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Molecularly and/or enzymatically-confirmed PMM2-CDG, Age ≥4 years old, and Affected with ataxia evidenced by mini International Cooperative Ataxia Rating Scale (Mini-ICARS) score >0 at baseline. Exclusion Criteria: Hepatic impairment defined as AST/ALT >5x ULN in the last 12 months Renal impairment defined as serum creatinine: > 0.5 mg/dL (<6 years); > 0.7 mg/dL (7-10 years); > 1.24 mg/dL (> 11 years)- Hypersensitivity to acetazolamide Hypersensitivity to any of the components of the placebo History of treatment with experimental drug within 28 days of Visit 1 Currently taking Mecamylamine, Sodium Phosphates, Salicylates, Mefloquine, Methenamine and other Carbonic Anhydrase Inhibitors

Ages Eligible for Study
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Minimum Age: 4 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double blind, placebo controlled, with optional extension period
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acetazolamide<br>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 | Drug: Acetazolamide<br>* administered orally or enterally<br>* Other names: Diamox;|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* administered orally or enterally<br>* Other names: Gelatin, lactose, and Ora-blend;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of Acetazolamide on ataxia measured via Miniature International Cooperative Ataxia Rating Scale (mini-ICARS) | To achieve this goal, we will compare 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with assessed adverse events of long term acetazolamide administration as seen on blood pH value | Blood pH level will be assessed through venous blood gas test. Percentage of patients treated with Acetazolamide who experience a drug related adverse event related to abnormal blood pH value. | through study completion, an average of three years | 
| Percentage of participants with assessed adverse events of long term acetazolamide administration as seen on electrolyte balance testing | Electrolyte balance will be assessed through combination testing on concentration of potassium, sodium, chloride, bicarbonate, magnesium, calcium, and phosphate. Percentage of patients treated with Acetazolamide who experience a drug related adverse event related to abnormal electrolyte balance. | through study completion, an average of three years | 
| Percentage of participants with assessed adverse events of long term acetazolamide administration as seen on urine calcium excretion testing. | Urine calcium excretion is measured by mg excreted per day. Percentage of patients treated with Acetazolamide who experience a drug related adverse event related to abnormal excretion of calcium. | through study completion, an average of three years | 
| Examine effect of Acetazolamide on PMM2 biomarker carbohydrate deficient transferrin | Carbohydrate deficient transferrin is reported by ratio. Number of patients with abnormal ratio result will be recorded to understand the effect acetazolamide has on this biomarker | baseline and 6 months | 
| Examine effect of Acetazolamide on Patient Reported Outcomes Measuremen Information System (PROMIS) Score | PROMIS score measures physical activity, strength impact, fatigue, mobility, pain interference, upper extremity coordination, global health, mobility, anxiety, depression, peer relationships, and pain intensity. These are patient reported scores. Higher score means more or the concept being measured (example: high score on Fatigue scale means high level of fatigue). | baseline and 6 months | 
| Examine effect of Acetazolamide on 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 PATAs spoken in 10 seconds indicates level of dysarthria. | baseline and 6 months | 
| Examine effect of Acetazolamide on disease progression as measured by the 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. A mild score is 0-14, moderate score is 15-25, and severe is a score >26. | baseline and 6 months |