Acetazolamide Efficacy in Ataxia in PMM2-CDG
Acetazolamide Efficacy in Ataxia in PMM2-CDG
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.
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