Acetazolamide Efficacy in Ataxia in PMM2-CDG

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.

• Placebo (Drug), also known as Gelatin, lactose, and Ora-blend: administered orally or enterally
• Acetazolamide (Drug), also known as Diamox: administered orally or enterally

Primary outcomes

• Efficacy of Acetazolamide on Ataxia Measured Via Miniature International Cooperative Ataxia Rating Scale (Mini-ICARS) [baseline-6 months]: 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.

Secondary outcomes

• Abnormal Blood pH Value [through study completion, approximately 2 years]: 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.
• Electrolyte Balance Testing [through study completion, approximately 2 years]: 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.
• Urine Calcium Excretion Testing [through study completion, approximately 2 years]: 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.
• Examine Effect of Acetazolamide on PMM2 Biomarker Carbohydrate Deficient Transferrin [6 months]: Number of patients with abnormal ratio result will be recorded to understand the effect acetazolamide has on this biomarker
• Change in Patient Reported Outcomes Measurement Information System (PROMIS) Score [baseline, 6 months]: 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
• Change in Dysarthria as Measured by the PATA Score [baseline, 6 months]: 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.
• Change in Nijmegen Pediatric CDG Rating Scale (NPCRS) [baseline, 6 months]: 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.

Sex: All, ages: 4 Years to any

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

Participant flow

Outcome results

• Efficacy of Acetazolamide on Ataxia Measured Via Miniature International Cooperative Ataxia Rating Scale (Mini-ICARS) (Primary), Mean, score on a scale: Acetazolamide 1.64 +/- 3.20; Placebo 1.36 +/- 3.23 (p 0.84)
• Abnormal Blood pH Value (Secondary), Count of participants, Participants: Acetazolamide 0; Placebo 1 (p 0.48)
• Electrolyte Balance Testing (Secondary), Count of participants, Participants: Acetazolamide 0; Placebo 1 (p 0.48)
• Urine Calcium Excretion Testing (Secondary), Count of participants, Participants: Acetazolamide 0; Placebo 0 (p >0.99)
• Examine Effect of Acetazolamide on PMM2 Biomarker Carbohydrate Deficient Transferrin (Secondary)
• Change in Patient Reported Outcomes Measurement Information System (PROMIS) Score (Secondary), Mean, score on a scale: Acetazolamide 3.02 +/- 4.45; Placebo 0.75 +/- 4.09
• Change in Dysarthria as Measured by the PATA Score (Secondary), Mean, words/10 sec: Acetazolamide 2.30 +/- 3.71; Placebo 0.59 +/- 3.11 (p 0.31)
• Change in Nijmegen Pediatric CDG Rating Scale (NPCRS) (Secondary), Mean, score on a scale: Acetazolamide 1.20 +/- 1.99; Placebo 0.27 +/- 1.79 (p 0.09)

Adverse events

Time frame: Adverse Events were collected from baseline to end of study, approximately 3 years

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2024-01-26)

• Eva Morava-Kozicz, MD, PhD, Principal investigator, Mayo Clinic