Acetazolamide Efficacy in Ataxia in PMM2-CDG

A Randomized, Double-blind, Placebo-controlled Study Evaluating 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.

Study Overview

• Status: Terminated
• Conditions: Pmm2-CDG; CDG1A
• Intervention / Treatment: Drug: Acetazolamide; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Acetazolamide; 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; administered orally or enterally; Other Names: Diamox
Placebo Comparator: Placebo; 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; administered orally or enterally; Other Names: Gelatin, lactose, and Ora-blend

What is the study measuring?

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 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

Secondary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: Children's Hospital of Philadelphia; Seattle Children's Hospital
• Investigators: Principal Investigator: Eva Morava-Kozicz, MD, PhD, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): March 17, 2021
• Primary Completion (Actual): January 24, 2024
• Study Completion (Actual): January 24, 2024

Study Registration Dates

• First Submitted: December 14, 2020
• First Submitted That Met QC Criteria: December 17, 2020
• First Posted (Actual): December 22, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 15, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Carbohydrate Metabolism, Inborn Errors; Congenital Disorders of Glycosylation; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Diuretics; Natriuretic Agents; Anticonvulsants; Carbonic Anhydrase Inhibitors; Acetazolamide
• Other Study ID Numbers: 20-000634

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: De-identified data may be shared amongst member of the consortium FCDGC and with the NIH.

Drug and device information, study documents

• 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