Clinical trial NCT04679389: Acetazolamide Efficacy in Ataxia in PMM2-CDG
Official title: A Randomized, Double-blind, Placebo-controlled Study Evaluating Acetazolamide Efficacy in Ataxia in PMM2-CDG
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Pmm2-CDG
CDG1A
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: Seattle Children's Hospital
name: Children's Hospital of Philadelphia
First posted: 2020-12-22
Enrollment: 25
Sex: ALL
Minimum age (years): 4
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double blind, placebo controlled, with optional extension period
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Efficacy of Acetazolamide on Ataxia Measured Via Miniature International Cooperative Ataxia Rating Scale (Mini-ICARS)
timeFrame: baseline-6 months
Secondary outcomes:
measure: Abnormal Blood pH Value
timeFrame: through study completion, approximately 2 years
measure: Electrolyte Balance Testing
timeFrame: through study completion, approximately 2 years
measure: Urine Calcium Excretion Testing
timeFrame: through study completion, approximately 2 years
measure: Examine Effect of Acetazolamide on PMM2 Biomarker Carbohydrate Deficient Transferrin
timeFrame: 6 months
measure: Change in Patient Reported Outcomes Measurement Information System (PROMIS) Score
timeFrame: baseline, 6 months
measure: Change in Dysarthria as Measured by the PATA Score
timeFrame: baseline, 6 months
measure: Change in Nijmegen Pediatric CDG Rating Scale (NPCRS)
timeFrame: baseline, 6 months
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
Study officials:
affiliation: Mayo Clinic
name: Eva Morava-Kozicz, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: