Acetazolamide Efficacy in Ataxia in PMM2-CDG

Study Results

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Basic Information

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Recruitment Status

TERMINATED

Clinical Phase

PHASE2/PHASE3

Total Enrollment

25 participants

Study Classification

INTERVENTIONAL

Study Start Date

2021-03-17

Study Completion Date

2024-01-24

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.

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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.

Conditions

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Pmm2-CDG CDG1A

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Randomized, double blind, placebo controlled, with optional extension period

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Double blind

Study Groups

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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

Group Type EXPERIMENTAL

Acetazolamide

Intervention Type DRUG

administered orally or enterally

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.

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

administered orally or enterally

Interventions

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Placebo

administered orally or enterally

Intervention Type DRUG

Acetazolamide

administered orally or enterally

Intervention Type DRUG

Other Intervention Names

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Gelatin, lactose, and Ora-blend Diamox

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

Minimum Eligible Age

4 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No