oral epalrestat therapy in pediatric subjects with pmm2-cdg

Conditions: Pmm2-CDG; Phosphomannomutase 2 Deficiency; Phosphomannomutase 2 Congenital Disorder of Glycosylation; Phosphomannomutase II Congenital Disorder of Glycosylation; Phosphomannomutase II Deficiency

Summary: this is a prospective, single-center, randomized, double-blind, placebo-controlled study designed to assess the safety, tolerability, and clinical and metabolic improvement of pediatric subjects with pmm2-cdg on oral epalrestat therapy vs. placebo.

this is a prospective, single-center, randomized, double-blind, placebo-controlled study designed to assess the safety, tolerability, and clinical and metabolic improvement of pediatric subjects with pmm2-cdg on oral epalrestat therapy vs. placebo. the primary study objective is to evaluate the safety and probable benefit of oral epalrestat therapy in pediatric subjects with pmm2-cdg. study outcomes include evaluating the metabolic improvement of pediatric subjects treated with oral epalrestat therapy compared to placebo, evaluating safety, clinical improvement, and pharmocokinetics (pk) of oral epalrestat therapy in pediatric subjects compared to placebo, and evaluating urine polyols, adverse events, laboratory data, other safety measures, pk, and quality of life surveys to measure clinical improvement.

Eligibility criteria:
inclusion criteria: 1. age ≥ 2 and \< 18 years 2. diagnosis of pmm2-cdg, based on molecularly confirmed biallelic pmm2 pathogenic variants (can be historical diagnosis with lab report on file) 3. informed consent (and assent, as applicable) document personally signed by the legally authorized representative of the patient, indicating that the patient's parent/guardian has been informed and agreed to all aspects of the study 4. be willing and able to adhere to the study assessments and schedule described in the protocol and consent/assent documents 5. negative urine pregnancy test (only for female subjects of child-bearing potential) 6. for subjects of child-bearing potential-only, subject has been counseled on and agrees to the requirement either for double barrier contraceptive methods and/or for total abstinence from prior to randomization through 3-months after the cessation of treatment. exclusion criteria: 1. known or suspected other known cdg 2. known allergy to aldose reductase inhibitors 3. hypersensitivity to epalrestat 4. hepatic impairment defined as any one of the following: 1. ast/alt \>5x uln in the 6 months prior to screening 2. bilirubin \>2x uln in the last 6 months prior to screening 3. synthetic liver dysfunction (albumin deficiency \< 2.8 mmol/l) at screening, or 4. diagnosis of liver fibrosis (fibroscan \> 7 kpa) confirmed by liver elastogram at screening 5. 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) 6. low platelet count (\< 125x109 /l) 7. any other clinically significant lab abnormality which, in the opinion of the investigator, should be exclusionary 8. anemia (hgb \< 10 g/dl) 9. use of an investigational drug, including acetazolamide, in the past 28 days; use of an investigational biologic in the past 12 months 10. concurrent or planned participation in interventional protocol or use of any other unapproved therapeutics, and, 11. any other medical condition, which, in the opinion of the investigator, will interfere with the patient's ability to comply with the protocol, compromises patient safety, or interferes with the interpretation of the study results.