Oral Epalrestat Therapy in Pediatric Subjects With PMM2-CDG

NCT04925960 | Terminated Phase 3 DMC FDA Drug

• 1 other identifier: 21-000492
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

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

Outcome Measures

Primary Outcomes (3)

• Change in sorbitol (mmol/mol creatinine)

  Change in sorbitol from baseline between study arms

  9 months

• Change in ICARS

  Change in ICARS from baseline between study arms

  9 months

• Change in Antithrombin III (ATIII)

  Change in ATIII from baseline between study arms

  9 months

Secondary Outcomes (6)

• Change of Body Max Index (BMI) percentile

  9 months

• Change of factor XI activity percentage

  9 months

• Change of liver transaminases (U/L)

  9 months

• Change of transferrin glycosylation (ratio)

  9 months

• Change in Nijmegen Pediatric CDG Rating Scale (NPCRS) score

  9 months

Study Arms (2)

Epalrestat

EXPERIMENTAL

Epalrestat will be administered orally, 3 times per day (TID) spaced out as evenly as possible over 24 hours in a divided dose starting on Day 1 of the Study.

Drug: Epalrestat

Placebo

PLACEBO COMPARATOR

Placebo will be administered orally, 3 times per day (TID) spaced out as evenly as possible over 24 hours in a divided dose starting on Day 1 of the Study.

Drug: Placebo

Interventions

Epalrestat DRUG

Epalrestat is a noncompetitive and reversible aldose reductase inhibitor (ARI) used for the treatment of diabetic neuropathy in Japan. The drug's ability to safely improve symptoms of neuropathy alone by reducing oxidative stress, increasing glutathione levels, and reducing intracellular sorbitol accumulation make it a desirable medication for PMM2-CDG patients who commonly suffer with various neuropathies. However, work recently conducted by Perlara, a public benefit company with the mandate to screen existing commercially available drugs for possible application in rare diseases, has demonstrated that Epalrestat can also elevate the level PMM2 produced endogenously. This may reduce the severity of the morbidities associated with PMM2-CDG.

Epalrestat

Placebo DRUG

The placebo capsule with be identical in appearance to the Epalrestat capsule. It will contain microcrystalline cellulose filler in a gelatin capsule.

Placebo

Eligibility Criteria

• Age: 2 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Age ≥ 2 and \< 18 years
• Diagnosis of PMM2-CDG, based on molecularly confirmed biallelic PMM2 pathogenic variants (can be historical diagnosis with lab report on file)
• 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
• Be willing and able to adhere to the study assessments and schedule described in the protocol and consent/assent documents
• Negative urine pregnancy test (only for female subjects of child-bearing potential)
• 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.

You may not qualify if:

• Known or suspected other known CDG
• Known allergy to aldose reductase inhibitors
• Hypersensitivity to epalrestat
• Hepatic impairment defined as any one of the following:
• AST/ALT \>5x ULN in the 6 months prior to screening
• Bilirubin \>2X ULN in the last 6 months prior to screening
• Synthetic liver dysfunction (albumin deficiency \< 2.8 mmol/L) at screening, or
• Diagnosis of liver fibrosis (Fibroscan \> 7 kPa) confirmed by liver elastogram at screening
• 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)
• Low platelet count (\< 125x109 /L)
• Anemia (Hgb \< 10 g/dL)
• Use of an investigational drug, including acetazolamide, in the past 28 days; use of an investigational biologic in the past 12 months
• Concurrent or planned participation in interventional protocol or use of any other unapproved therapeutics, and,
• 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.

Sponsors & Collaborators

• Maggie's Pearl, LLC: lead

Study Sites (1)

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

MeSH Terms

Conditions

Congenital disorder of glycosylation type 1A

Interventions

epalrestat

Study Officials

• Eva Morava-Kozicz, MD, PhD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Patients and all study personnel will remain blinded to the original treatment assignment until study close.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Subjects will be randomized to treatment or placebo. Patients and study staff will be blinded to the study arm.

Study Record Dates

• First Submitted: June 8, 2021
• First Posted: June 14, 2021
• Study Start: November 10, 2022
• Primary Completion: February 28, 2025
• Study Completion: February 28, 2025
• Last Updated: September 25, 2025

Record last verified: 2025-09

Locations

US (1)