Oral Epalrestat Therapy in Pediatric Subjects With PMM2-CDG

Study Overview
=================
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.

Detailed Description
-----------------
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.

Official Title
-----------------
A Prospective, Randomized, Double-Blind, Placebo-Controlled, Single-Center Study of Oral Epalrestat Therapy in Pediatric Subjects With Phosphomannomutase 2-congenital Disorder of Glycosylation (PMM2-CDG)

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

Intervention / Treatment
-----------------
* Drug: Epalrestat
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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. Exclusion Criteria: 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) Any other clinically significant lab abnormality which, in the opinion of the investigator, should be exclusionary 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.

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects will be randomized to treatment or placebo. Patients and study staff will be blinded to the study arm.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Epalrestat<br>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<br>* 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.<br>|
| Placebo Comparator: Placebo<br>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<br>* The placebo capsule with be identical in appearance to the Epalrestat capsule. It will contain microcrystalline cellulose filler in a gelatin capsule.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Body Max Index (BMI) percentile | Change of BMI percentile from baseline between study arms | 9 months | 
| Change of factor XI activity percentage | Change of factor XI activity from baseline between study arms | 9 months | 
| Change of liver transaminases (U/L) | Change of liver transaminases from baseline between study arms | 9 months | 
| Change of transferrin glycosylation (ratio) | Change of transferrin glycosylationfrom baseline between study arms | 9 months | 
| Change in Nijmegen Pediatric CDG Rating Scale (NPCRS) score | Change in NPCRS from baseline between study arms | 9 months | 
| Change of normalized mannitol (mmol/mol creatinine) | Change of normalized mannitol from baseline between study arms | 9 months |