Oral Epalrestat Therapy in Pediatric Subjects With PMM2-CDG

• ClinicalTrials.gov Identifier: NCT04925960
• Recruitment Status: Active, not recruiting
• First Posted: June 14, 2021
• Last Update Posted: January 11, 2024
• Sponsor: Maggie's Pearl, LLC
• Information provided by (Responsible Party): Maggie's Pearl, LLC

Tracking Information

• First Submitted Date: June 8, 2021
• First Posted Date: June 14, 2021
• Last Update Posted Date: January 11, 2024
• Actual Study Start Date: November 10, 2022
• Estimated Primary Completion Date: February 28, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 4, 2022)

• Change in sorbitol (mmol/mol creatinine) [ Time Frame: 9 months ]
  Change in sorbitol from baseline between study arms
• Change in ICARS [ Time Frame: 9 months ]
  Change in ICARS from baseline between study arms
• Change in Antithrombin III (ATIII) [ Time Frame: 9 months ]
  Change in ATIII from baseline between study arms

Original Primary Outcome Measures (submitted: June 8, 2021)

• Change in NPCRS score from baseline to twelve months [ Time Frame: 12 months ]
  The primary endpoint will be a composite score encompassing the NPCRS and ICARS scales. Each of the two scores (NPCRS and ICARS) is to be normalized, and equally weighted. Change from baseline of the composite will be assessed at 12 months. 0.5* (NPCRS) + 0.5 * (ICARS), change from baseline compared to a change of zero (0).
• Change in ICARS score from baseline to twelve months [ Time Frame: 12 months ]
  The primary endpoint will be a composite score encompassing the NPCRS and ICARS scales. Each of the two scores (NPCRS and ICARS) is to be normalized, and equally weighted. Change from baseline of the composite will be assessed at 12 months. 0.5* (NPCRS) + 0.5 * (ICARS), change from baseline compared to a change of zero (0).

Current Secondary Outcome Measures (submitted: January 4, 2022)

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

Original Secondary Outcome Measures (submitted: June 8, 2021)

• Change of BMI percentile from baseline to twelve months [ Time Frame: 12 months ]
  Change of BMI percentile from baseline to twelve months
• Change of urine polyols (mmol/mol creatinine) from baseline to twelve months [ Time Frame: 12 months ]
  Change of urine polyols from baseline to twelve months
• Change of antithrombin III activity (%) from baseline to twelve months [ Time Frame: 12 months ]
  Change of antithrombin III activity from baseline to twelve months
• Change of factor XI activity (%) from baseline to twelve months [ Time Frame: 12 months ]
  Change of factor XI activity from baseline to twelve months
• Change of liver transaminases (U/L) from baseline to twelve months [ Time Frame: 12 months ]
  Change of liver transaminases from baseline to twelve months
• Change of transferrin glycosylation (ratio) from baseline to twelve months [ Time Frame: 12 months ]
  Change of transferrin glycosylation from baseline to twelve months
• Change in Goal Attainment Scale score from baseline to twelve months [ Time Frame: 12 months ]
  Change in Goal Attainment Scale score from baseline to twelve months

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Oral Epalrestat Therapy in Pediatric Subjects With PMM2-CDG
• 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)
• 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.
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Patients and all study personnel will remain blinded to the original treatment assignment until study close.

Primary Purpose: Treatment

Condition

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

Intervention

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

Study Arms

• Experimental: Epalrestat
  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.
  Intervention: Drug: Epalrestat
• Placebo Comparator: Placebo
  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.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: January 4, 2022): 40
• Original Estimated Enrollment (submitted: June 8, 2021): 30
• Estimated Study Completion Date: December 31, 2025
• Estimated Primary Completion Date: February 28, 2024 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04925960
• Other Study ID Numbers: 21-000492
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Maggie's Pearl, LLC
• Original Responsible Party: Eva Morava-Kozicz, Mayo Clinic, MD, PhD
• Current Study Sponsor: Maggie's Pearl, LLC
• Original Study Sponsor: Eva Morava-Kozicz
• Collaborators: Not Provided

Investigators

• Principal Investigator: Eva Morava-Kozicz, MD, PhD; Mayo Clinic

• PRS Account: Maggie's Pearl, LLC
• Verification Date: January 2024