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Oral Epalrestat Therapy in Pediatric Subjects With PMM2-CDG

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04925960
Recruitment Status : Not yet recruiting
First Posted : June 14, 2021
Last Update Posted : April 5, 2022
Sponsor:
Information provided by (Responsible Party):
Maggie's Pearl, LLC

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.

Condition or disease Intervention/treatment Phase
Pmm2-CDG Phosphomannomutase 2 Deficiency Phosphomannomutase 2 Congenital Disorder of Glycosylation Phosphomannomutase II Congenital Disorder of Glycosylation Phosphomannomutase II Deficiency Drug: Epalrestat Drug: Placebo Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
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
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)
Estimated Study Start Date : July 1, 2022
Estimated Primary Completion Date : February 28, 2026
Estimated Study Completion Date : December 31, 2026


Arm Intervention/treatment
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.
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.

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




Primary Outcome Measures :
  1. Change in sorbitol (mmol/mol creatinine) [ Time Frame: 9 months ]
    Change in sorbitol from baseline between study arms

  2. Change in ICARS [ Time Frame: 9 months ]
    Change in ICARS from baseline between study arms

  3. Change in Antithrombin III (ATIII) [ Time Frame: 9 months ]
    Change in ATIII from baseline between study arms


Secondary Outcome Measures :
  1. Change of Body Max Index (BMI) percentile [ Time Frame: 9 months ]
    Change of BMI percentile from baseline between study arms

  2. Change of factor XI activity percentage [ Time Frame: 9 months ]
    Change of factor XI activity from baseline between study arms

  3. Change of liver transaminases (U/L) [ Time Frame: 9 months ]
    Change of liver transaminases from baseline between study arms

  4. Change of transferrin glycosylation (ratio) [ Time Frame: 9 months ]
    Change of transferrin glycosylationfrom baseline between study arms

  5. Change in Nijmegen Pediatric CDG Rating Scale (NPCRS) score [ Time Frame: 9 months ]
    Change in NPCRS from baseline between study arms

  6. Change of normalized mannitol (mmol/mol creatinine) [ Time Frame: 9 months ]
    Change of normalized mannitol from baseline between study arms



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04925960


Contacts
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Contact: Eva Morava-Kozicz, MD, PhD 507-266-2967 morava-kozicz.eva@mayo.edu
Contact: Kaitlin Schwartz, BS 507-293-9114 schwartz.kaitlin@mayo.edu

Sponsors and Collaborators
Maggie's Pearl, LLC
Investigators
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Principal Investigator: Eva Morava-Kozicz, MD, PhD Mayo Clinic
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Responsible Party: Maggie's Pearl, LLC
ClinicalTrials.gov Identifier: NCT04925960    
Other Study ID Numbers: 21-000492
First Posted: June 14, 2021    Key Record Dates
Last Update Posted: April 5, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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
Additional relevant MeSH terms:
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Congenital Disorders of Glycosylation
Disease
Pathologic Processes
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Epalrestat
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action