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

Tracking Information
First Submitted Date  ICMJE June 8, 2021
First Posted Date  ICMJE June 14, 2021
Last Update Posted Date January 11, 2024
Actual Study Start Date  ICMJE November 10, 2022
Estimated Primary Completion Date February 28, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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).
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE Oral Epalrestat Therapy in Pediatric Subjects With PMM2-CDG
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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  ICMJE
  • Pmm2-CDG
  • Phosphomannomutase 2 Deficiency
  • Phosphomannomutase 2 Congenital Disorder of Glycosylation
  • Phosphomannomutase II Congenital Disorder of Glycosylation
  • Phosphomannomutase II Deficiency
Intervention  ICMJE
  • 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  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: January 4, 2022)
40
Original Estimated Enrollment  ICMJE
 (submitted: June 8, 2021)
30
Estimated Study Completion Date  ICMJE December 31, 2025
Estimated Primary Completion Date February 28, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04925960
Other Study ID Numbers  ICMJE 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  ICMJE
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  ICMJE Maggie's Pearl, LLC
Original Study Sponsor  ICMJE Eva Morava-Kozicz
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Eva Morava-Kozicz, MD, PhD Mayo Clinic
PRS Account Maggie's Pearl, LLC
Verification Date January 2024

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP