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Multi-Center Study of ManNAc for GNE Myopathy (MAGiNE)

Primary Purpose

GNE Myopathy

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
ManNAc
Placebo
Sponsored by
Leadiant Biosciences, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for GNE Myopathy focused on measuring GNE Myopathy, Hereditary Inclusion Body Myopathy (HIBM), Distal Myopathy with Rimmed Vacuoles (DMRV), Nonaka Myopathy, Inclusion Body Myopathy type 2 (IBM-2)

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Subject should be 18-70 years of age at the time of enrollment, inclusive, and of either gender.
  2. Subject has a diagnosis of GNE myopathy based upon a consistent clinical course and biallelic GNE gene mutations that classify as pathogenic or likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines.
  3. Subjects must have 10.00-65.99% of predicted muscle strength measured by QMA at screening in at least one of the selected muscle groups (ankle dorsiflexion, knee flexion, grip, shoulder abduction and elbow flexion).
  4. Subject has the ability to travel to the Clinical Trial Site for visits.
  5. Subjects must be able to communicate effectively with study staff and understand the requirements of the protocol without translators.
  6. Subject must be able to comply with requirements of the protocol, including blood collection, drug administration, and muscle strength assessments.
  7. Women of childbearing potential must be willing to use an effective method of contraception for the duration of the trial. It is recommended that male subjects follow birth control measures for the duration of the trial.
  8. Subject must be able to provide informed consent.

Exclusion Criteria:

  1. Subject had an infection or medical illness requiring intravenous antibiotics or hospitalization within 30 days prior to the baseline/randomization visit.
  2. Subject has another comorbid condition which may affect physical function.
  3. Subject has a psychiatric illness or neurological disease that would interfere with the ability to comply with the requirements of this protocol.
  4. Subject with hepatic laboratory parameters (AST, ALT, GGTP), equal to or greater than 3 times the upper limit of normal at screening.
  5. Subject with existing renal dysfunction, as defined by glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 at screening.
  6. Subject is anemic (defined as Hematocrit <30%) or has platelets <75 x 10^3/µL or white blood cell count less than 3 x 10^3/µL at screening.
  7. Subject shows evidence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematological, metabolic, or gastrointestinal disease, or has a condition that requires immediate surgical intervention.
  8. Subject is pregnant or breastfeeding at any time during the study.
  9. Subject has received treatment with another investigational drug, investigational device, or approved therapy for investigational use less than 90 days prior to screening.
  10. Subject has received any dose of ManNAc, sialic acid, intravenous immunoglobulin (IVIG), and/or other compounds containing, or that can be metabolized into sialic acid, within 6 months prior to enrollment as reported by subject at the time of screening.
  11. Subject has received stem cell therapy or gene therapy within 1 year prior to screening.
  12. Subject has hypersensitivity to ManNAc or erythritol or in the judgment of the investigator, has a condition that places the subject at increased risk for adverse effects.
  13. The presence of persistent diarrhea or malabsorption that could interfere with the subject's ability to absorb drugs or to tolerate ManNAc therapy.

Sites / Locations

  • UCLA
  • University of Iowa
  • University of Kansas, Medical Center
  • NIH Clinical Center
  • Brigham and Women's Hospital
  • Washington University
  • Columbia University Medical Center
  • University of Rochester
  • Ohio State University, Wexner Medical Center
  • University of Utah

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

ManNAc

Placebo

Arm Description

Oral ManNAc will be administered at a dose of 4 grams three times daily (total of 12 grams daily).

Oral Placebo will be administered three times daily.

Outcomes

Primary Outcome Measures

Muscle strength of ankle dorsiflexion, knee flexion, knee extension, shoulder abduction, elbow flexion and grip measured by fixed-frame Quantitative Muscle Assessment (QMA)
The primary endpoint is the change in muscle strength decline under treatment compared to placebo. The primary analysis is based on the disease progression ratio (γ) comparing the rate of progression from baseline until last visit, under placebo to that under treatment.

Secondary Outcome Measures

Inclusion Body Myositis Functional Rating Scale (IBMFRS)
Change in patient-reported function as measured by the Inclusion Body Myositis Functional Rating Scale (IBMFRS).

Full Information

First Posted
January 8, 2020
Last Updated
June 7, 2023
Sponsor
Leadiant Biosciences, Inc.
Collaborators
Brigham and Women's Hospital, National Human Genome Research Institute (NHGRI), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Neurological Disorders and Stroke (NINDS)
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1. Study Identification

Unique Protocol Identification Number
NCT04231266
Brief Title
Multi-Center Study of ManNAc for GNE Myopathy
Acronym
MAGiNE
Official Title
A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Efficacy of ManNAc in Subjects With GNE Myopathy
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
April 5, 2022 (Actual)
Primary Completion Date
March 28, 2024 (Anticipated)
Study Completion Date
July 15, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Leadiant Biosciences, Inc.
Collaborators
Brigham and Women's Hospital, National Human Genome Research Institute (NHGRI), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Neurological Disorders and Stroke (NINDS)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
GNE myopathy is a rare genetic muscle disease characterized by progressive muscle atrophy and weakness. The disease is caused by mutations in the gene that encodes the enzyme that initiates and regulates N-acetylneuraminic acid (Neu5Ac) biosynthesis and glycan sialylation. Currently, there is no therapy available for this disease. N-Acetylmannosamine (ManNAc), an orphan drug in development for GNE myopathy, is an uncharged monosaccharide and the first committed precursor in Neu5Ac biosynthesis. In this randomized, double-blind, placebo-controlled trial the efficacy and long-term safety of ManNAc will be evaluated in subjects with GNE myopathy.
Detailed Description
This is a randomized, placebo-controlled, double-blind, multi-center study to evaluate the long-term safety and clinical efficacy of ManNAc in subjects with GNE myopathy. A total of 51 eligible subjects will be randomized in a 2:1 ratio to receive either ManNAc at 4 g three times daily (total of 12 g/day) or placebo. Subjects will have follow-up visits every 6 months (±7 days) and take study drug for a minimum of 24 months, until their final study visit . The final on-site study visit for a subject is the last expected 6-month follow-up visit that occurs prior to the time the last randomized subject is expected to reach 24 months (extended follow-up). Subjects will undergo screening and baseline evaluations that include clinical laboratory tests, Quantitative Muscle Assessment (QMA), the Inclusion Body Functional Myositis Rating Scale (IBMFRS), and other patient-reported outcomes (PROs), and rehabilitation medicine functional assessments. Follow-up evaluations will occur every six months following baseline, until 24 months after randomization of the last subject. Phone follow-up will occur every month without a clinic visit for the duration of the trial, and the last visit for each subject will be followed by phone follow-up 1 month after the final study visit.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
GNE Myopathy
Keywords
GNE Myopathy, Hereditary Inclusion Body Myopathy (HIBM), Distal Myopathy with Rimmed Vacuoles (DMRV), Nonaka Myopathy, Inclusion Body Myopathy type 2 (IBM-2)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
54 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ManNAc
Arm Type
Active Comparator
Arm Description
Oral ManNAc will be administered at a dose of 4 grams three times daily (total of 12 grams daily).
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Oral Placebo will be administered three times daily.
Intervention Type
Drug
Intervention Name(s)
ManNAc
Other Intervention Name(s)
N-acetyl-D-mannosamine monohydrate
Intervention Description
Oral N-acetyl-D-mannosamine monohydrate (ManNAc)
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
Muscle strength of ankle dorsiflexion, knee flexion, knee extension, shoulder abduction, elbow flexion and grip measured by fixed-frame Quantitative Muscle Assessment (QMA)
Description
The primary endpoint is the change in muscle strength decline under treatment compared to placebo. The primary analysis is based on the disease progression ratio (γ) comparing the rate of progression from baseline until last visit, under placebo to that under treatment.
Time Frame
Minimum 2 years, until 24 months from randomization of last subject
Secondary Outcome Measure Information:
Title
Inclusion Body Myositis Functional Rating Scale (IBMFRS)
Description
Change in patient-reported function as measured by the Inclusion Body Myositis Functional Rating Scale (IBMFRS).
Time Frame
Minimum 2 years, until 24 months from randomization of last subject
Other Pre-specified Outcome Measures:
Title
Adverse Events
Description
Safety and tolerability will be evaluated by comparing the frequency of adverse events (AEs) across groups, collected using information from in-person assessments, clinical laboratory tests, vital signs, electronic diary reports, and physical examinations.
Time Frame
Minimum 2 years, until 24 months from randomization of last subject
Title
Correlation muscle strength measured Exploratory GNEM Functional Questions (ExGNEM)
Description
Evaluate the effect of ManNAc on patient-reported physical functioning assessed by ExGNEM, a six-question rating scale that assesses lower body function.
Time Frame
Minimum 2 years, until 24 months from randomization of last subject
Title
Adult Myopathy Assessment Tool
Description
Evaluate the effect of ManNAc on physical function as measured by the Adult Myopathy Assessment Tool (AMAT), a 13-item standardized test that assesses physical performance, to be performed at baseline and every 6 months thereafter until completion of the study.
Time Frame
Minimum 2 years, until 24 months from randomization of last subject
Title
Six-Minute Walk Test
Description
Evaluate the effect of ManNAc on physical function as measured by the Six-Minute Walk Test (whenever possible) to be performed at baseline and every 6 months thereafter until completion of the study.
Time Frame
Minimum 2 years, until 24 months from randomization of last subject
Title
Timed Up and Go Test
Description
Evaluate the effect of ManNAc on physical function as measured by the Timed Up and Go, performance test to evaluate functional mobility, to be performed at baseline and every 6 months thereafter until completion of the study.
Time Frame
Minimum 2 years, until 24 months from randomization of last subject
Title
Functional Reach Test
Description
Evaluate the effect of ManNAc on physical function as measured by the Functional Reach, a measure of stability, to be performed at baseline and every 6 months thereafter until completion of the study.
Time Frame
Minimum 2 years, until 24 months from randomization of last subject
Title
Jebsen Hand Function Test
Description
Evaluate the effect of ManNAc on physical function as measured by the Jebsen Hand Function Test, a performance measure which assesses unilateral hand function, to be performed at baseline and every 6 months thereafter until completion of the study.
Time Frame
Baseline and every 12 months thereafter
Title
Inclusion Body Myositis Functional Rating Scale
Description
Evaluate effect of ManNAc on activities of daily living (ADLs) compared to placebo as measured by the Inclusion Body Myositis Functional Rating Scale (IBMFRS), a patient-reported outcome completed at baseline, and every 6 months thereafter until completion of the study.
Time Frame
Minimum 2 years, until 24 months from randomization of last subject
Title
Human Activity Profile
Description
Evaluate effect of ManNAc on activities of daily living (ADLs) compared to placebo as measured by the Human Activity Profile, a patient-reported outcome completed at baseline, and every 6 months thereafter until completion of the study.
Time Frame
Minimum 2 years, until 24 months from randomization of last subject
Title
Activities-specific Balance Confidence (ABC) scale
Description
Evaluate effect of ManNAc on activities of daily living (ADLs) compared to placebo as measured by the Activities-specific Balance Confidence (ABC) scale, a patient-reported outcome completed at baseline, and every 6 months thereafter until completion of the study.
Time Frame
Minimum 2 years, until 24 months from randomization of last subject

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Subject should be 18-70 years of age at the time of enrollment, inclusive, and of either gender. Subject has a diagnosis of GNE myopathy based upon a consistent clinical course and biallelic GNE gene mutations that classify as pathogenic or likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines. Subjects must have 10.00-65.99% of predicted muscle strength measured by QMA at screening in at least one of the selected muscle groups (ankle dorsiflexion, knee flexion, grip, shoulder abduction and elbow flexion). Subject has the ability to travel to the Clinical Trial Site for visits. Subjects must be able to communicate effectively with study staff and understand the requirements of the protocol without translators. Subject must be able to comply with requirements of the protocol, including blood collection, drug administration, and muscle strength assessments. Women of childbearing potential must be willing to use an effective method of contraception for the duration of the trial. It is recommended that male subjects follow birth control measures for the duration of the trial. Subject must be able to provide informed consent. Exclusion Criteria: Subject had an infection or medical illness requiring intravenous antibiotics or hospitalization within 30 days prior to the baseline/randomization visit. Subject has another comorbid condition which may affect physical function. Subject has a psychiatric illness or neurological disease that would interfere with the ability to comply with the requirements of this protocol. Subject with hepatic laboratory parameters (AST, ALT, GGTP), equal to or greater than 3 times the upper limit of normal at screening. Subject with existing renal dysfunction, as defined by glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 at screening. Subject is anemic (defined as Hematocrit <30%) or has platelets <75 x 10^3/µL or white blood cell count less than 3 x 10^3/µL at screening. Subject shows evidence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematological, metabolic, or gastrointestinal disease, or has a condition that requires immediate surgical intervention. Subject is pregnant or breastfeeding at any time during the study. Subject has received treatment with another investigational drug, investigational device, or approved therapy for investigational use less than 90 days prior to screening. Subject has received any dose of ManNAc, sialic acid, intravenous immunoglobulin (IVIG), and/or other compounds containing, or that can be metabolized into sialic acid, within 6 months prior to enrollment as reported by subject at the time of screening. Subject has received stem cell therapy or gene therapy within 1 year prior to screening. Subject has hypersensitivity to ManNAc or erythritol or in the judgment of the investigator, has a condition that places the subject at increased risk for adverse effects. The presence of persistent diarrhea or malabsorption that could interfere with the subject's ability to absorb drugs or to tolerate ManNAc therapy.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anthony A. Amato, MD
Organizational Affiliation
Brigham and Women's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
UCLA
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
University of Iowa
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
University of Kansas, Medical Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Facility Name
NIH Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
University of Rochester
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
Ohio State University, Wexner Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
30511500
Citation
Quintana M, Shrader J, Slota C, Joe G, McKew JC, Fitzgerald M, Gahl WA, Berry S, Carrillo N. Bayesian model of disease progression in GNE myopathy. Stat Med. 2019 Apr 15;38(8):1459-1474. doi: 10.1002/sim.8050. Epub 2018 Dec 3.
Results Reference
background
PubMed Identifier
30338442
Citation
Carrillo N, Malicdan MC, Huizing M. GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges. Neurotherapeutics. 2018 Oct;15(4):900-914. doi: 10.1007/s13311-018-0671-y.
Results Reference
background
PubMed Identifier
28641925
Citation
Xu X, Wang AQ, Latham LL, Celeste F, Ciccone C, Malicdan MC, Goldspiel B, Terse P, Cradock J, Yang N, Yorke S, McKew JC, Gahl WA, Huizing M, Carrillo N. Safety, pharmacokinetics and sialic acid production after oral administration of N-acetylmannosamine (ManNAc) to subjects with GNE myopathy. Mol Genet Metab. 2017 Sep;122(1-2):126-134. doi: 10.1016/j.ymgme.2017.04.010. Epub 2017 Apr 26.
Results Reference
background
Links:
URL
https://neuronext.org/projects/nn109-magine
Description
Study NN109/MAGiNE website

Learn more about this trial

Multi-Center Study of ManNAc for GNE Myopathy

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