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

• ClinicalTrials.gov Identifier: NCT04231266
• Recruitment Status: Recruiting
• First Posted: January 18, 2020
• Last Update Posted: March 27, 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)
• Information provided by (Responsible Party): Leadiant Biosciences, Inc.

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.

Condition or disease	Intervention/treatment	Phase
GNE Myopathy	Drug: ManNAc; Other: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 51 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Efficacy of ManNAc in Subjects With GNE Myopathy
• Actual Study Start Date: April 5, 2022
• Estimated Primary Completion Date: March 28, 2024
• Estimated Study Completion Date: July 15, 2024

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: ManNAc; Oral ManNAc will be administered at a dose of 4 grams three times daily (total of 12 grams daily).	Drug: ManNAc; Oral N-acetyl-D-mannosamine monohydrate (ManNAc); Other Name: N-acetyl-D-mannosamine monohydrate
Placebo Comparator: Placebo; Oral Placebo will be administered three times daily.	Other: Placebo; Placebo

Outcome Measures

Primary Outcome Measures :

1. Muscle strength of ankle dorsiflexion, knee flexion, knee extension, shoulder abduction, elbow flexion and grip measured by fixed-frame Quantitative Muscle Assessment (QMA) [ Time Frame: Minimum 2 years, until 24 months from randomization of last subject ]
   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 :

1. Inclusion Body Myositis Functional Rating Scale (IBMFRS) [ Time Frame: Minimum 2 years, until 24 months from randomization of last subject ]
   Change in patient-reported function as measured by the Inclusion Body Myositis Functional Rating Scale (IBMFRS).

Other Outcome Measures:

1. Adverse Events [ Time Frame: Minimum 2 years, until 24 months from randomization of last subject ]
   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.
2. Correlation muscle strength measured Exploratory GNEM Functional Questions (ExGNEM) [ Time Frame: Minimum 2 years, until 24 months from randomization of last subject ]
   Evaluate the effect of ManNAc on patient-reported physical functioning assessed by ExGNEM, a six-question rating scale that assesses lower body function.
3. Adult Myopathy Assessment Tool [ Time Frame: Minimum 2 years, until 24 months from randomization of last subject ]
   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.
4. Six-Minute Walk Test [ Time Frame: Minimum 2 years, until 24 months from randomization of last subject ]
   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.
5. Timed Up and Go Test [ Time Frame: Minimum 2 years, until 24 months from randomization of last subject ]
   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.
6. Functional Reach Test [ Time Frame: Minimum 2 years, until 24 months from randomization of last subject ]
   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.
7. Jebsen Hand Function Test [ Time Frame: Baseline and every 12 months thereafter ]
   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.
8. Inclusion Body Myositis Functional Rating Scale [ Time Frame: Minimum 2 years, until 24 months from randomization of last subject ]
   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.
9. Human Activity Profile [ Time Frame: Minimum 2 years, until 24 months from randomization of last subject ]
   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.
10. Activities-specific Balance Confidence (ABC) scale [ Time Frame: Minimum 2 years, until 24 months from randomization of last subject ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Anthony A Amato, MD; 617-732-8046; aamato@bwh.harvard.edu

Contact: Daniel Falleroni; 1-800-447-0169; daniel.falleroni@leadiant.com

Locations

United States, California

UCLA; Recruiting

Los Angeles, California, United States, 90095

Contact: Merve Kaleli 310-825-3264 MKaleli@mednet.ucla.edu

Contact: Perry B Shieh, MD, PhD

Principal Investigator: Perry B Shieh, MD, PhD

United States, Iowa

University of Iowa; Recruiting

Iowa City, Iowa, United States, 52242

Contact: Loraine Brenner 319-356-8744 loraine-brenner@uiowa.edu

Principal Investigator: Chris Nance, MD

United States, Kansas

University of Kansas, Medical Center; Recruiting

Kansas City, Kansas, United States, 66160

Contact: Lilli Saavedra 913-945-9937 lsaavedra2@kumc.edu

Principal Investigator: Duaa Jabari, MD

United States, Maryland

NIH Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Contact: Jessica Jang, NP 301-827-7746 GNEMyopathyStudies@mail.nih.gov

Principal Investigator: Francis Rossignol, MD

United States, Massachusetts

Brigham and Women's Hospital; Recruiting

Boston, Massachusetts, United States, 02115

Contact: Kylie Yamauchi 808-393-5379 kcyamauchi@bwh.harvard.edu

Contact: Louis Beers

Principal Investigator: Anthony A Amato, MD

United States, Missouri

Washington University; Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Mengesha Teshome 314-747-8420 teshomem@wustl.edu

Principal Investigator: Alan Pestronk, MD

United States, New York

Columbia University Medical Center; Recruiting

New York, New York, United States, 10032

Contact: Joyce Moran 212-305-8367 jt617@cumc.columbia.edu

Principal Investigator: Jinsy Andrews, MD

University of Rochester; Recruiting

Rochester, New York, United States, 14642

Contact: Erin Richardson 585-275-7867 erin_richardson@urmc.rochester.edu

Principal Investigator: Johanna Hamel, MD

United States, Ohio

Ohio State University, Wexner Medical Center; Recruiting

Columbus, Ohio, United States, 43210

Contact: Marco Tellez 614-366-9050 marco.tellez@osumc.edu

Principal Investigator: Michael Isfort, MD

United States, Utah

University of Utah; Recruiting

Salt Lake City, Utah, United States, 84112

Contact: Mariana Doudova 801-581-3818 mariana.doudova@hsc.utah.edu

Principal Investigator: J. Robinson Singleton, MD

Sponsors and Collaborators

Leadiant Biosciences, Inc.

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)

Investigators

• Principal Investigator: Anthony A. Amato, MD; Brigham and Women's Hospital

More Information

Additional Information:

Study NN109/MAGiNE website 

Publications:

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.

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.

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.

• Responsible Party: Leadiant Biosciences, Inc.
• ClinicalTrials.gov Identifier: NCT04231266
• Other Study ID Numbers: NN109; 1U01AR070498-01A1 ( U.S. NIH Grant/Contract )
• First Posted: January 18, 2020
• Last Update Posted: March 27, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Leadiant Biosciences, Inc.:

GNE Myopathy; Hereditary Inclusion Body Myopathy (HIBM); Distal Myopathy with Rimmed Vacuoles (DMRV); Nonaka Myopathy; Inclusion Body Myopathy type 2 (IBM-2)

Additional relevant MeSH terms:

Muscular Diseases; Distal Myopathies; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Muscular Dystrophies; Muscular Disorders, Atrophic; Genetic Diseases, Inborn