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

• ClinicalTrials.gov Identifier: NCT04231266
• Recruitment Status: Not yet recruiting
• First Posted: January 18, 2020
• Last Update Posted: February 6, 2020
• Sponsor: William A. Gahl, MD, PhD
• 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); Leadiant Biosciences, Inc.
• Information provided by (Responsible Party): William A. Gahl, MD, PhD, National Human Genome Research Institute (NHGRI)

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 GNE Myopathy Physical Function Scale (GNEM-PFS), 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 stopping study drug.

The primary endpoint is the change in muscle strength of ankle dorsiflexion, knee flexion, knee extension, shoulder abduction, elbow flexion and grip reported as proportion of predicted strength. Muscle strength will be measured by fixed-frame Quantitative Muscle Assessment (QMA; Aeverl Medical).

The primary analysis is based on comparing the rate of disease progression under placebo to that under treatment. The design of the trial is based on a Disease Progression Model of GNE myopathy that was generated using QMA muscle strength data collected in subjects with GNE myopathy as part of a prospective Natural History Study of the disease.

It was estimated that 51 subjects with 2:1 randomization (ManNAc: Placebo) will provide a power of 89% under a treatment-related slowing in the rate of decline of 50% and a Type I error of 1%, accounting for lost-to follow-up and intend to treat analysis.

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
• Estimated Study Start Date: February 1, 2020
• Estimated Primary Completion Date: January 31, 2023
• Estimated Study Completion Date: January 31, 2023

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. Muscle strength is measured by the Quantitative Muscle Assessment (QMA; Aeverl Medical). 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. GNE Myopathy Physical Function Scale (GNEM-PFS) [ Time Frame: Minimum 2 years, until 24 months from randomization of last subject ]
   The effect of ManNAc on patient reported physical functioning will be assessed by the GNE Myopathy Physical Function Scale (GNEM-PFS). This is a newly developed, disease-specific patient-reported outcome that consists of 18 items scored on an 11-point numerical rating scale (NRS) from 0 (no difficulty) to 10 (unable to do) where lower scores indicate better patient reported physical functioning. The GNEM-PFS is assessed at baseline and then again every six months until 24 months after the final subject is randomized. Change from baseline to each follow-up time point on the 18-item Total score will be calculated, and comparisons between the ManNAc group and placebo group will be based on a linear mixed effects model.

Other Outcome Measures:

1. Adverse Events [ Time Frame: Minimum 2 years, until 24 months from randomization of last subject ]
   Safety of orally administered ManNAc will be compared to placebo.
2. Correlation muscle strength measured by QMA and the GNEM-PFS. [ Time Frame: Minimum 2 years, until 24 months from randomization of last subject ]
   Evaluate the correlation between QMA assessments and patient-reported physical functioning assessed by GNEM-PFS.
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.
3. Subjects must have 10-65% 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/m2 at screening.
6. Subject is anemic (defined as hematocrit <30%) or has platelets <75,000 or white blood cell count less than 3,000/mL 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 ManNAc, sialic acid, IVIG and/or other compounds containing, or that can be metabolized into sialic acid, for a cumulative total of more than 30 days within 1 year of enrolling in this trial.
12. Subject has received stem cell therapy or gene therapy within 1 year prior to screening.
13. 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.
14. 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: David Klements, MS, CCRP; 617-726-3430; DKlements@mgh.harvard.edu

Contact: Timothy Leonard, BS; 617-726-5782; TPLeonard@partners.org

Locations

United States, California

UCLA

Los Angeles, California, United States, 90095

Contact: Shreya Chadda 310-825-3264 Schadda@mednet.ucla.edu

Contact: Perry B Shieh, MD, PhD

Principal Investigator: Perry B Shieh, MD, PhD

United States, Iowa

University of Iowa

Iowa City, Iowa, United States, 52242

Contact: Jeri Sieren 319-356-8744 jeri-sieren@uiowa.edu

Principal Investigator: Laurie Gutmann, MD

United States, Kansas

University of Kansas, Medical Center

Kansas City, Kansas, United States, 66160

Contact: Samantha Colgan 913-945-9938 scolgan@kumc.edu

Principal Investigator: Duaa Jabari, MD

United States, Maryland

NIH Clinical Center

Bethesda, Maryland, United States, 20892

Contact: Andrea Bowling, NP 301-827-7746 andrea.bowling@nih.gov

Principal Investigator: Nuria Carrillo, MD

United States, Massachusetts

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02115

Contact: Marie Guthrie 617-525-6763 mguthrie1@bwh.harvard.edu

Contact: Louis Beers

Principal Investigator: Anthony A Amato, MD

United States, Missouri

Washington University

Saint Louis, Missouri, United States, 63110

Contact: June Smith 314-362-6986 smith.june@wustl.edu

Principal Investigator: Alan Pestronk, MD

United States, New York

Columbia University Medical Center

New York, New York, United States, 10032

Contact: Jasim Uddin 212-342-0267 ju2189@cumc.columbia.edu

Principal Investigator: Jinsy Andrews, MD

University of Rochester

Rochester, New York, United States, 14642

Contact: Christine Annis 585-276-3037 christine_annis@urmc.rochester.edu

Principal Investigator: Johanna Hamel, MD

United States, Ohio

Ohio State University, Wexner Medical Center

Columbus, Ohio, United States, 43210

Contact: Amy Bartlett 614-366-9050 amy.bartlett@osumc.edu

Principal Investigator: Samantha LoRusso, MD

United States, Utah

University of Utah

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

William A. Gahl, MD, PhD

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)

Leadiant Biosciences, Inc.

Investigators

• Principal Investigator: Anthony A. Amato, MD; Brigham and Women's Hospital
• Principal Investigator: Nuria Carrillo, MD; National Human Genome Research Institute (NHGRI), NIH

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. Review.

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: William A. Gahl, MD, PhD, Senior Investigator, National Human Genome Research Institute (NHGRI)
• ClinicalTrials.gov Identifier: NCT04231266
• Other Study ID Numbers: NN109; 1U01AR070498-01A1 ( U.S. NIH Grant/Contract )
• First Posted: January 18, 2020
• Last Update Posted: February 6, 2020
• Last Verified: February 2020

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 William A. Gahl, MD, PhD, National Human Genome Research Institute (NHGRI):

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