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An Open Label Phase 2 Study of ManNAc in Subjects With GNE Myopathy

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ClinicalTrials.gov Identifier: NCT02346461
Recruitment Status : Active, not recruiting
First Posted : January 27, 2015
Last Update Posted : January 15, 2018
Information provided by (Responsible Party):

Study Description
Brief Summary:


- People with GNE myopathy have muscle weakness and can have difficulty walking . The disease comes from a gene mutation related to the production of a sugar called sialic acid. Researchers think decreased sialic acid may cause the muscle problems. Researchers are testing the drug ManNAc which is a building block of sialic acid. It is a powder that is dissolved in water.


- To evaluate the safety of 90 days of ManNAc given by mouth.


- Adults ages 18 60 diagnosed with GNE myopathy.


  • Eligible participants will be admitted to the NIH Clinical Center for the first visit and will stay 10 14 days. Participants will have:
  • Medical history and physical exam
  • Electrocardiogram to measure heart function
  • Blood and urine tests
  • Muscle strength tests
  • Magnetic resonance imaging (MRI) muscle scans. Participants will lie on a table that slides in and out of a metal tube that takes pictures
  • Questionnaires
  • Muscle biopsies. Samples of muscle will be taken, one each from the arm and leg.
  • The study drug as a liquid twice a day
  • Participants may wear a small activity monitor throughout the study. It can be worn on a waistband.
  • After discharge from the initial visit, participants will take the study drug at home. Participants will need to record if they miss any doses.
  • Visit 2 will be at 6 weeks for 1 2 days of medical evaluation. Blood samples will be drawn.
  • Visit 3 will be at the end of the study. Participants will stay in the NIH Clinical Center for 5 6 days for medical evaluations, muscle tests, and scans. Another muscle biopsy will be taken. Blood samples will be drawn.
  • Participants will be contacted by telephone or email about 4 times after leaving the clinic.

Condition or disease Intervention/treatment Phase
GNE Myopathy Drug: ManNac. Drug: ManNac Phase 1 Phase 2

Detailed Description:
GNE myopathy, previously known as hereditary inclusion body myopathy (HIBM), is a rare, autosomal recessive myopathy with onset in early adulthood that is characterized by progressive muscle weakness and atrophy, which leads to wheelchair use and dependent care. The causative gene, GNE, encodes the rate-limiting enzyme in the biosynthesis of sialic acid. While the exact pathophysiology of GNE myopathy remains unknown, decreased sialic acid production and subsequent hyposialylation of muscle glycoproteins are thought to be key factors leading to muscle deterioration in GNE myopathy. This hypothesis is supported by prevention of disease after administration of N-acetyl-D-mannosamine (ManNAc) in mouse models of GNE myopathy. A recent first-in-human, Phase 1 single ascending dose study evaluated the safety, pharmacokinetics, and pharmacodynamics of a single dose of 3,000, 6,000, or 10,000 mg drug product-grade ManNAc in subjects with GNE myopathy (ClinicalTrials.gov NCT01634750; IND No.78,091). ManNAc was safe and well-tolerated in all subjects who participated in this study. In this Phase 2, open-label, single-center study we propose to administer ManNAc orally to 12 subjects for 912 days (30 months). The objectives of the study are to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and biochemical efficacy of orally administered ManNAc in GNE myopathy subjects and to evaluate disease-related biomarkers and relevant clinical endpoints. In the first phase of pharmacokinetic assessment, two cohorts of 6 subjects will receive ManNAc at doses of 3,000 mg twice a day (6,000 mg per day) or 6,000 mg twice a day (12,000 mg per day) for 7 days while admitted to the NIH Clinical Center to assess PK and safety. Safety and tolerability will be assessed on an individual basis. In the second phase of the study, all subjects will receive treatment with ManNAc at a dose of 6,000 mg twice daily for the remainder of the study. Follow-up safety and efficacy evaluations will occur at 42 days, and at 91 (3 months), 182 (6 months), 365 (12 months), 548 (18 months), 730 (24 months) and 912 (30 months) days. Safety lab evaluation will be performed also at 456 (15 months), 638 (21 months) and 820 (27 months) days either at the NIH clinical center or subjects home laboratory or physician s office. Final dosing will occur at the 30-month visit. After the final dose, all Grade (Bullet)2 AEs at least possibly related to study drug will be followed to resolution. Safety will be evaluated by adverse events (AEs), clinical laboratory tests, vital signs, and physical examinations. PK will be assessed for plasma ManNAc and Neu5Ac. Biochemical efficacy will be measured by change in the sialylation of proteins and clinical efficacy will be assessed using a battery of clinical assessments deemed to be relevant based on disease natural history.

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: An Open-Label Phase 2 Study of ManNAc in Subjects With GNE Myopathy
Study Start Date : January 24, 2015
Primary Completion Date : December 30, 2017
Estimated Study Completion Date : August 30, 2018

Arms and Interventions

Arm Intervention/treatment
Active Comparator: Cohot A
6 subjects on Cohort A will receive ManNAc 3,000 mg twice daily (6,000 mg/day) for 7 days and, if safe, continue on 6,000 mg twice daily (12,000 mg/day) for the remainder of the study.
Drug: ManNac.
At doses of 3,000 mg and 6,000 mg twice daily for a total dose of 6,000 and 12,000 mg per day
Active Comparator: Cohort B
6 subjects on Cohort B will receive ManNAc 6,000 mg twice daily (12,000 mg/day) for 90 days.
Drug: ManNac
At doses of 6,000 mg twice daily (12,000 mg per day).

Outcome Measures

Primary Outcome Measures :
  1. Safety [ Time Frame: Day 1-120 ]
  2. Pharmacokinetics and Pharmacodynamics [ Time Frame: Baseline, Day 1-93 ]
  3. Biochemical efficacy [ Time Frame: Baseline, Day 1-93 ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
  • Subject is age 18-60 years, inclusive, and of either gender.
  • Subject has a diagnosis of GNE myopathy based upon a consistent clinical course and identification of two GNE gene mutations.
  • Subject must be willing to stop any treatment with ManNAc, sialic acid, intravenous immunoglobulin (IVIG), and/or other supplements containing sialic acid (e.g. St. John s wort, sialyllactose) 90 days prior to dosing and remain off such treatment for the duration of the trial.
  • Subjects must have a body mass index (BMI) between 18 and 30 kg/m2, with a bodyweight of >50 kg
  • Subjects must have 20-75% of predicted strength measured by QMA at baseline on at least one of the following: 1) ankle dorsiflexion, 2) knee flexion, 3) hip extension, 4) grip, 5) elbow flexion, shoulder abduction

    • 20-75% of predicted strength measures by OMA at baseline, or
    • If predicted muscle strength above 75%, a documented change of at least 10% per year.
  • Subject has the ability to travel to the NIH Clinical Center for admissions.
  • Subject has an INR less than or equal to 1.5 and must have stopped warfarin and other anticoagulants 2 weeks prior and after muscle biopsy procedures. Aspirin and clopidogrel should be stopped 3 days and 5 days before the procedure, respectively.
  • Subject must be able to comply with requirements of the protocol, including blood collection, drug administration, muscle MRI/MRS, muscle biopsy and muscle strength assessments.
  • If a woman of reproductive age, subject must be willing to use an effective method of contraception for the duration of the trial.
  • Subject must be able to provide informed consent.


  • Subject had a clinical significant infection or medical illness 30 days prior to the first protocol visit.
  • Subject has a psychiatric illness or neurological disease that would interfere with the ability to comply with the requirements of this protocol. This includes, but is not limited to, uncontrolled/untreated psychotic depression, bipolar disorder, schizophrenia, substance abuse or dependence, antisocial personality disorder, panic disorder, or behavioral problems, which interfere with effective communication.
  • Subject has hepatic laboratory parameters (AST, ALT, GGTP) or renal laboratory parameters (creatinine, BUN) greater than 3 times the upper limit of normal.
  • Subject has known adverse reactions to anesthetic or sedatives utilized for muscle biopsy.
  • Subject is anemic (defined as Hematocrit <30%) or has platelets <100,000 or white blood cell count less than 3,000.
  • 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 the first protocol visit.
  • Subject has hypersensitivity to DEX-M74/ManNAc or in the judgment of the investigator, has a condition that places the subject at increased risk for adverse effects.
  • Subject has received ManNAc, sialic acid, intravenous immunoglobulin (IVIG), and/or other supplements containing sialic acid (e.g. St. John s wort, sialyllactose) less than 90 days prior to the first protocol visit.
  • 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

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): NCT02346461

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Human Genome Research Institute (NHGRI)
National Center for Advancing Translational Science (NCATS)
Principal Investigator: Nuria Carrillo-Carrasco, M.D. National Human Genome Research Institute (NHGRI)
More Information

Additional Information:
Responsible Party: National Human Genome Research Institute (NHGRI)
ClinicalTrials.gov Identifier: NCT02346461     History of Changes
Other Study ID Numbers: 150068
First Posted: January 27, 2015    Key Record Dates
Last Update Posted: January 15, 2018
Last Verified: October 26, 2017

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) ):
Hereditary Inclusion Body Myopathy (HIBM)
Sialic Acid
GNE Myopathy
N-Acetyl-D-mannosamine (ManNAc)
GNE Gene

Additional relevant MeSH terms:
Muscular Diseases
Distal Myopathies
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Muscular Dystrophies
Muscular Disorders, Atrophic
Genetic Diseases, Inborn