Phase I Clinical Trial of ManNAc in Patients With GNE Myopathy or Hereditary Inclusion Body Myopathy (HIBM)
Condition: Hereditary Inclusion Body Myopathy (HIBM); GNE Myopathy
MeSH terms: Muscular Diseases; Distal Myopathies
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - Hereditary inclusion body myopathy (HIBM) is a genetic disorder caused by mutations in a
      gene called GNE. This gene is responsible for producing a sugar called sialic acid. Low
      levels of sialic acid may cause muscle problems. Symptoms of HIBM include walking
      difficulties and muscle weakness, which usually start in a person s 20s or 30s and become
      worse over time.

      Researchers are studying a drug called ManNAc. It may be useful for treating HIBM. However,
      this drug is still being tested. Researchers want to see how ManNAc is absorbed into and
      removed from the blood. They will not be looking specifically at whether ManNAc can stop or
      slow the symptoms of HIBM.

      Objectives:

        -  <TAB>To study how MaNAc is absorbed into and removed from the blood in people with HIBM.

        -  <TAB>To study of safety of ManNAc in people with HIBM.

      Eligibility:

      - Individuals between 18 and 70 years of age who have HIBM.

      Design:

        -  Participants will be screened with a physical exam and medical history. Blood and urine
           samples will be collected.

        -  Participants will have a 3 to 4-day inpatient stay for the main part of the study.

        -  Participants will be divided into groups of six. In each group, four will take ManNAc
           and two will take a placebo. Participants will not know which one they will receive.

        -  Participants will have a single dose of either ManNAc or placebo. They will be monitored
           for any possible side effects. Frequent blood samples will be collected during the 4-day
           stay.

        -  No treatment for HIBM will be provided as part of this study.
    

Detailed description: 
      Hereditary inclusion body myopathy (HIBM) is an autosomal recessive, neuromuscular disorder
      characterized by progressive muscle weakness with onset in early adulthood. The causative
      gene, GNE, codes for the bifunctional enzyme uridine diphospho-N-acetylglucosamine
      (UDP-GlcNAc)-2-epimerase/N-acetylmannosamine (ManNAc) kinase (GNE/MNK), which catalyzes the
      first 2 steps in the biosynthesis of sialic acid. The subsequent paucity of sialic acid
      production is presumed to cause decreased sialylation of HIBM muscle glycoproteins, resulting
      in muscle deterioration. In this Phase 1, randomized, placebo-controlled, double-blind,
      escalating single-dose study, we propose to provide ManNAc (N-acetyl-D-mannosamine
      monohydrate) orally as a liquid solution to 3 cohorts of 6 subjects (Cohorts A, B, C) at
      doses of 3,000 mg, 6,000 mg, and 10,000 mg ManNAc, respectively, or up to the maximum
      tolerated dose (MTD). The objectives of this study are to evaluate the safety, tolerability,
      and pharmacokinetics (PK) of a single dose of orally administered ManNAc to HIBM subjects, to
      identify the MTD of a single dose of orally administered ManNAc to HIBM subjects, and to
      explore the effect of a single dose of ManNAc on potential pharmacodynamic (PD) markers of
      HIBM. All subjects will be randomly assigned in a 2:1 ratio to receive ManNAc (n equals 4) or
      placebo (n equals 2) and the decision to dose-escalate will be the responsibility of the
      Safety Review Committee (SRC). Safety will be assessed by adverse events (AEs), clinical
      laboratory tests, vital signs, physical examinations, and electrocardiograms (ECGs). PK will
      be assessed for both ManNAc and sialic acid.
    

Intervention name(s): ManNAc
Intervention type(s): Drug
Intervention description(s): Single dose
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: N-Acetyl-D-mannosamine (ManNAc); HIBM; GNE Myopathy