Phase I Clinical Trial of ManNAc in Patients With GNE Myopathy or Hereditary Inclusion Body Myopathy (HIBM)

October 18, 2017 updated by: National Human Genome Research Institute (NHGRI)

A Phase 1 Randomized, Placebo-Controlled, Double-Blind, Escalating Single-Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of ManNAc in Subjects With GNE Myopathy or Hereditary Inclusion Body Myopathy (HIBM)

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

26

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 66 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  • INCLUSIONI CRITERIA:
  • Subject is 18-70 years, either gender, inclusive.
  • Subject has a diagnosis of HIBM (or IBM2, GNE myopathy, DMRV or Nonaka myopathy) based upon a consistent clinical course and identification of 2 GNE mutations. Molecular confirmation of the diagnosis will be obtained for all subjects in the study.
  • Subject must be willing to stop any treatment with ManNAc, sialic acid, IVIG, and/or other supplements containing sialic acid (eg, St John s wort, sialyllactose) 30 days prior to randomization and remain off such treatment for the duration of the trial.
  • Subject has the ability to travel to the NIH Clinical Center (CC) for admissions.
  • Subject (if a woman of reproductive age) must be willing to use an effective method of contraception for the duration of the trial.
  • Subject provides written informed consent.

EXCLUSION CRITERIA:

  • Subject has a severe disease manifestation that would interfere with the ability to comply with the requirements of this protocol.
  • 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, or panic disorder.
  • 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 a QTcB >450 msec (males) or QTcB >470 msec (females).
  • Subject is anemic (defined as two standard deviations below normal for age and gender).
  • 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 within 4 weeks of initial screening.
  • Subject has a hypersensitivity to ManNAc or in the judgment of the investigator, has a condition that places the subject at increased risk for adverse effects.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
Drug: ManNAc
Single dose
Experimental: ManNac
Drug: ManNAc
Single dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure
To evaluate the safety and tolerability of a single dose of orally administered ManNAc to HIBM subjects.

Secondary Outcome Measures

Outcome Measure
Pharmacokinetics

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Human Genome Research Institute (NHGRI)

Collaborators

National Center for Advancing Translational Sciences (NCATS)
Therapeutics for Rare and Neglected Diseases (TRND)

Investigators

  • Principal Investigator: Nuria Carrillo-Carrasco, M.D., National Human Genome Research Institute (NHGRI)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 11, 2012

Study Completion (Actual)

May 29, 2013

Study Registration Dates

First Submitted

July 3, 2012

First Submitted That Met QC Criteria

July 3, 2012

First Posted (Estimate)

July 6, 2012

Study Record Updates

Last Update Posted (Actual)

October 19, 2017

Last Update Submitted That Met QC Criteria

October 18, 2017

Last Verified

February 24, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 120207
  • 12-HG-0207

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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