Back to results

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

Primary Purpose

Hereditary Inclusion Body Myopathy (HIBM), GNE Myopathy

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

ManNAc

About this trial

This is an interventional treatment trial for Hereditary Inclusion Body Myopathy (HIBM) focused on measuring N-Acetyl-D-mannosamine (ManNAc), HIBM, GNE Myopathy

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

ManNac

Placebo

Arm Description

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Pharmacokinetics

Full Information

NCT ID

NCT01634750

First Posted

July 3, 2012

Last Updated

October 18, 2017

Sponsor

National Human Genome Research Institute (NHGRI)

Collaborators

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

1. Study Identification

Unique Protocol Identification Number

NCT01634750

Brief Title

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

Official Title

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)

Study Type

Interventional

2. Study Status

Record Verification Date

February 24, 2017

Overall Recruitment Status

Completed

Study Start Date

September 11, 2012 (undefined)

Primary Completion Date

undefined (undefined)

Study Completion Date

May 29, 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Human Genome Research Institute (NHGRI)

Collaborators

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

4. Oversight

5. Study Description

Brief 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hereditary Inclusion Body Myopathy (HIBM), GNE Myopathy

Keywords

N-Acetyl-D-mannosamine (ManNAc), HIBM, GNE Myopathy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

26 (Actual)

8. Arms, Groups, and Interventions

Arm Title

ManNac

Arm Type

Experimental

Arm Title

Placebo

Arm Type

Placebo Comparator

Intervention Type

Drug

Intervention Name(s)

ManNAc

Intervention Description

Single dose

Primary Outcome Measure Information:

Title

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

Secondary Outcome Measure Information:

Title

Pharmacokinetics

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Nuria Carrillo-Carrasco, M.D.

Organizational Affiliation

National Human Genome Research Institute (NHGRI)

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Institutes of Health Clinical Center, 9000 Rockville Pike

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

5970419

Citation

Amir SM, Barker SA, Butt WR, Crooke AC, Davies AG. Administration of N-acetyl-D-mannosamine to mammals. Nature. 1966 Aug 27;211(5052):976-7. doi: 10.1038/211976a0. No abstract available.

Results Reference

background

PubMed Identifier

19019317

Citation

Argov Z, Mitrani-Rosenbaum S. The hereditary inclusion body myopathy enigma and its future therapy. Neurotherapeutics. 2008 Oct;5(4):633-7. doi: 10.1016/j.nurt.2008.07.004.

Results Reference

background

PubMed Identifier

16137682

Citation

Bork K, Reutter W, Gerardy-Schahn R, Horstkorte R. The intracellular concentration of sialic acid regulates the polysialylation of the neural cell adhesion molecule. FEBS Lett. 2005 Sep 12;579(22):5079-83. doi: 10.1016/j.febslet.2005.08.013.

Results Reference

background

PubMed Identifier

33893973

Citation

Van Wart S, Mager DE, Bednasz CJ, Huizing M, Carrillo N. Population Pharmacokinetic Model of N-acetylmannosamine (ManNAc) and N-acetylneuraminic acid (Neu5Ac) in Subjects with GNE Myopathy. Drugs R D. 2021 Jun;21(2):189-202. doi: 10.1007/s40268-021-00343-6. Epub 2021 Apr 24.

Results Reference

derived

Links:

URL

https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2012-HG-0207.html

Description

NIH Clinical Center Detailed Web Page

Learn more about this trial

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

We'll reach out to this number within 24 hrs