Hereditary Inclusion Body Myopathy (HIBM)Phase 1NCT01634750
Phase I Clinical Trial of ManNAc in Patients With GNE Myopathy or Hereditary Inclusion Body Myopathy (HIBM)
A Phase 1 study testing ManNAc in people with Hereditary Inclusion Body Myopathy (HIBM) and GNE Myopathy, run by National Human Genome Research Institute (NHGRI) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Hereditary Inclusion Body Myopathy (HIBM), GNE Myopathy
- What is being tested?
- ManNAc
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 26 participants
- Where
- 1 siteUnited States
- Study dates
- 11 Sep 2012to 29 May 2013
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
None listed.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
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)
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.
Read more
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.
Read the 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.
- Being tested
- ManNAc
- Keywords
- N-Acetyl-D-mannosamine (ManNAc), HIBM, GNE Myopathy
- Medical subject headings
- Distal myopathy, Nonaka type
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ManNAcDrug
Single dose
| Study group | Role | What they receive |
|---|---|---|
| ManNac | Experimental | Not described Receives: Drug: ManNAc |
| Placebo | Placebo comparator | Not described Receives: Drug: ManNAc |
What is being measured
The primary outcome is the main question the study is designed to answer.
To evaluate the safety and tolerability of a single dose of orally administered ManNAc to HIBM subjects.
Secondary outcomes (1)
Pharmacokinetics
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Jul 2012 (estimated)
- Study start11 Sep 2012
- Study completion29 May 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Hereditary Inclusion Body Myopathy (HIBM)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 26 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Human Genome Research Institute (NHGRI)
- Sponsor type
- US National Institutes of Health
- Collaborators
- National Center for Advancing Translational Sciences (NCATS), Therapeutics for Rare and Neglected Diseases (TRND)
- Responsible party
- Sponsor
- Investigators
- Nuria Carrillo-Carrasco, M.D., Principal investigator, National Human Genome Research Institute (NHGRI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01634750
- Sponsor's protocol ID
- 120207
- Other IDs
- 12-HG-0207
- Status last verified
- 24 Feb 2017
- First submitted
- 3 Jul 2012
- Last updated
- 19 Oct 2017
- Results posted
- No
Publications
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.
PubMed 5970419Argov 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.
PubMed 19019317Bork 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.
PubMed 16137682Van 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.
PubMed 33893973
Study at a glance
From the registry record, last updated by the sponsor on 19 Oct 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT01634750
- Acronym / sponsor ID
- 120207
- Keywords
- N-Acetyl-D-mannosamine (ManNAc), HIBM, GNE Myopathy
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 26 participants (actual)
- Lead sponsor
- National Human Genome Research Institute (NHGRI)US National Institutes of Health
- Collaborators
- National Center for Advancing Translational Sciences (NCATS), Therapeutics for Rare and Neglected Diseases (TRND)
- Study start
- 11 Sep 2012
- Study completion
- 29 May 2013 (actual)
- First posted
- 6 Jul 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| ManNac | Experimental | Drug: ManNAc |
| Placebo | Placebo comparator | Drug: ManNAc |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (0 listed)
Key exclusion criteria (9 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ManNAcSingle dose | Drug | ManNac, Placebo |
Primary outcome
To evaluate the safety and tolerability of a single dose of orally administered ManNAc to HIBM subjects.
1 secondary outcome
Pharmacokinetics
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Oct 2017.
- Background: PubMed 5970419Amir 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.
- Background: PubMed 19019317Argov 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.
- Background: PubMed 16137682Bork 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.
- Derived from this study: PubMed 33893973Van 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.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nuria Carrillo-Carrasco, M.D. principal investigator
National Human Genome Research Institute (NHGRI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing ManNAc in people with Hereditary Inclusion Body Myopathy (HIBM) and GNE Myopathy, run by National Human Genome Research Institute (NHGRI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 0 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Oct 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To evaluate the safety and tolerability of a single dose of orally administered ManNAc to HIBM subjects.. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01634750, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Oct 2017.