GNE MyopathyPhase 2NCT02346461
An Open Label Phase 2 Study of ManNAc in Subjects With GNE Myopathy
A Phase 2 study testing ManNAc in people with GNE Myopathy, run by National Human Genome Research Institute (NHGRI) at 1 site in United States.
Trial summary
Background: Patients with GNE myopathy have progressive muscle weakness and can have difficulty walking and decreased mobility. The disease is a rare genetic disorder that results from a gene mutation in a key step in the body's production of a sugar called sialic acid, (also called N-acetylneuraminic acid, Neu5Ac). Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- GNE Myopathy
- What is being tested?
- ManNAc
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- 5 Feb 2015to 15 Nov 2018
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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
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- 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.
Who cannot join
- 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.
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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 less than 90 days prior to the first protocol visit.
- Subject has hypersensitivity to 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.
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: An Open-Label Phase 2 Study of ManNAc in Subjects With GNE Myopathy
Background:
Patients with GNE myopathy have progressive muscle weakness and can have difficulty walking and decreased mobility. The disease is a rare genetic disorder that results from a gene mutation in a key step in the body's production of a sugar called sialic acid, (also called N-acetylneuraminic acid, Neu5Ac). Researchers think decreased sialic acid bound to muscle proteins may be the cause of muscle wasting in GNE myopathy. Researchers are testing the drug ManNAc which is a precursor in the production of sialic acid within cells. ManNAc is provided as a powder dissolved in water to be administered orally.
Read the detailed description
GNE myopathy is a rare genetic (autosomal recessive) disorder that causes progressive skeletal muscle atrophy and weakness. The disease presents in young adults typically between the ages of 20 and 40 years, and includes foot drop and difficulty walking. The disease progresses to involve all skeletal muscles, eventually leading to the use of a wheelchair and, in some cases, dependence on a caregiver. The causative gene, GNE, encodes the rate-limiting enzyme in the biosynthesis of CMP-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 oral N-acetyl-D-mannosamine (ManNAc) in mouse models of GNE myopathy. A first-in-human, Phase 1 single ascending dose study evaluated the safety, pharmacokinetics, and pharmacodynamics of a single dose of 3, 6, or 10 g of oral 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 ManNAc will be administered orally to 12 subjects. The objectives of the study are to assess the long-term safety, tolerability, pharmacokinetics, and biochemical efficacy of oral ManNAc in GNE myopathy subjects. In the first phase of pharmacokinetic assessment, two cohorts of 6 subjects will receive ManNAc at doses of 3 g twice a day (6 g per day) or 6 g twice a day (12 g per day) for 7 days to assess safety and PK. In the second phase of the study, all subjects will receive treatment with ManNAc at a dose of 6 g twice daily (12 g per day) for the remainder of the study. The study was extended to include follow-up evaluations at 6, 12, 18, 24 and 30 months. During the 30 month visit, PK of 4 g three times daily was assessed. Biochemical efficacy was assessed by change in the sialylation of proteins at 3 months compared to baseline. To evaluate the effect of ManNAc on clinical measures of GNE myopathy, a battery of clinical assessments was performed at every visit to identify clinical endpoints suitable for subsequent clinical trials.
- Conditions
- GNE Myopathy
- Being tested
- ManNAc
- Keywords
- Hereditary Inclusion Body Myopathy (HIBM), Sialic Acid (N-acetylneuraminic acid, Neu5Ac), GNE Myopathy, N-Acetyl-D-mannosamine (ManNAc), GNE Gene
- 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
At doses of 3 g and 6 g twice daily for a total dose of 6 and 12 g per day.
ManNAcDrug
At doses of 6 g twice daily (12 g per day).
| Study group | Role | What they receive |
|---|---|---|
| Cohort A | Active comparator | 6 subjects on Cohort A will receive oral ManNAc 3 g twice daily (6 g/day) for 7 days and, if safe, continue on 6 g twice daily (12 g/day) for the remainder of the study. Receives: Drug: ManNAc |
| Cohort B | Active comparator | 6 subjects on Cohort B will receive oral ManNAc 6 g twice daily (12 g/day) for the duration of the study. Receives: Drug: ManNAc |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mean Area Under the Curve (AUClast) of Plasma ManNAc (Baseline-adjusted)
The mean area under the plasma ManNAc concentration-versus time curve from time 0 (dosing) to the time of last quantifiable concentration.
Measured: Day 7
Maximum Observed Plasma Concentration (Cmax) of ManNAc (Baseline-adjusted)
The maximum (or peak) plasma ManNAc concentration that the drug achieves in the body after the drug has been administrated.
Measured: Day 7
The Time to Cmax (Tmax) for ManNAc
The time taken to achieve the maximum observed plasma concentration for ManNAc .
Measured: Day 7
Half-life (t ½) for ManNAc
The amount of time it takes for plasma ManNAc concentration to decline by half.
Measured: Day 7
Mean Area Under the Curve (AUClast) of Plasma Neu5Ac (Baseline-adjusted)
The mean area under the plasma Neu5Ac concentration-versus time curve from time 0 (dosing) to the time of last quantifiable concentration.
Measured: Day 7
Maximum Observed Plasma Concentration (Cmax) of Neu5Ac (Baseline-adjusted)
The maximum (or peak) plasma Neu5Ac concentration that the drug achieves in the body after the drug has been administrated.
Measured: Day 7
The Time to Cmax (Tmax) for Neu5Ac
The time taken to achieve the maximum observed plasma concentration for Neu5Ac.
Measured: Day 7
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jan 2015 (estimated)
- Study start5 Feb 2015
- Primary completion30 Dec 2017
- Study completion15 Nov 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for GNE MyopathyStudies 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 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 12 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)
- Responsible party
- Sponsor
- Investigators
- Nuria Carrillo, M.D., Principal investigator, National Human Genome Research Institute (NHGRI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02346461
- Sponsor's protocol ID
- 150068
- Other IDs
- 15-HG-0068
- Status last verified
- Mar 2019
- First submitted
- 24 Jan 2015
- Last updated
- 16 Apr 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
Publications
Carrillo N, Malicdan MC, Leoyklang P, Shrader JA, Joe G, Slota C, Perreault J, Heiss JD, Class B, Liu CY, Bradley K, Jodarski C, Ciccone C, Driscoll C, Parks R, Van Wart S, Bayman L, Coffey CS, Quintana M, Berry SM, Huizing M, Gahl WA. Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study. Genet Med. 2021 Nov;23(11):2067-2075. doi: 10.1038/s41436-021-01259-x. Epub 2021 Jul 13.
PubMed 34257421Van 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 16 Apr 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-Label Phase 2 Study of ManNAc in Subjects With GNE Myopathy
- ClinicalTrials.gov ID
- NCT02346461
- Acronym / sponsor ID
- 150068
- Conditions
- GNE Myopathy
- Keywords
- Hereditary Inclusion Body Myopathy (HIBM), Sialic Acid (N-acetylneuraminic acid, Neu5Ac), GNE Myopathy, N-Acetyl-D-mannosamine (ManNAc), GNE Gene
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- National Human Genome Research Institute (NHGRI)US National Institutes of Health
- Collaborators
- National Center for Advancing Translational Sciences (NCATS)
- Study start
- 5 Feb 2015 (actual)
- Primary completion
- 30 Dec 2017 (actual)
- Study completion
- 15 Nov 2018 (actual)
- First posted
- 27 Jan 2015 (estimated)
- Results
- Posted 16 Apr 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background:
Patients with GNE myopathy have progressive muscle weakness and can have difficulty walking and decreased mobility. The disease is a rare genetic disorder that results from a gene mutation in a key step in the body's production of a sugar called sialic acid, (also called N-acetylneuraminic acid, Neu5Ac). Researchers think decreased sialic acid bound to muscle proteins may be the cause of muscle wasting in GNE myopathy. Researchers are testing the drug ManNAc which is a precursor in the production of sialic acid within cells. ManNAc is provided as a powder dissolved in water to be administered orally.
Detailed description
GNE myopathy is a rare genetic (autosomal recessive) disorder that causes progressive skeletal muscle atrophy and weakness. The disease presents in young adults typically between the ages of 20 and 40 years, and includes foot drop and difficulty walking. The disease progresses to involve all skeletal muscles, eventually leading to the use of a wheelchair and, in some cases, dependence on a caregiver. The causative gene, GNE, encodes the rate-limiting enzyme in the biosynthesis of CMP-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 oral N-acetyl-D-mannosamine (ManNAc) in mouse models of GNE myopathy. A first-in-human, Phase 1 single ascending dose study evaluated the safety, pharmacokinetics, and pharmacodynamics of a single dose of 3, 6, or 10 g of oral 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 ManNAc will be administered orally to 12 subjects. The objectives of the study are to assess the long-term safety, tolerability, pharmacokinetics, and biochemical efficacy of oral ManNAc in GNE myopathy subjects. In the first phase of pharmacokinetic assessment, two cohorts of 6 subjects will receive ManNAc at doses of 3 g twice a day (6 g per day) or 6 g twice a day (12 g per day) for 7 days to assess safety and PK. In the second phase of the study, all subjects will receive treatment with ManNAc at a dose of 6 g twice daily (12 g per day) for the remainder of the study. The study was extended to include follow-up evaluations at 6, 12, 18, 24 and 30 months. During the 30 month visit, PK of 4 g three times daily was assessed. Biochemical efficacy was assessed by change in the sialylation of proteins at 3 months compared to baseline. To evaluate the effect of ManNAc on clinical measures of GNE myopathy, a battery of clinical assessments was performed at every visit to identify clinical endpoints suitable for subsequent clinical trials.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Cohort A | Active comparator | Drug: ManNAc6 subjects on Cohort A will receive oral ManNAc 3 g twice daily (6 g/day) for 7 days and, if safe, continue on 6 g twice daily (12 g/day) for the remainder of the study. |
| Cohort B | Active comparator | Drug: ManNAc6 subjects on Cohort B will receive oral ManNAc 6 g twice daily (12 g/day) for the duration of the study. |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (12 listed)
- 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
Key exclusion criteria (11 listed)
- 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.
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 |
|---|---|---|
| ManNAcAt doses of 3 g and 6 g twice daily for a total dose of 6 and 12 g per day. | Drug | Cohort A |
| ManNAcAt doses of 6 g twice daily (12 g per day). | Drug | Cohort B |
Primary outcome
Mean Area Under the Curve (AUClast) of Plasma ManNAc (Baseline-adjusted)
Time frame: Day 7
The mean area under the plasma ManNAc concentration-versus time curve from time 0 (dosing) to the time of last quantifiable concentration.
Maximum Observed Plasma Concentration (Cmax) of ManNAc (Baseline-adjusted)
Time frame: Day 7
The maximum (or peak) plasma ManNAc concentration that the drug achieves in the body after the drug has been administrated.
The Time to Cmax (Tmax) for ManNAc
Time frame: Day 7
The time taken to achieve the maximum observed plasma concentration for ManNAc .
Half-life (t ½) for ManNAc
Time frame: Day 7
The amount of time it takes for plasma ManNAc concentration to decline by half.
Mean Area Under the Curve (AUClast) of Plasma Neu5Ac (Baseline-adjusted)
Time frame: Day 7
The mean area under the plasma Neu5Ac concentration-versus time curve from time 0 (dosing) to the time of last quantifiable concentration.
Maximum Observed Plasma Concentration (Cmax) of Neu5Ac (Baseline-adjusted)
Time frame: Day 7
The maximum (or peak) plasma Neu5Ac concentration that the drug achieves in the body after the drug has been administrated.
The Time to Cmax (Tmax) for Neu5Ac
Time frame: Day 7
The time taken to achieve the maximum observed plasma concentration for Neu5Ac.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Apr 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 34257421Carrillo N, Malicdan MC, Leoyklang P, Shrader JA, Joe G, Slota C, Perreault J, Heiss JD, Class B, Liu CY, Bradley K, Jodarski C, Ciccone C, Driscoll C, Parks R, Van Wart S, Bayman L, Coffey CS, Quintana M, Berry SM, Huizing M, Gahl WA. Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study. Genet Med. 2021 Nov;23(11):2067-2075. doi: 10.1038/s41436-021-01259-x. Epub 2021 Jul 13.
- 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.
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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, 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 2 study testing ManNAc in people with 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 12 inclusion and 11 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 16 Apr 2019. 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. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 16 Apr 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Mean Area Under the Curve (AUClast) of Plasma ManNAc (Baseline-adjusted) (time frame: Day 7). The study lists 7 primary outcomes in all. 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 NCT02346461, which also lists 2 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 16 Apr 2019.