Clinical trial NCT02377921: Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Sialic Acid in Patients With Glucosamine (UDP-N-acetyl)-2-epimerase Myopathy (GNEM) or Hereditary Inclusion Body Myopathy (HIBM)
Official title: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Sialic Acid Extended-Release Tablets in Patients With GNE Myopathy (GNEM) or Hereditary Inclusion Body Myopathy (HIBM)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hereditary Inclusion Body Myopathy
Distal Myopathy With Rimmed Vacuoles
Distal Myopathy, Nonaka Type
GNE Myopathy
Keywords: GNE Myopathy
GNEM
HIBM
Nonaka
Hereditary Inclusion Body Myopathy
DMRV
Lead sponsor: Ultragenyx Pharmaceutical Inc
Sponsor class: INDUSTRY
First posted: 2015-03-04
Enrollment: 89
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of this study is to evaluate the effect of 6 g/day aceneuramic acid extended-release (Ace-ER) treatment of participants with GNEM on upper extremity muscle strength (upper extremity composite \[UEC\] score) as measured by dynamometry.


Eligibility criteria: Inclusion Criteria:

* Male or female, aged 18 to 55 years, inclusive
* Willing and able to provide written, signed informed consent after the nature of the study has been explained, and before any research-related procedures are conducted
* Have a documented diagnosis of GNEM, HIBM, distal myopathy with rimmed vacuoles (DMRV), or Nonaka disease due to previously demonstrated mutations in the gene encoding the GNE/N-acetylmannosamine kinase (MNK) enzyme (genotyping will not be conducted in this study)
* Able to provide reproducible force in elbow flexors (i.e. two dynamometry force values with no more than 15% variability in the dominant arm) at Screening
* Able to walk a minimum of 200 meters during the six-meter walk test (6MWT) at Screening without the use of assistive devices, including a cane, crutch(es), walker, wheelchair or scooter (ankle foot orthosis/orthoses are permitted)
* Willing and able to comply with all study procedures
* Participants of child-bearing potential or with partners of child-bearing potential who have not undergone a bilateral salpingo-oophorectomy and are sexually active must consent to use a highly effective method of contraception as determined by the site investigator (i.e. oral hormonal contraceptives, patch hormonal contraceptives, vaginal ring, intrauterine device, physical double-barrier methods, surgical hysterectomy, vasectomy, tubal ligation, or true abstinence \[when this is in line with the preferred and usual lifestyle of the subject\], which means not having sex because the subject chooses not to), from the period following the signing of the informed consent through 3 months after last dose of study drug
* Females of childbearing potential must have a negative pregnancy test at Screening and be willing to have additional pregnancy tests during the study. Females considered not of childbearing potential include those who have been in menopause for at least two years, have had tubal ligation at least one year prior to Screening, or who have had a total hysterectomy or bilateral salpingo-oophorectomy

Exclusion Criteria:

* Ingestion of N-acetyl-D-mannosamine (ManNAc), sialic acid (SA), or related metabolites; intravenous immunoglobulin (IVIG); or anything that can be metabolized to produce SA in the body within 60 days prior to the Screening Visit
* History of more than 30 days treatment with SA-ER and/or Sialic Acid Immediate Release (SA-IR) in prior clinical trials in the past year
* Has had any hypersensitivity to SA or its excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects
* Has serum transaminase (i.e. aspartate aminotransferase \[AST\] or gamma-glutamyl transpeptidase \[GGT\]) levels greater than 3X the upper limit of normal (ULN) for age/gender, or serum creatinine of greater than 2X ULN at Screening
* Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) at any time during the study
* Use of any investigational product or investigational medical device within 30 days prior to Screening, or anticipated requirement for any investigational agent prior to completion of all scheduled study assessments
* Has a condition of such severity and acuity, in the opinion of the investigator, that it warrants immediate surgical intervention or other treatment or may not allow safe participation in the study
* Has a concurrent disease, active suicidal ideation, or other condition that, in the view of the investigator, places the subject at high risk of poor treatment compliance or of not completing the study, or would interfere with study participation or would affect safety

Primary outcomes:
measure: Change From Baseline in UEC Score (Total Force in kg) at Week 48
timeFrame: Baseline, Week 48
Secondary outcomes:
measure: Change From Baseline in Muscle Strength in the Knee Extensors at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in LEC Score (Total Force in kg) at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in GNEM FAS Mobility Domain Score at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in Number of Lifts in the 30 Second Weighted Arm Lift Test at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in Number of Stands in the Sit to Stand Test at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in Meters Walked in the 6MWT at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in Percent Predicted Meters Walked in the 6MWT at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in GNEM FAS Upper Extremity Domain Score at Week 48
timeFrame: Baseline, Week 48
Other outcomes:
Locations:
city: Irvine
country: United States
facility: University of California, Irvine
state: California
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: New York University School of Medicine
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Sofia
country: Bulgaria
facility: UMHAT "Alexandrovska"
city: Hamilton
country: Canada
facility: McMaster University
state: Ontario
city: Saint-Pierre
country: France
facility: CHU La Réunion - site GHSR
state: Reunion
city: Paris
country: France
facility: Institut de Myologie GH Pitié-Salpêtrière
city: Jerusalem
country: Israel
facility: Hadassah-Hebrew University Medical Center
city: Messina
country: Italy
facility: University of Messina
city: Milan
country: Italy
facility: University of Milan
city: Rome
country: Italy
facility: Università Cattolica
city: Newcastle Upon Tyne
country: United Kingdom
facility: The Newcastle upon Tyne Hospitals
state: Tyne And Wear
Study officials:
References:
citation: Lochmuller H, Behin A, Caraco Y, Lau H, Mirabella M, Tournev I, Tarnopolsky M, Pogoryelova O, Woods C, Lai A, Shah J, Koutsoukos T, Skrinar A, Mansbach H, Kakkis E, Mozaffar T. A phase 3 randomized study evaluating sialic acid extended-release for GNE myopathy. Neurology. 2019 Apr 30;92(18):e2109-e2117. doi: 10.1212/WNL.0000000000006932. Epub 2019 Jan 25.
citation: Tandon PK, Kakkis ED. The multi-domain responder index: a novel analysis tool to capture a broader assessment of clinical benefit in heterogeneous complex rare diseases. Orphanet J Rare Dis. 2021 Apr 19;16(1):183. doi: 10.1186/s13023-021-01805-5.