A Phase 1 Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of ManNAc in Subjects With Primary Podocyte Diseases
|Study Design:||Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
|Official Title:||A Phase 1 Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of ManNAc in Subjects With Primary Podocyte Diseases|
- To assess safety by self-reported symptoms and by standard laboratory testing [ Time Frame: 3 years ]
- The effects of low serum albumin and reduced eGFR will be assessed [ Time Frame: 1/31/2018 ]
|Study Start Date:||December 10, 2015|
|Estimated Study Completion Date:||January 31, 2018|
|Estimated Primary Completion Date:||January 31, 2018 (Final data collection date for primary outcome measure)|
Experimental: Cohort A
Drug: N-acetyl-mannosamine (ManNAc)
Experimental: Cohort B
Drug: N-acetyl-mannosamine (ManNAc)
Background. ManNAc (N-acetyl D-mannosamine) is an uncharged monosaccharide that is the biologic precursor of N-acetyl neuraminic acid (Neu5Ac, sialic acid). Sialic acids are the negatively charged, terminal monosaccharides of carbohydrate chains that are attached to glycoproteins and glycolipids (glycans). Most glycans serve cellular signaling functions, and frequently appear on the cell surface or are secreted into the circulation. ManNAc is currently in development as a therapy for the rare muscular dystrophy, GNE Myopathy (also called HIBM, hereditary inclusion body myopathy), caused by deficiency of GNE, the key enzyme in sialic acid synthesis (clinicaltrials.gov; NCT01634750).
A Phase 1a trial was completed and a Phase 2 trial for ManNAc for GNE myopathy subjects has been initiated through efforts of NCATS (TRND program; PI: Dr. Carrillo-Carrasco) and NHGRI (Dr. Huizing, Dr. Malicdan; Sponsor: Dr. Gahl), most of whom are Associate Investigators on this protocol. The NHGRI basic research group has documented podocytopathy, glomerular protein hyposialylation and severe proteinuria in mice deficient in GNE and found that their podocyte ultrastructure improved, sialylation increased and proteinuria decreased with oral ManNAc therapy. Human kidney biopsy tissue from subjects with various primary podocyte diseases, including minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and membranous nephropathy (MN), also showed glomerular hyposialylation (manuscript in preparation).
Purpose. We propose to carry out a Phase 1 escalating dose study to evaluate the safety, tolerability, and pharmacokinetics of ManNAc in nephrotic subjects with primary podocyte diseases.
Subjects. We propose to enroll 12 subjects with MCD, FSGS or MN. We will recruit subjects in 4 groups (2-3 subjects each) grouped by estimated glomerular filtration rate (eGFR).
Intervention. This dose escalation study will involve two progressive ManNAc dose cohorts (each with N= 6) of 3,000 mg/day and 10,000 mg/day. Drug exposure will occur in a single dose phase, involving one dose of oral ManNAc followed by a 72 hour pharmacokinetics and safety study, and a multiple dose phase, involving ManNAc administered two times/day for 5 days. Dose escalation will occur when the lower dose is assessed safe in all subjects by a Safety Review Committee.
Outcomes. We will assess safety by self-reported symptoms and by standard laboratory testing. Pharmacokinetics will be analyzed using plasma ManNAc and Neu5Ac (sialic acid) levels. The effects of reduced eGFR on these parameters will be assessed. While the study duration is short and there is no placebo control, the effect of ManNAc therapy on proteinuria, from the baseline to the end of the extension phase, will be examined on a research basis.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02639260
|Contact: Jeffrey B Kopp, M.D.||(301) firstname.lastname@example.org|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL) 800-411-1222 ext TTY8664111010 email@example.com|
|Principal Investigator:||Jeffrey B Kopp, M.D.||National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)|