Tests oral N-acetylglucosamine for Crohn's disease in adults

Trial details

Who runs it

Johns Hopkins University

Trial code

NCT07225998

Record updated

5 November 2026

Original description

Protein glycosylation is a critical post-translational modification that regulates protein trafficking and protein-protein interactions impacting a host of physiological processes. There is a growing appreciation of glycosylation defects in chronic human diseases, including Crohns disease. Crohns disease (CD), and the related condition of ulcerative colitis, are chronic inflammatory bowel diseases (IBD) that impact 3.1 million Americans. While the development of medications has revolutionized care of CD patients, clinical remission is only achieved in ~40% of patients a therapeutic ceiling that has not changed in 20 years. These data underscore the need for new CD treatment strategies. The investigators are focused on understanding the role of defective N-glycosylation in CD, as an innovative strategy to identify and develop new therapeutics. Depending on ancestral background, 7-25% of CD patients carry a pathogenic, missense mutation in the manganese (Mn) transporter ZIP8 (rs13107325; ZIP8 A391T). ZIP8 regulates systemic Mn homeostasis with ZIP8 391-Thr causing a relative Mn insufficiency. Mn is a required metal cofactor for enzymes regulating key cellular processes, like N-glycosylation. In the gut, protein N-glycosylation plays key roles in host-pathogen interactions, inflammation, and cell-cell interactions. The investigator's central hypothesis is that in patients carrying ZIP8 391-Thr - CD is exacerbated by aberrant N-glycosylation and that this defect can be targeted by specific, safe therapy. Supporting this hypothesis, Mn levels are reduced (~15%) in ZIP8 391-Thr allele carriers and this is associated with a decrease in complex N-glycan branching in plasma. Further, the investigators uncovered a microbiota signature in the ileal mucosa that implicated altered bile acid homeostasis in ZIP8 391-Thr carriers. To better understand CD in ZIP8 391 carriers, the investigators generated a knock-in mouse model of ZIP8 391-Thr (Zip8393T/393T). Like patient data, the investigators observe reduced branching of N-glycans and disrupted bile acid homeostasis in the Zip8393T/393T mice. Promising human trials have shown that defects in N-glycan branching can be safely restored by raising levels of the rate-limiting metabolite UDP-N-acetylglucosamine (GlcNAc) via supplementation with free GlcNAc. The investigator's preliminary data in Zip8393T/393T mice have demonstrated that GlcNAc supplementation restores N-glycan branching deficits, rescues the defect in bile acid homeostasis, and ameliorates colitis susceptibility. Thus, the objective of the proposed research is to test a safe and effective therapy for patients carrying ZIP8 391-Thr and others who may have underlying changes in N-glycosylation.Read full original descriptionShow less

The NAGIC Study: Multi-center, Randomized, Double-blind, Placebo-controlled Cross-over Study of Oral N-acetylglucosamine in Ileal/Ileocolonic Crohn's Disease

Protein glycosylation is a critical post-translational modification that regulates protein trafficking and protein-protein interactions impacting a host of physiological processes. There is a growing appreciation of glycosylation defects in chronic human diseases, including Crohns disease. Crohns disease (CD), and the related condition of ulcerative colitis, are chronic inflammatory bowel diseases (IBD) that impact 3.1 million Americans. While the development of medications has revolutionized care of CD patients, clinical remission is only achieved in ~40% of patients a therapeutic ceiling that has not changed in 20 years. These data underscore the need for new CD treatment strategies. The investigators are focused on understanding the role of defective N-glycosylation in CD, as an innovative strategy to identify and develop new therapeutics. Depending on ancestral background, 7-25% of CD patients carry a pathogenic, missense mutation in the manganese (Mn) transporter ZIP8 (rs13107325; ZIP8 A391T). ZIP8 regulates systemic Mn homeostasis with ZIP8 391-Thr causing a relative Mn insufficiency. Mn is a required metal cofactor for enzymes regulating key cellular processes, like N-glycosylation. In the gut, protein N-glycosylation plays key roles in host-pathogen interactions, inflammation, and cell-cell interactions. The investigator's central hypothesis is that in patients carrying ZIP8 391-Thr - CD is exacerbated by aberrant N-glycosylation and that this defect can be targeted by specific, safe therapy. Supporting this hypothesis, Mn levels are reduced (~15%) in ZIP8 391-Thr allele carriers and this is associated with a decrease in complex N-glycan branching in plasma. Further, the investigators uncovered a microbiota signature in the ileal mucosa that implicated altered bile acid homeostasis in ZIP8 391-Thr carriers. To better understand CD in ZIP8 391 carriers, the investigators generated a knock-in mouse model of ZIP8 391-Thr (Zip8393T/393T). Like patient data, the investigators observe reduced branching of N-glycans and disrupted bile acid homeostasis in the Zip8393T/393T mice. Promising human trials have shown that defects in N-glycan branching can be safely restored by raising levels of the rate-limiting metabolite UDP-N-acetylglucosamine (GlcNAc) via supplementation with free GlcNAc. The investigator's preliminary data in Zip8393T/393T mice have demonstrated that GlcNAc supplementation restores N-glycan branching deficits, rescues the defect in bile acid homeostasis, and ameliorates colitis susceptibility. Thus, the objective of the proposed research is to test a safe and effective therapy for patients carrying ZIP8 391-Thr and others who may have underlying changes in N-glycosylation.

The investigators will perform a multi-center, randomized, double-blind, placebo-controlled cross-over study to test the safety and tolerability of oral GlcNAc as a proof-of-concept study. The investigators will use two cohorts stratified by ZIP8 391-Thr genotype status (carriers and non-carriers, n= 20 participants in each cohort, total= 40 participants).

Inclusion: Age 18 and 80 years of age; Diagnosis of CD involving ileum (L1) or ileocolonic disease (L3) of any disease behavior; On stable dosing of any CD therapy for >/= 8 weeks (inclusive of biologics, small molecules, immunomodulators); CDAI <450; Willing to undergo genetic testing for ZIP8 genotype; No steroids within the past 4 weeks; No antibiotics within the past 2 weeks; Willing to provide informed consent; Willing to participate in all at-home and clinic-based follow-up; Willing to provide most recent endoscopy and imaging results; when possible, access to prior pathology specimens; Willing to use all forms of "highly effective" contraception throughout the study period and for 30 days after the last dose of study drug (all subjects of child-bearing potential).

Exclusion: Have taken GlcNAc or glucosamine in the previous 3 months; Steroids within the past 4 weeks; Surgery within 12 weeks; Recent initiation or escalation of immunosuppressive therapy (<8 weeks); Allergy to shellfish; Simple Endoscopic Score for Crohn's Disease (SES-CD) score >/= 16 (or >/= 8 for isolated ileitis) on colonoscopy within 8 weeks of screening, if available; Stricture with high-grade obstruction, significant fistulizing disease, presence of intra-abdominal or perianal abscess, perforation, or fulminant colitis requiring imminent surgical management; History of peripheral vascular disease, coronary artery disease, stroke, transient ischemic attack; History of cancer; History of organ transplant; History of bleeding disorder; History of chronic respiratory disorder, including asthma; History of chronic renal failure; History of chronic liver disease, including primary sclerosing cholangitis; History of seizure disorder; Any clinically significant abnormalities on routine clinical labs, including unexplained white blood cells (WBC) >16,000, hemoglobin <7, AST/ALT >2x ULN, alkaline phosphatase >2x ULN, eGFR <60, ferritin <30 ng/ml2; History of type 1 diabetes, inadequately controlled type 2 diabetes (HbA1c>6.5%), type 2 diabetes on insulin; Severely-active CD defined as CDAI >450 AND/OR; Antibiotics within the past 2 weeks; Pregnant, less than 6 months postpartum, breastfeeding, or attempting to conceive.

ClinicalTrials.gov NCT07225998