Oral N-acetylglucosamine in Crohn's Disease

NCT07225998 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 3 other identifiers: IRB00533883R01DK1418702604-09127
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Crohns Disease

Keywords

Crohns disease; manganese; GlcNAc; N-acetylglucosamine; ZIP8 protein; SLC39A8 gene; genetics; glycosylation disorder

Outcome Measures

Primary Outcomes (1)

• Safety and tolerability: Number of Crohn's disease exacerbations

  Safety and tolerability will be defined as freedom from Crohn's disease (CD) disease exacerbation. Number of CD exacerbations will be one composite outcome with exacerbation of CD activity defined as the occurrence of ANY of the following during each treatment phase: i. Crohn's disease activity index (CDAI) score (patient reported measure) change of \>100 points, ii. initiation or change of CD therapy due to symptom worsening, iii. need for steroids related to CD disease activity, iv. CD-associated hospitalization, v. CD-associated surgery, vi. severe adverse events (CTCAE grade 3-5, attributed to CD disease activity, e.g. life-threatening perforation or sepsis)

  Weeks 0-6, Weeks 6-9, Weeks 9-15, Weeks 15-18

Secondary Outcomes (16)

• Clinical response as assessed by CDAI score

  Week 6, week 15 for each treatment phase (GlcNAc and placebo)

• Clinical response as assessed by mean change in CDAI score

  Week 6, week 15 for each treatment phase (GlcNAc and placebo).

• Clinical remission as assessed by CDAI score

  Week 6, week 15 for each treatment phase (GlcNAc and placebo).

• Change in serum N-glycome

  Week 0, 6, 9, 15, 18

• Change in saliva N-glycome

  Week 0, 6, 9, 15, 18

Study Arms (2)

Participants with Crohn's disease and carry ZIP8 391-Thr (heterozygous or homozygous carriers)

EXPERIMENTAL

N-acetylglucosamine

Drug: N-Acetylglucosamine (GlcNAc)

Participants with Crohn's disease who do not carry ZIP8 391-Thr

EXPERIMENTAL

N-acetylglucosamine

Drug: N-Acetylglucosamine (GlcNAc)

Interventions

N-Acetylglucosamine (GlcNAc) DRUG

This is a placebo-controlled, cross-over design. The sequence in which the participant receives the GlcNAc or placebo is randomized. Participants will take GlcNAc 2 grams three times daily or placebo (glucose 2 grams three times daily) for 6 weeks. There will then be a 3 week washout period and then cross-over to GlcNAc or placebo for 6 weeks. Participants will be followed for 3 weeks off all drug/placebo to complete the study at week 18.

Participants with Crohn's disease and carry ZIP8 391-Thr (heterozygous or homozygous carriers); Participants with Crohn's disease who do not carry ZIP8 391-Thr

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• Have taken GlcNAc or glucosamine in the previous 3 months
• Allergy to shellfish
• Severely-active CD defined as CDAI \>450 AND/OR
• 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
• Steroids within the past 4 weeks
• Antibiotics within the past 2 weeks
• Stricture with high-grade obstruction, significant fistulizing disease, presence of intra-abdominal or perianal abscess, perforation, or fulminant colitis requiring imminent surgical management
• Surgery within 12 weeks
• Recent initiation or escalation of immunosuppressive therapy (\<8 weeks)
• 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
• History of peripheral vascular disease, coronary artery disease, stroke, transient ischemic attack
• History of cancer
• History of organ transplant
• History of bleeding disorder

Sponsors & Collaborators

• Johns Hopkins University: lead
• Leona M. & Harry B. Helmsley Charitable Trust: collaborator
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Johns Hopkins University School of Medicine

Baltimore, Maryland, 21205, United States

Location

Related Publications (2)

• Salvatore S, Heuschkel R, Tomlin S, Davies SE, Edwards S, Walker-Smith JA, French I, Murch SH. A pilot study of N-acetyl glucosamine, a nutritional substrate for glycosaminoglycan synthesis, in paediatric chronic inflammatory bowel disease. Aliment Pharmacol Ther. 2000 Dec;14(12):1567-79. doi: 10.1046/j.1365-2036.2000.00883.x.

  PMID: 11121904 BACKGROUND

• Tomar V, Kang SD, Lin R, Brant SR, Lazarev M, Tressler C, Glunde K, Zachara N, Melia J. Aberrant N-glycosylation may be a therapeutic target in carriers of a common and highly pleiotropic variant in the manganese transporter ZIP8. HGG Adv. 2026 Jan 15;7(1):100517. doi: 10.1016/j.xhgg.2025.100517. Epub 2025 Sep 16.

  PMID: 40963256 BACKGROUND

MeSH Terms

Conditions

Crohn Disease

Interventions

Acetylglucosamine

Condition Hierarchy (Ancestors)

Inflammatory Bowel Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Glucosamine; Hexosamines; Amino Sugars; Carbohydrates

Study Officials

• Joanna Melia, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Joanna MP Melia, MD

CONTACT

410-502-1559; jpeloqu2@jhmi.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 29, 2025
• First Posted: November 10, 2025
• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): October 31, 2027
• Last Updated: April 17, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Data will be available approximately 18 months after trial completion (after publication of results) and available for at least 5 years.
• Access Criteria: Individuals interested in access the IPD and supporting information will be able to access data collected for each person, including demographics, Crohn's disease history, lab results, adverse events, after data use agreement is signed by relevant parties.

Locations

US (1)