Alanyl-glutamine for Clostridium Difficile Infection

(ACT Trial)

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Virginia

Must be taking: Vancomycin, Fidaxomicin

Must not be taking: Probiotics, Other antibiotics

Disqualifiers: COVID-19, IBD flare, Cirrhosis, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 10 days

260 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on alternative treatments for C. difficile infection or probiotics unless you are willing to stop them.

How is the drug Alanyl-glutamine unique in treating Clostridium difficile infection?

Alanyl-glutamine is unique because it is a dipeptide that may help in gut health and repair, potentially offering a novel approach to treating Clostridium difficile infection by supporting the intestinal lining, unlike traditional antibiotics that target the bacteria directly. ^{1 2 3 4 5}

What is the purpose of this trial?

This is a randomized, double-blind, placebo-controlled trial to determine the optimal dose and safety of oral alanyl-glutamine between 4, 24, and 44 g doses administered for 10 days with standard therapy among first time incident cases of uncomplicated C. difficile infection (CDI) in hospitalized, or outpatient, persons aged 18 or older. The investigators hypothesis is that alanyl-glutamine supplementation will decrease recurrence and mortality from CDI and these outcomes will be associated with improvement of inflammatory markers and restoration of intestinal microbiota function.

Eligibility Criteria

This trial is for adults aged 18 or older with a first-time, uncomplicated C. difficile infection who are within 96 hours of receiving standard therapy and can consent to the study. It's not for those with severe conditions like shock, megacolon, acute abdomen, ICU patients, intolerance to oral medication, other diarrhea causes or on conflicting treatments.

Inclusion Criteria

Must be able to provide informed consent in person or electronically, or if not able to have a LAR to provide consent, in person or remotely via virtual or electronic means

I am currently experiencing diarrhea.

Provision of signed and dated informed consent form

Exclusion Criteria

I had a bone marrow or organ transplant within the last 100 days.

My inflammatory bowel disease is under control and not currently flaring.

I am taking probiotics and do not want to stop.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral alanyl-glutamine or placebo for 10 days concurrent with standard treatment

10 days

Daily visits (in-person or virtual)

Follow-up

Participants are monitored for recurrence and survival, with specimen collection for inflammation and microbial profiling

60 days

Weekly visits (in-person or virtual)

Treatment Details

Interventions

• Alanyl-glutamine

Trial Overview The ACT trial tests different doses (4g, 24g, and 44g) of alanyl-glutamine given orally for ten days alongside standard therapy to see if it reduces recurrence and mortality from C. difficile infections while improving inflammatory markers and gut microbiota function.

Participant Groups

Group I: Alanyl-glutamine 4g Experimental Treatment 1 Intervention

Group II: Alanyl-glutamine 44g Experimental Treatment 1 Intervention

Group III: Alanyl-glutamine 24g Experimental Treatment 1 Intervention

Group IV: Alanyl-glutamine 0g Placebo Group 1 Intervention

Who Is Running the Clinical Trial?

University of Virginia

Lead Sponsor

Trials

802

Recruited

1,342,000+

Carilion Clinic

Collaborator

Trials

85

Recruited

15,400+

University of Southampton

Collaborator

Trials

232

Recruited

2,469,000+

Imperial College London

Collaborator

Trials

1,052

Recruited

15,030,000+

Findings from Research

A new class of biaryl peptidomimetics was developed, showing potent antibacterial activity against Clostridioides difficile and methicillin-resistant Staphylococcus aureus, with the monocationic compound demonstrating an MIC of 8 μg/mL against C. difficile.

In in vivo studies using a murine model, compounds 28 and 67 significantly reduced the severity and slowed the onset of C. difficile infection, indicating their potential as effective treatments for this serious gastrointestinal infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles targeting Clostridioides (Clostridium) difficile: Synthesis, antibacterial evaluation and an in vivo C. difficile infection model. Tague, AJ., Putsathit, P., Hutton, ML., et al.[2020]

Clostridium difficile infections, particularly antibiotic-associated colitis, are increasingly dangerous due to the emergence of more virulent strains, highlighting the need for effective treatments beyond traditional antibiotics like vancomycin and metronidazole.

New therapeutic strategies, including polymer-based toxin-binding agents and monoclonal antibodies targeting the toxins produced by C. difficile, show promise as non-antibiotic options that could effectively manage this toxin-mediated disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxin-binding treatment for Clostridium difficile: a review including reports of studies with tolevamer. Weiss, K.[2020]

Peptides derived from a specific region of the TcdB toxin in Clostridium difficile can protect cells from its harmful effects by destabilizing the toxin's structure and preventing it from binding to cells.

One particular peptide, PepB2, forms a complex that alters TcdB's conformation, suggesting a novel approach to developing treatments for Clostridium difficile infections by targeting this critical virulence factor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrinsic Toxin-Derived Peptides Destabilize and Inactivate Clostridium difficile TcdB. Larabee, JL., Bland, SJ., Hunt, JJ., et al.[2020]

Aryl-alkyl-lysines, particularly the compound NCK-10, show promising antimicrobial activity against Clostridium difficile, with effectiveness comparable to the antibiotic vancomycin, and in some cases, even superior to it in vitro.

NCK-10 demonstrated limited permeation across the intestinal tract, suggesting it may be a targeted treatment option for CDI that minimizes systemic exposure, warranting further research into its potential as a novel therapeutic agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aryl-alkyl-lysines: Novel agents for treatment of C. difficile infection. Ghosh, C., AbdelKhalek, A., Mohammad, H., et al.[2021]

C. difficile can survive in the presence of host antimicrobial proteins like lysozyme due to the Dlt pathway, which enhances its resistance by modifying its cell wall.

The study identified that the σ(V) sigma factor is crucial for regulating the Dlt pathway in response to lysozyme, and both Dlt and σ(V) mutants showed increased virulence in a hamster infection model, highlighting their roles in C. difficile's ability to cause disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Clostridium difficile Dlt Pathway Is Controlled by the Extracytoplasmic Function Sigma Factor σV in Response to Lysozyme. Woods, EC., Nawrocki, KL., Suárez, JM., et al.[2020]

References

1. France pubmed.ncbi.nlm.nih.gov

Cationic biaryl 1,2,3-triazolyl peptidomimetic amphiphiles targeting Clostridioides (Clostridium) difficile: Synthesis, antibacterial evaluation and an in vivo C. difficile infection model. [2020]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Toxin-binding treatment for Clostridium difficile: a review including reports of studies with tolevamer. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Intrinsic Toxin-Derived Peptides Destabilize and Inactivate Clostridium difficile TcdB. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Aryl-alkyl-lysines: Novel agents for treatment of C. difficile infection. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

The Clostridium difficile Dlt Pathway Is Controlled by the Extracytoplasmic Function Sigma Factor σV in Response to Lysozyme. [2020]