Personalized AZithromycin/metronidAZole Therapy in Pediatric Crohn's Disease (CD)

NCT ID: NCT04186247

Last Updated: 2025-06-29

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 13 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-08-13
• Study Completion Date: 2023-12-31

Brief Summary

This is a multi-center, randomized, controlled open-label add-on design trial pilot study to evaluate the efficacy of personalized adjunctive antibiotic (azithromycin + metronidazole) therapy in pediatric subjects with mild to moderate Crohn's disease (CD) who have a microbiome profile associated with increased risk of early relapse. This an add-on design trial for subjects already receiving standard of care therapy to induce remission; there will be no placebos.

Detailed Description

The study hypothesis is that adjunctive antibiotic therapy will improve clinical response to standard of care (SOC) induction therapy in a subgroup of CD patients with a relapse-associated microbiome profile.

Prior to starting SOC induction therapy at week 0, subjects will provide a baseline stool sample that will be screened for microbiome profiles associated with risk of relapse according to an established statistical model.

At week 4, subjects with a relapse-associated microbiome will be randomized into either a control arm that will continue to receive SOC induction therapy for an additional 8 weeks, or a treatment arm that will receive adjunctive antibiotic therapy in addition to continuing to receive SOC induction therapy for an additional 8 weeks. Subjects who do not have a relapse-associated microbiome will enter a separate control arm that will continue to receive SOC induction therapy and will have data collected for exploratory objectives. Subjects who are not in clinical remission by week 4 will receive antibiotic therapy regardless of microbiome signature at baseline. Subjects will be monitored for an additional 40 weeks after the treatment period (52 weeks total).

Conditions

Crohn Disease; Pediatric Crohns Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Standard of Care

SOC induction (nutritional therapy) for up to 12 weeks, as assigned by the treating gastroenterologist prior to study entry.

Group Type: OTHER

Standard of Care

Intervention Type: OTHER

SOC induction therapy is nutritional therapy (Crohn's disease exclusion diet + partial enteral nutrition) for up to 12 weeks. Induction therapy is as assigned by the treating gastroenterologist prior to study entry.

Standard of Care + Antibiotics

SOC induction (nutritional therapy) for up to 12 weeks, as assigned by the treating gastroenterologist prior to study entry.

Azithromycin (weeks 4-12)

Metronidazole (weeks 4-12)

Group Type: EXPERIMENTAL

Azithromycin

Intervention Type: DRUG

Weeks 4-12: 7.5 mg/kg azithromycin once daily (500 mg/day maximum) for five consecutive days/ week for 4 weeks, and 3 times a week for the following 4 weeks

Metronidazole

Intervention Type: DRUG

Weeks 4-12: 20 mg/kg/day of metronidazole (10 mg/kg twice daily to a maximum of 1000 mg/day) for 8 weeks

Standard of Care

Intervention Type: OTHER

SOC induction therapy is nutritional therapy (Crohn's disease exclusion diet + partial enteral nutrition) for up to 12 weeks. Induction therapy is as assigned by the treating gastroenterologist prior to study entry.

Interventions

Azithromycin

Weeks 4-12: 7.5 mg/kg azithromycin once daily (500 mg/day maximum) for five consecutive days/ week for 4 weeks, and 3 times a week for the following 4 weeks

Intervention Type: DRUG

Metronidazole

Weeks 4-12: 20 mg/kg/day of metronidazole (10 mg/kg twice daily to a maximum of 1000 mg/day) for 8 weeks

Intervention Type: DRUG

Standard of Care

SOC induction therapy is nutritional therapy (Crohn's disease exclusion diet + partial enteral nutrition) for up to 12 weeks. Induction therapy is as assigned by the treating gastroenterologist prior to study entry.

Intervention Type: OTHER

Other Intervention Names

Zithromax; Zmax; Flagyl

Eligibility Criteria

Inclusion Criteria

1. Provision of signed and dated informed consent form (and assent form, as applicable);

2. Stated willingness to comply with all study procedures and availability for the duration of the study;

3. Male or female, aged 3 to 17 years;

4. Diagnosed with CD according to standard clinical and histological criteria, within 36 months of week 0;

5. Exhibiting mild to moderate symptoms of active disease, as determined by a Pediatric Crohn's Disease Activity Index (PCDAI) score >10 (or > 7.5 excluding the height item) and ≤37.5;

6. Fecal calprotectin level >=250 µg/g within 30 days prior to week 0 visit based on local measurement, if available, or to be arranged with lead site if an endoscopy is not performed within 30 days prior to week 0 visit.

Exclusion Criteria

1. Current or previous use of biologic therapy;

2. Presence of stricturing, penetrating (intestinal or perianal) and/or fistulizing CD;

3. Pregnancy or lactation;

4. Have undergone intestinal resection;

5. Positive Clostridium Difficile toxin;

6. Treatment with another investigational drug or other intervention within 30 days before week 0;

7. Risk factors for arrhythmia including history of prolonged corrected QT interval (QTc), hypokalemia or hypomagnesemia, resting bradycardia, or concurrent treatment with other drugs with potential for QT prolongation;

8. History of cockayne syndrome;

9. Prior diagnosis of any hematologic condition/blood dyscrasia which may result in leukopenia (even if leukocyte count is normal at screening);

10. Known allergy or intolerance to azithromycin or metronidazole;

11. Subjects who received intravenous anti-infective within 35 days prior to week 0 visit or anti-infectives within 14 days prior to the week 0 visit;

12. Subject on oral aminosalicylates who has not been on stable doses for greater than, or discontinued within, at least 14 days prior to week 0;

13. Subject on cyclosporine, tacrolimus or mycophenolate mofetil. Stable doses (no change within 14 days prior to week 0) of azathioprine, 6-mercaptopurine or methotrexate (MTX) are not a reason for exclusion;

14. Subject who received fecal microbial transplantation within 35 days prior to week 0 visit;

15. Screening laboratory and other analyses show any of the following abnormal results:

• aspartate transaminase (AST), alanine transaminase (ALT) > 2 X upper limit of the reference range,
• White blood cell (WBC) count < 3.0 X 109/L,
• Total bilirubin >= 20 micromol/liter (1.17 mg/dL); except for subjects with isolated elevation of indirect bilirubin relating to Gilbert syndrome,
• Estimated glomerular filtration rate (GFR) by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula of < 30 mL/min/1.73 m²,
• Hemoglobin < 80 gram/liter,
• Platelets < 100,000/µL.

• Minimum Eligible Age: 3 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Crohn's and Colitis Foundation

OTHER

Sponsor Role: collaborator

University of Amsterdam

OTHER

Sponsor Role: collaborator

OM Pharma SA

INDUSTRY

Sponsor Role: collaborator

University of North Carolina, Chapel Hill

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Johan E Van Limbergen, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Amsterdam UMC

Arie Levine, MD

Role: STUDY_CHAIR

Edith Wolfson Medical Centre, Tel Aviv

Francisco Sylvester, MD

Role: STUDY_CHAIR

University North Carolina

Locations

UCSF Benioff Children's Hospital

San Francisco, California, United States

University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States

IWK Health Centre

Halifax, , Canada

Wolfson Medical Centre

Tel Aviv, , Israel

Amsterdam UMC

Amsterdam, , Netherlands

Countries

United States; Canada; Israel; Netherlands

References

Verburgt CM, Dunn KA, Otley A, Heyman MB, Verstraete S, Sunseri W, Sylvester F, de Meij T, Comeau A, Langille M, de Jonge WJ, Benninga MA, Van Limbergen JE. Personalised azithromycin+metronidazole (PAZAZ), in combination with standard induction therapy, to achieve a faecal microbiome community structure and metagenome changes associated with sustained remission in paediatric Crohn's disease (CD): protocol of a pilot study. BMJ Open. 2023 Feb 1;13(2):e064944. doi: 10.1136/bmjopen-2022-064944.

Reference Type: DERIVED

PMID: 36725090 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

585718

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

19-3100

Identifier Type: -

Identifier Source: org_study_id