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

Phase 2

Completed

• Conditions: Crohn Disease; Pediatric Crohns Disease
• Interventions: Other: Standard of Care; Drug: Azithromycin; Drug: Metronidazole

• Registration Number: NCT04186247
• Lead Sponsor: University of North Carolina, Chapel Hill

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).

Study Timeline

• Study First Submitted: 2019-12-02
• Study First Submitted QC: 2019-12-02
• Study First Posted: 2019-12-04
• Study Start: 2021-08-13
• Primary Completion: 2023-12-31
• Study Completion: 2023-12-31
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-02
• Last Update Posted: 2024-08-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 12

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 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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard of Care	Standard of Care	SOC induction (nutritional therapy) for up to 12 weeks, as assigned by the treating gastroenterologist prior to study entry.
Standard of Care + Antibiotics	Azithromycin	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)
Standard of Care + Antibiotics	Metronidazole	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)
Standard of Care + Antibiotics	Standard of Care	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)

Primary Outcome Measures

Name	Time	Method
Percent of Subjects with Sustained Remission	Week 52	Subjects without need for re-induction for clinical flare (new course of nutritional therapy, need to restart steroids), steroid dependence, biologic (e.g. anti-TNF) use, and/or intestinal surgery
Feasibility of multinational microbiome-randomized trial	week 52	Proportion of subjects that are successfully randomized in randomization procedure, proportion of patients per treatment arm, proportion of subjects that complete 1 year endpoint

Secondary Outcome Measures

Name	Time	Method
Change in Fecal Calprotectin Levels in Stool over Baseline to Week 52	Baseline to Week 52	Fecal calprotectin is a non-invasive surrogate protein marker for bowel inflammation.
Change in C-Reactive Protein (CRP) Levels in Blood over Baseline to Week 52	Baseline to Week 52	CRP is a blood protein marker of inflammation. CRP levels are classified as 'normal/low' or 'elevated/high' based on standard laboratory reference ranges.
Change in Pediatric Crohn's Disease Activity Index (PCDAI) Score over Baseline to Week 52	Baseline to Week 52	Pediatric Crohn's Disease Activity Index (PCDAI) is an index used to measure disease activity of pediatric patients with Crohn's Disease assessing abdominal pain, stool frequency, patient functioning, hematocrit, erythrocyte sedimentation rate, albumin, weight, height, examination of abdomen, perirectal disease, and extraintestinal manifestations. Scores range from 0 to 100, with higher scores indicating greater disease activity.
Change in IMPACT-III Score over Baseline to Week 52	Baseline to Week 52	The IMPACT III questionnaire is a 35-item assessment of health-related quality of life in patients with inflammatory bowel disease (Crohn's disease \[CD\] or ulcerative colitis). In this study, subjects aged 9 and older will complete this questionnaire at week 0, 12, 24, and 52. Subjects mark an option from 1 to 5 for each item.The total scores range from 35 to 175, with higher scores representing a better quality of life.

Trial Locations

Locations (5)

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

Amsterdam UMC; 🇳🇱 Amsterdam, Netherlands

Wolfson Medical Centre; 🇮🇱 Tel Aviv, Israel