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

Personalized AZithromycin/metronidAZole, in Combination With Standard Induction Therapy, to Achieve a Fecal Microbiome Community Structure and Metagenome Changes Associated With Sustained Remission in Pediatric Crohn's Disease (CD): a Pilot Study

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.

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).

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.