personalized azithromycin/metronidazole therapy in pediatric crohn's disease (cd)

Conditions: Crohn Disease; Pediatric Crohns Disease

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.

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).

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 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.

Keywords: microbiome