Crohn Disease, Pediatric Crohns Disease
Conditions
Keywords
Microbiome
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).
Interventions
DRUGAzithromycin
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
DRUGMetronidazole
Weeks 4-12: 20 mg/kg/day of metronidazole (10 mg/kg twice daily to a maximum of 1000 mg/day) for 8 weeks
OTHERStandard 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.
Sponsors
Crohn's and Colitis Foundation
University of Amsterdam
OM Pharma SA
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 17 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Sustained Remission | Week 52 | Participants stratified based on carriage of an at-risk microbiome 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 4/5 | The number of participants with microbiome data available at Week 4/5. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Normal Pediatric Crohn's Disease Activity Index (PCDAI) Score at Week 52 | 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. |
| Number of Participants With Normal Fecal Calprotectin Levels in Stool at Week 52 | Week 52 | Fecal calprotectin is a non-invasive surrogate protein marker for bowel inflammation. The normal range is \<200 mcg/g. |
| Number of Participants With Normal C-Reactive Protein (CRP) Levels in Blood at Week 52 | 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. |
| IMPACT-III Score at Week 52 | 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, participants aged 9 and older will complete this questionnaire at week 0, 12, 24, and 52. Participants 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. |
Countries
Canada, Israel, Netherlands, United States
Participant flow
Recruitment details
Thirteen children were enrolled in the study to assess microbiome by Week 4. All participants received standard of care.
Pre-assignment details
Of the 13 included children, 12 had microbiome data available by Week 4. One participant refused to continue SOC diet treatment and dropped out 1 week after starting. Three (23%) were predicted to be non-responders based on their baseline microbiome. Of these, 2 of 3 had a primary non-response to Standard of Care (SOC) treatment and did not reach clinical remission within 4 weeks. Ten participants were predicted to be responders. No participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| High Risk for Relapse (Group A1) SOC induction (nutritional therapy) for up to 12 weeks, as assigned by the treating gastroenterologist prior to study entry.
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. | 1 |
| High Risk for Relapse Standard of Care + Antibiotics (Group A2) 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)
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
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
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. | 2 |
| Normal Risk for Relapse Standard of Care (Group B) SOC induction (nutritional therapy) for up to 12 weeks, as assigned by the treating gastroenterologist prior to study entry. | 9 |
| No Remission Independent of Microbiome + 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)
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
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
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. | 1 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Standard of Care (Week 0 to Week 4) | Withdrawal by Subject | 2 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Normal Risk for Relapse Standard of Care (Group B) | Total | High Risk for Relapse (Group A1) | High Risk for Relapse Standard of Care + Antibiotics (Group A2) | No Remission Independent of Microbiome + Antibiotics |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 9 Participants | 13 Participants | 1 Participants | 2 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — | — | — |
| Region of Enrollment Netherlands | 9 Participants | 13 Participants | 1 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Female | 6 Participants | 7 Participants | 0 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 1 Participants | 2 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 2 | 0 / 9 | 0 / 1 |
| other Total, other adverse events | 0 / 1 | 2 / 2 | 2 / 9 | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 | 0 / 2 | 0 / 9 | 0 / 1 |
Outcome results
Primary
Feasibility of Multinational Microbiome-randomized Trial
The number of participants with microbiome data available at Week 4/5.
Time frame: Week 4/5
Population: Two participants provided microbiome data at Baseline but did not continue after Week 1. No participants were randomized into Group A1 or Group A2. Eight participants continued SOC in Group B and three participants were eligible for antibiotics based on microbiome data and not achieving remission in Group C (two participants received antibiotics).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard of Care | Feasibility of Multinational Microbiome-randomized Trial | 2 Participants |
| Normal Risk for Relapse Standard of Care (Group B) | Feasibility of Multinational Microbiome-randomized Trial | 8 Participants |
| No Remission Independent of Microbiome + Antibiotics | Feasibility of Multinational Microbiome-randomized Trial | 3 Participants |
Primary
Number of Participants With Sustained Remission
Participants stratified based on carriage of an at-risk microbiome 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.
Time frame: Week 52
Population: No children carrying an at-risk microbiome achieved remission by Week 4; therefore, no participants were eligible for randomization and thus these data were not collected. Only participants who remained in the study until Week 52 are reported. The other participants either refused to continue dietary therapy or needed additional medical therapy in the course of the 52 weeks due to disease activity.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard of Care | Number of Participants With Sustained Remission | 2 Participants |
| Standard of Care + Antibiotics | Number of Participants With Sustained Remission | 1 Participants |
Secondary
IMPACT-III Score at 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, participants aged 9 and older will complete this questionnaire at week 0, 12, 24, and 52. Participants 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.
Time frame: Week 52
Population: No children carrying an at-risk microbiome achieved remission by Week 4. Consequently, no participants were eligible for randomization, and these data were not collected. Additionally, no questionnaires were completed at Week 52 for any participants. Although three children continued participation through Week 52, they were not asked to complete the IMPACT-III questionnaire after the DSMB decision to stop the study.
Secondary
Number of Participants With Normal C-Reactive Protein (CRP) Levels in Blood at 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.
Time frame: Week 52
Population: No children carrying an at-risk microbiome achieved remission by Week 4; therefore, no participants were eligible for randomization and thus these data were not collected. Only 3 participants were maintained in the study until Week 52, the other participants either refused to continue dietary therapy or needed additional medical therapy in the course of the 52 weeks due to disease activity.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard of Care | Number of Participants With Normal C-Reactive Protein (CRP) Levels in Blood at Week 52 | 2 Participants |
| Standard of Care + Antibiotics | Number of Participants With Normal C-Reactive Protein (CRP) Levels in Blood at Week 52 | 1 Participants |
Secondary
Number of Participants With Normal Fecal Calprotectin Levels in Stool at Week 52
Fecal calprotectin is a non-invasive surrogate protein marker for bowel inflammation. The normal range is \<200 mcg/g.
Time frame: Week 52
Population: No children carrying an at-risk microbiome achieved remission by Week 4; therefore, no participants were eligible for randomization and thus these data were not collected. Only 3 participants were maintained in the study until Week 52, the other participants either refused to continue dietary therapy or needed additional medical therapy in the course of the 52 weeks due to disease activity.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard of Care | Number of Participants With Normal Fecal Calprotectin Levels in Stool at Week 52 | 1 Participants |
| Standard of Care + Antibiotics | Number of Participants With Normal Fecal Calprotectin Levels in Stool at Week 52 | 1 Participants |
Secondary
Number of Participants With Normal Pediatric Crohn's Disease Activity Index (PCDAI) Score at 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.
Time frame: Week 52
Population: No children carrying an at-risk microbiome achieved remission by Week 4; therefore, no participants were eligible for randomization and thus these data were not collected. Only 3 participants were maintained in the study until Week 52, the other participants either refused to continue dietary therapy or needed additional medical therapy in the course of the 52 weeks due to disease activity.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard of Care | Number of Participants With Normal Pediatric Crohn's Disease Activity Index (PCDAI) Score at Week 52 | 2 Participants |
| Standard of Care + Antibiotics | Number of Participants With Normal Pediatric Crohn's Disease Activity Index (PCDAI) Score at Week 52 | 1 Participants |