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| ID | Type | Description | Link |
|---|---|---|---|
| 585718 | Other Grant/Funding Number | Crohn's & Colitis Foundation |
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The DSMB concluded that feasibility endpoints were reached in time for Week 4 but no participants receiving standard of care dietary treatment could be randomized based on the at-risk of the microbiome signature.
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| Name | Class |
|---|---|
| Crohn's and Colitis Foundation | OTHER |
| University of Amsterdam | OTHER |
| OM Pharma SA | INDUSTRY |
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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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Standard of Care | Other | SOC induction (nutritional therapy) for up to 12 weeks, as assigned by the treating gastroenterologist prior to study entry. |
|
| Standard of Care + Antibiotics | Experimental | 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) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Azithromycin | 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 |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Week 52 |
| Feasibility of Multinational Microbiome-randomized Trial | The number of participants with microbiome data available at Week 4/5. | Week 4/5 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Current or previous use of biologic therapy;
Presence of stricturing, penetrating (intestinal or perianal) and/or fistulizing CD;
Pregnancy or lactation;
Have undergone intestinal resection;
Positive Clostridium Difficile toxin;
Treatment with another investigational drug or other intervention within 30 days before week 0;
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;
History of cockayne syndrome;
Prior diagnosis of any hematologic condition/blood dyscrasia which may result in leukopenia (even if leukocyte count is normal at screening);
Known allergy or intolerance to azithromycin or metronidazole;
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;
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;
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;
Subject who received fecal microbial transplantation within 35 days prior to week 0 visit;
Screening laboratory and other analyses show any of the following abnormal results:
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| Name | Affiliation | Role |
|---|---|---|
| Johan E Van Limbergen, MD, PhD | Amsterdam UMC | Principal Investigator |
| Arie Levine, MD | Edith Wolfson Medical Centre, Tel Aviv | Study Chair |
| Francisco Sylvester, MD | University North Carolina | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UCSF Benioff Children's Hospital | San Francisco | California | 94158 | United States | ||
| University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36725090 | Derived | 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. |
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Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with University of North Carolina.
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Beginning 9 to 36 months following publication
IRB, IEC, or REB approval, as applicable, and an executed data use/sharing agreement with University of North Carolina.
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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.
Thirteen children were enrolled in the study to assess microbiome by Week 4. All participants received standard of care.
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| ID | Title | Description |
|---|---|---|
| FG000 | Standard of Care | All participants received standard of care during the first four weeks. |
| FG001 | 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. |
| FG002 | 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. |
| FG003 | 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. |
| FG004 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Standard of Care (Week 0 to Week 4) |
|
| ||||||||||||||||||
| Microbiome Result at Week 4/5 |
| |||||||||||||||||||
| Randomization/Ongoing SOC/Antibiotics |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Count of Participants | Participants | Week 52 |
|
From the time of signing informed consent until study conclusion (up to 52 weeks).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Johan Van Limbergen, MD, PhD | Amsterdam University Medical Center | +31-20 566 9111 | j.e.vanlimbergen@amsterdamumc.nl |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 21, 2021 | Nov 4, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D003424 | Crohn Disease |
| ID | Term |
|---|---|
| D015212 | Inflammatory Bowel Diseases |
| D005759 | Gastroenteritis |
| D005767 | Gastrointestinal Diseases |
| D004066 | Digestive System Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D017963 | Azithromycin |
| D008795 | Metronidazole |
| D059039 | Standard of Care |
| ID | Term |
|---|---|
| D004917 | Erythromycin |
| D018942 | Macrolides |
| D061065 | Polyketides |
| D007783 | Lactones |
| D009930 |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
| Metronidazole | 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 | 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. |
|
| Week 52 |
| 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. | Week 52 |
| 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. | Week 52 |
| 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. | Week 52 |
| Pittsburgh |
| Pennsylvania |
| 15224 |
| United States |
| IWK Health Centre | Halifax | Canada |
| Wolfson Medical Centre | Tel Aviv | Israel |
| Amsterdam UMC | Amsterdam | Netherlands |
| COMPLETED |
|
| NOT COMPLETED |
|
| COMPLETED |
|
| NOT COMPLETED |
|
| BG001 | 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. |
| BG002 | 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. |
| BG003 | 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. |
| BG004 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| OG001 | 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) 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. |
|
|
| Primary | Feasibility of Multinational Microbiome-randomized Trial | The number of participants with microbiome data available at Week 4/5. | 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). | Posted | Count of Participants | Participants | Week 4/5 |
|
|
|
| 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. | 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. | Posted | Count of Participants | Participants | Week 52 |
|
|
|
| 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. | 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. | Posted | Count of Participants | Participants | Week 52 |
|
|
|
| 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. | 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. | Posted | Count of Participants | Participants | Week 52 |
|
|
|
| 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. | 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. | Posted | Week 52 |
|
|
| 0 |
| 1 |
| 0 |
| 1 |
| 0 |
| 1 |
| EG001 | 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. | 0 | 2 | 0 | 2 | 2 | 2 |
| EG002 | 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. | 0 | 9 | 0 | 9 | 2 | 9 |
| EG003 | No Remission Independent of Microbiome + Antibiotics (Group C) | 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. | 0 | 1 | 0 | 1 | 1 | 1 |
| Headache | Nervous system disorders | Systematic Assessment |
|
| Nausea | Nervous system disorders | Systematic Assessment |
|
| Change in taste | Gastrointestinal disorders | Systematic Assessment |
|
| Dizziness | Nervous system disorders | Systematic Assessment |
|
| Elevated Liver Enzymes | Gastrointestinal disorders | Systematic Assessment |
|
| Dilated Bile Duct | Gastrointestinal disorders | Systematic Assessment |
|
| Limb Pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
Not provided
Not provided
Not provided
| D007410 | Intestinal Diseases |
| Organic Chemicals |
| D009593 | Nitroimidazoles |
| D009574 | Nitro Compounds |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D019984 | Quality Indicators, Health Care |
| D011787 | Quality of Health Care |
| D006298 | Health Services Administration |
| D017530 | Health Care Quality, Access, and Evaluation |
| Between 18 and 65 years |
|
| >=65 years |
|
| Male |
|