Antimicrobial Therapy for Ulcerative Colitis (UC)

Study Overview
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Brief Summary
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The Aim of this randoized controlled pilot study is to find a better treatment strategy for active UC based on the recent knowledge regarding the microbiota in UC and the beneficial or detrimental effects of antibiotics in restoring gut health and reducing inflammation. This study is designed to determine whether therapy with two antibiotics during a flare - amoxicillin and doxycillin, will be better than the current published antibiotic treatment combination using these antibiotics with metronidazole ( as the latter which may degrade beneficial species without adding benefit towards reducing pathobionts)

Detailed Description
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Recent studies suggest that UC is associated with alterations of the microbiota. Further support for targeting the microbiota includes several studies demonstrating that antibiotics might be helpful for severe refractory colitis. Antibiotics may work by reducing pathobionts, by causing niche expansion of beneficial bacteria , and may harm if they do not reduce pathobionts or reduce beneficial commensals Recently, a triple antibiotic therapy with amoxicillin, metronidazole and tetracycline was developed for UC. However, a recent study on the effect of 11 different oral antibiotics on gut bacteria found that seven of them including metronidazole might cause lbacterial translocation . Anaerobes are critical for butyrate production. . Based on these recent studies, it would appear that tetracycline and amoxicillin are more likely to cause the beneficial effect, while metronidazole might actually be detrimental. Thus by removing metronidazole the investigators might actually have a better effect both for efficacy and safety.

Official Title
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Antimicrobial Therapy for Ulcerative Colitis : Evaluation of Two Antibiotic Combinations for Refractory Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: amoxicillin, metronidazole and doxycycline
* Drug: amoxicillin and doxycyclin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Established diagnosis of UC, disease confined to the large intestine, involving the rectosigmoid for at least 3 months. Weight >30 kg Mild to Moderate active disease, SCCAI of ≥5 and ≤ 10, 10 ≤ PUCAI ≤4. Refractory to mesalamine 6 weeks, or steroids > 14 days, or immunomodulator 12 weeks or biologics at least 12 weeks therapy. Exclusion Criteria: Start of a new biologic in the previous 12 weeks. Proctitis Evidence for Clostridium difficile infection. Any proven current infection such as CMV, positive stool culture or parasite. Current Extra intestinal manifestation of UC such as active arthritis or PSC. Immune deficiency (other than drug induced). Current use of a calcineurin inhibitor Pregnancy. Suspected toxic megacolon, guarding on palpation, or signs of peritoneal inflammation Patients with other IBD unrelated disease such as autoimmune disorders, renal failure, fever or current infection (UTI, strep throat, pneumonia, etc), prior or current neoplasia Fever >38 Participation in another clinical interventional trial An active malignant disease or a prior malignancy during the previous 5 years (excluding skin BCC). Anticipation for antibiotic use within the study period (such as for elective surgery or dental treatment). Acute severe UC in the past 3 months. Presence of a pouch or pouchitis.

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 2 groups with 1:1 randomization
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1 -Amoxycillin Doxycyclin and metronidazole<br>triple therapy with amoxicillin, metronidazole and tetracycline twice daily, for 2 weeks. | Drug: amoxicillin, metronidazole and doxycycline<br>* antibiotics: Patient weight 30-50 kg Patient weight > 50 kg Tetracycline 50 mg X 2 Day X 2 weeks 100 mg X 2 Day X 2 weeks Amoxicillin 750 mg X 2 Day X 2 weeks 750 mg X 2 Day X 2 weeks Metronidazole 250 mg X 2 Day X 2 weeks 375 mg X 2 Day X 2 weeks<br>* Other names: Amoxy, Flagyl, Doxylin;|
| Experimental: Group 2 -Amoxycillin and Doxycyclin<br>double therapy with Amoxycillin and Doxycyclin twice daily, for 2 weeks. | Drug: amoxicillin and doxycyclin<br>* antibiotics: Patient weight 30-50 kg Patient weight > 50 kg Tetracycline 50 mg X 2 Day X 2 weeks 100 mg X 2 Day X 2 weeks Amoxicillin 750 mg X 2 Day X 2 weeks 750 mg X 2 Day X 2 weeks<br>* Other names: Amoxy, Doxylin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy - Clinical Response in group 1 and 2 or Clinical Remission | Response defined as a 3 point drop in SCCAI / 20 point drop in PUCAI or drop in less than 3/20 point but entering clinical remission, defined as a SCCAI score<5 / PUCAI score<10. Remission defined as SCCAI score<5 / PUCAI score<10. SCCAI - simple clinical colitis activity index. The calculated score ranges from 0 to 19, where active disease is a score of 5 or higher. PUCAI - pediatric Ulcerative colitis activity index. The calculated score ranges from 0 to 85, where active disease is a score of 10 or higher. | Week 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy - Clinical Response in group 1 and 2 | Mean/median SCCAI / PUCAI SCCAI - simple clinical colitis activity index. The calculated score ranges from 0 to 19, where active disease is a score of 5 or higher. PUCAI - pediatric Ulcerative colitis activity index. The calculated score ranges from 0 to 85, where active disease is a score of 10 or higher. | Week 6 | 
| EFFICACY - Remission | SCCAI score<5 / PUCAI score<10. SCCAI - simple clinical colitis activity index. The calculated score ranges from 0 to 19, where active disease is a score of 5 or higher. PUCAI - pediatric Ulcerative colitis activity index. The calculated score ranges from 0 to 85, where active disease is a score of 10 or higher. | Week 6 | 
| EFFICACY - PGA | Physicians Global Assessment Values: Normal, not at all ill Borderline ill Mildly ill Moderately ill Markedly ill Severely ill Among the most extremely ill patients | Week 6 | 
| EFFICACY - Corticosteroid free remission | Remission defined as SCCAI score<5 / PUCAI score<10. SCCAI - simple clinical colitis activity index. The calculated score ranges from 0 to 19, where active disease is a score of 5 or higher. PUCAI - pediatric Ulcerative colitis activity index. The calculated score ranges from 0 to 85, where active disease is a score of 10 or higher. | Week 6 | 
| EFFICACY - Corticosteroid free remission | Remission defined as SCCAI score<5 / PUCAI score<10. SCCAI - simple clinical colitis activity index. The calculated score ranges from 0 to 19, where active disease is a score of 5 or higher. PUCAI - pediatric Ulcerative colitis activity index. The calculated score ranges from 0 to 85, where active disease is a score of 10 or higher. | Week 12 | 
| EFFICACY - Decrease in endoscopic disease activity | Decrease in endoscopic disease activity mesured with the Simple Endoscopic Score for Crohn's Disease (SES-CD). The calculated score ranges from 0 to 60 | Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ulcerative Colitis