Antimicrobial Therapy for Ulcerative Colitis (UC)

Ulcerative Colitis Clinical Trial

— UC  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03986996
• Other study ID #: AntimicrobialUC
• Status: Terminated
• Phase: Phase 2
• Start date: July 25, 2019
• Est. completion date: May 30, 2022

Study information

• Verified date: May 2022
• Source: Wolfson Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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)

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 20
• Est. completion date: May 30, 2022
• Est. primary completion date: May 29, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 13 Years to 60 Years

Eligibility

Inclusion Criteria:

1. Established diagnosis of UC, disease confined to the large intestine, involving the rectosigmoid for at least 3 months.

2. Weight >30 kg

3. Mild to Moderate active disease, SCCAI of =5 and = 10, 10 = PUCAI =4.

4. Refractory to mesalamine 6 weeks, or steroids > 14 days, or immunomodulator 12 weeks or biologics at least 12 weeks therapy.

Exclusion Criteria:

1. Start of a new biologic in the previous 12 weeks.

2. Proctitis

3. Evidence for Clostridium difficile infection.

4. Any proven current infection such as CMV, positive stool culture or parasite.

5. Current Extra intestinal manifestation of UC such as active arthritis or PSC.

6. Immune deficiency (other than drug induced).

7. Current use of a calcineurin inhibitor

8. Pregnancy.

9. Suspected toxic megacolon, guarding on palpation, or signs of peritoneal inflammation

10. 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

11. Fever >38

12. Participation in another clinical interventional trial

13. An active malignant disease or a prior malignancy during the previous 5 years (excluding skin BCC).

14. Anticipation for antibiotic use within the study period (such as for elective surgery or dental treatment).

15. Acute severe UC in the past 3 months.

16. Presence of a pouch or pouchitis.

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Ulcer
• Ulcerative Colitis

Intervention

Drug:
• amoxicillin, metronidazole and doxycycline
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
• amoxicillin and doxycyclin
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

Locations

Country	Name	City	State
Israel	The E.Wolfson Medical Center	Holon

Sponsors (1)

Lead Sponsor	Collaborator
Wolfson Medical Center

Country where clinical trial is conducted

Israel, 

References & Publications (16)

Davenport M, Poles J, Leung JM, Wolff MJ, Abidi WM, Ullman T, Mayer L, Cho I, Loke P. Metabolic alterations to the mucosal microbiota in inflammatory bowel disease. Inflamm Bowel Dis. 2014 Apr;20(4):723-31. doi: 10.1097/MIB.0000000000000011. — View Citation

David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA, Biddinger SB, Dutton RJ, Turnbaugh PJ. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014 Jan 23;505(7484):559-63. doi: 10.1038/nature12820. Epub 2013 Dec 11. — View Citation

De Preter V, Arijs I, Windey K, Vanhove W, Vermeire S, Schuit F, Rutgeerts P, Verbeke K. Decreased mucosal sulfide detoxification is related to an impaired butyrate oxidation in ulcerative colitis. Inflamm Bowel Dis. 2012 Dec;18(12):2371-80. doi: 10.1002/ibd.22949. Epub 2012 Mar 20. — View Citation

James SL, Christophersen CT, Bird AR, Conlon MA, Rosella O, Gibson PR, Muir JG. Abnormal fibre usage in UC in remission. Gut. 2015 Apr;64(4):562-70. doi: 10.1136/gutjnl-2014-307198. Epub 2014 Jul 18. — View Citation

Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Schumm LP, Sharma Y, Anderson CA, Essers J, Mitrovic M, Ning K, Cleynen I, Theatre E, Spain SL, Raychaudhuri S, Goyette P, Wei Z, Abraham C, Achkar JP, Ahmad T, Amininejad L, Ananthakrishnan AN, Andersen V, Andrews JM, Baidoo L, Balschun T, Bampton PA, Bitton A, Boucher G, Brand S, Büning C, Cohain A, Cichon S, D'Amato M, De Jong D, Devaney KL, Dubinsky M, Edwards C, Ellinghaus D, Ferguson LR, Franchimont D, Fransen K, Gearry R, Georges M, Gieger C, Glas J, Haritunians T, Hart A, Hawkey C, Hedl M, Hu X, Karlsen TH, Kupcinskas L, Kugathasan S, Latiano A, Laukens D, Lawrance IC, Lees CW, Louis E, Mahy G, Mansfield J, Morgan AR, Mowat C, Newman W, Palmieri O, Ponsioen CY, Potocnik U, Prescott NJ, Regueiro M, Rotter JI, Russell RK, Sanderson JD, Sans M, Satsangi J, Schreiber S, Simms LA, Sventoraityte J, Targan SR, Taylor KD, Tremelling M, Verspaget HW, De Vos M, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zeissig S, Zhang B, Zhang CK, Zhao H; International IBD Genetics Consortium (IIBDGC), Silverberg MS, Annese V, Hakonarson H, Brant SR, Radford-Smith G, Mathew CG, Rioux JD, Schadt EE, Daly MJ, Franke A, Parkes M, Vermeire S, Barrett JC, Cho JH. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012 Nov 1;491(7422):119-24. doi: 10.1038/nature11582. — View Citation

Jowett SL, Seal CJ, Pearce MS, Phillips E, Gregory W, Barton JR, Welfare MR. Influence of dietary factors on the clinical course of ulcerative colitis: a prospective cohort study. Gut. 2004 Oct;53(10):1479-84. — View Citation

Kato K, Ohkusa T, Terao S, Chiba T, Murakami K, Yanaka A, Uehara T, Ishii Y, Soma M, Tajiri H. Adjunct antibiotic combination therapy for steroid-refractory or -dependent ulcerative colitis: an open-label multicentre study. Aliment Pharmacol Ther. 2014 May;39(9):949-56. doi: 10.1111/apt.12688. Epub 2014 Mar 13. — View Citation

Khalil NA, Walton GE, Gibson GR, Tuohy KM, Andrews SC. In vitro batch cultures of gut microbiota from healthy and ulcerative colitis (UC) subjects suggest that sulphate-reducing bacteria levels are raised in UC and by a protein-rich diet. Int J Food Sci Nutr. 2014 Feb;65(1):79-88. doi: 10.3109/09637486.2013.825700. Epub 2013 Aug 13. — View Citation

Knoop KA, McDonald KG, Kulkarni DH, Newberry RD. Antibiotics promote inflammation through the translocation of native commensal colonic bacteria. Gut. 2016 Jul;65(7):1100-9. doi: 10.1136/gutjnl-2014-309059. Epub 2015 Jun 4. — View Citation

Manichanh C, Borruel N, Casellas F, Guarner F. The gut microbiota in IBD. Nat Rev Gastroenterol Hepatol. 2012 Oct;9(10):599-608. doi: 10.1038/nrgastro.2012.152. Epub 2012 Aug 21. Review. — View Citation

Noor SO, Ridgway K, Scovell L, Kemsley EK, Lund EK, Jamieson C, Johnson IT, Narbad A. Ulcerative colitis and irritable bowel patients exhibit distinct abnormalities of the gut microbiota. BMC Gastroenterol. 2010 Nov 12;10:134. doi: 10.1186/1471-230X-10-134. — View Citation

Ohkusa T, Kato K, Terao S, Chiba T, Mabe K, Murakami K, Mizokami Y, Sugiyama T, Yanaka A, Takeuchi Y, Yamato S, Yokoyama T, Okayasu I, Watanabe S, Tajiri H, Sato N; Japan UC Antibiotic Therapy Study Group. Newly developed antibiotic combination therapy for ulcerative colitis: a double-blind placebo-controlled multicenter trial. Am J Gastroenterol. 2010 Aug;105(8):1820-9. doi: 10.1038/ajg.2010.84. Epub 2010 Mar 9. — View Citation

Ohkusa T, Nomura T, Terai T, Miwa H, Kobayashi O, Hojo M, Takei Y, Ogihara T, Hirai S, Okayasu I, Sato N. Effectiveness of antibiotic combination therapy in patients with active ulcerative colitis: a randomized, controlled pilot trial with long-term follow-up. Scand J Gastroenterol. 2005 Nov;40(11):1334-42. — View Citation

Pitcher MC, Beatty ER, Cummings JH. The contribution of sulphate reducing bacteria and 5-aminosalicylic acid to faecal sulphide in patients with ulcerative colitis. Gut. 2000 Jan;46(1):64-72. — View Citation

Terao S, Yamashiro K, Tamura I, Hirano T, Ohkusa T, Kato K. Antibiotic combination therapy for steroid withdrawal in steroid-dependent ulcerative colitis. Digestion. 2011;83(3):198-203. doi: 10.1159/000321811. Epub 2011 Jan 21. — View Citation

Turner D, Levine A, Kolho KL, Shaoul R, Ledder O. Combination of oral antibiotics may be effective in severe pediatric ulcerative colitis: a preliminary report. J Crohns Colitis. 2014 Nov;8(11):1464-70. doi: 10.1016/j.crohns.2014.05.010. Epub 2014 Jun 20. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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