A Phase IIa Randomized, Controlled, Open-label Clinical Trial to Assess the Efficacy, Safety, and Tolerability of the Investigational Medicinal Product MBK-01, FSPIM (Full Spectrum & Purified Intestinal Microbiota) Oral Capsules, as Well as to Determine the Optimal Dosage in the Treatment of Patients With Recurrent Diverticulitis (DIREBIOT)
A Phase IIa Randomized, Controlled, Open-label Clinical Trial to Assess the Efficacy, Safety, and Tolerability of the Investigational Medicinal Product MBK-01, FSPIM (Full Spectrum & Purified Intestinal Microbiota) Oral Capsules, as Well as to Determine the Optimal Dosage in the Treatment of Patients With Recurrent Diverticulitis (DIREBIOT)
Patients with diverticulitis experience a prolonged course of the disease and report a variety of physical, psychological and social symptoms, which highly impacts in their quality of life. Although antibiotic therapy has been the preferred treatment option for acute diverticulitis, it does not control the disease in 40 percent of the patients with complicated diverticulitis and 13 to 23 percent of the patients with non-complicated diverticulitis, which results in chronic and recurrent episodes of diverticulitis. As the episodes repeat, the outpatient conservative treatment has worse success rates and the incidence of complicated diverticulitis with abscess increases up to five times.
Therefore, it is of great importance to establish new treatments in order to avoid the recurrences of the disease. As of today, there is not enough evidence of the efficacy of current treatment options to prevent recurrences in patients with diverticulitis, but recent approaches suggest the modification of intestinal microbiota as a preventive strategy.
Microbial imbalance (dysbiosis) has been proposed as a mechanism involved in the transition from diverticulosis to diverticulitis, inflammation and some of the symptoms of the disease. In this way, fecal microbiota transplantation (FMT) could have an important role in the prevention of new episodes, as it can modify the composition of the intestinal microbiota in a less invasive and more physiological way. Until now the efficacy of FMT in patients with recurrent diverticulitis has not been assessed; however, its benefits and safety have been demonstrated in studies for inflammatory bowel disease (IBD), a pathology with similarities to diverticulitis in its symptoms and underlying inflammation.
The objective of the present clinical trial is to assess the efficacy of MBK-01 (heterologous lyophilized intestinal microbiota oral capsules) in reducing the frequency of episodes in recurrent diverticulitis, its safety and tolerability and to determine the optimal dosing regimen.
This is a phase IIa, randomized, controlled, open-label clinical trial with three treatment arms.
After an initial phase of screening, participants with recurrent diverticulitis will be randomly assigned (1:1:1) to one of the following arms:
Participants assigned to the experimental groups that receive MBK-01 will receive a pre-treatment with antibiotics that consists in the administration of amoxicillin 500 mg (1500 mg/day), fosfomycin 500 mg (3000 mg/day) and metronidazole 250 mg (750 mg/day) for 3 days. After those 3 days, participants will have a washout period of 2 days prior to starting the treatment with MBK-01.
Experimental group with MBK-01 and no maintenance dose will receive an initial dose of 4 oral capsules of MKB-01 in the first day, followed by a daily capsule during the next 16 days. In total, the participant will receive 20 capsules of MBK-01.
Experimental group with MBK-01 and maintenance dose will receive an initial dose of 4 oral capsules of MBK-01 in the first day, followed by a daily capsule during the next 16 days and a maintenance dose 3 months after finishing with the initial dose. The maintenance dose will be administered the same as the initial dose: 4 oral capsules in the first day, followed by a daily capsule during the next 16 days. In total, the participant will receive 40 oral capsules of MBK-01.
Control group with no intervention will not receive any medication oriented to prevent the recurrence of the episodes of diverticulitis.
Regardless of the treatment group to which they have been assigned, all participants will receive the usual rescue antibiotic treatment in the disease when a new episode occurs, and they can also receive the usual support measures they need during the episode (e.g. gastric protection diet or analgesics).
Objectives:
Follow up:
In addition to the initial screening visit, participants will attend to a total of 6 follow-up visits for 1 year. After the first follow-up visit, they will attend to the clinic after 1 week, 4 weeks, 16 weeks (3 months for group 2), 6 months and 1 year. During these visits: physical examination, anthropometric measurements, laboratory tests and stool samples will be taken; therapeutic adherence, acute diverticulitis episodes, hospitalizations due to acute diverticulitis and need of surgery due to acute diverticulitis will be evaluated; Gastrointestinal Quality of Life Index (GIQLI) and Short Form-36 (SF-36) questionnaires will be performed and adverse events will be monitored.
Rationale: fecal microbiota transplantation can treat the dysbiosis produced in diverticular disease by restoring the intestinal microbiota, regulating the immune system and improving the intestinal barrier function; the treatment of this dysbiosis could reduce the episodes in recurrent diverticulitis.
Donors: All donors are screened to ensure they meet the strict requirements necessary to maintain the safety of the MBK-01.
Justification:
Diverticulosis and acute diverticulitis are considered multifactorial origin diseases, affected by genetics, diet, microbial imbalance (dysbiosis), acute and chronical inflammation, altered colonic motility and neuromuscular alterations.
Current treatment of diverticular disease includes dietary fiber and pharmacological treatment with broad-spectrum antibiotics, anti-inflammatories and probiotics (alone or in combination). In addition, surgery is contemplated in severe cases.
Although antibiotic therapy has been the preferred treatment option for acute diverticulitis, it does not control the disease in 40 percent of the patients with complicated diverticulitis and 13-23% of the patients with non-complicated diverticulitis, which results in chronic and recurrent episodes of diverticulitis. As the episodes repeat, the outpatient conservative treatment has worse success rates and the incidence of complicated diverticulitis with abscess increases up to five times. Therefore, it is of great importance to establish new treatments in order to avoid the recurrence of the disease.
A preventive treatment regimen for recurrent episodes of diverticulitis has not been established yet. However, some strategies have been suggested, such as: lifestyle changes, high fiber diet, treatment with rifaximin, mesalazine and probiotics, and avoiding NSAIDs.
Microbial imbalance (dysbiosis) has been proposed as a mechanism involved in the transition from diverticulosis to diverticulitis, inflammation and some of the symptoms of the disease. It has been established that dysbiosis can lead to inflammation of the mucosa, neuromuscular dysfunction and a deterioration in the intestinal barrier. Changes in microbiota are associated with other digestive diseases, such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and Clostridioides difficile infections (CDI), which have a similar clinical presentation to diverticulitis.
Fecal microbiota transplantation could have an important role in the prevention of new episodes of diverticulitis, through the regulation of this dysbiosis. The efficacy of FMT for the treatment IBD and CDI has been clinically demonstrated, and there are also clinical trials with probiotics that show an improvement of the symptomatology in diverticular disease.
Inclusion Criteria:
Exclusion Criteria:
ensayosclinicos@mikrobiomik.net+34 944 540 166