Clinical trial NCT05201079: Primary or Recurrent Clostridioides Difficile Infection Treatment With Capsules of Lyophilised Faecal Microbiota vs Fidaxomicin
Official title: A Randomised, Controlled, Open-label Phase III Clinical Trial in Patients With Primary or Recurrent Clostridioides Difficile (CD) Infection, to Evaluate the Efficacy and Safety of Capsules of Lyophilised Faecal Microbiota vs Fidaxomicin.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Recurrent Clostridium Difficile Infection
Primary Clostridium Difficile Infection
Keywords: Clostridium difficile
FMT
Fecal Microbiota Transfer
Lead sponsor: Mikrobiomik Healthcare Company S.L.
Sponsor class: INDUSTRY
First posted: 2022-01-21
Enrollment: 93
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Patients with microbiota alterations developed after being exposed to antibiotics are especially susceptible to Clostridioides difficile infections (CDI). The incidence and severity of CDI has increased in recent years and CDI recurrences (r-CDI) due to the appearance of new episodes in patients with a previous cured CDI, represent a serious and complex clinical issue. Although antibiotics are the recommended therapy for the first episode of CDI, treatment with oral vancomycin and/or metronidazole often results in significant treatment failure. In addition, the treatment of r-CDI is not adequately standardized, and although the most widely used treatment is the administration of fidaxomicin and bezlotoxumab, its efficacy in patients who already have r-CDI is not proven. In the late years, Fecal Microbiota Transfer (FMT) has emerged as the preferred non-pharmacological treatment to manage CDI with multiple recurrences and recent clinical trials have evaluated its potential efficacy and safety in the treatment of patients with primary CD infection.

The objective of this study is to assess the efficacy and safety of the MBK-01 medication, consisting of heterologous lyophilized fecal microbiota capsules coming from healthy donors in comparison to the treatment with fidaxomicin, in 92 patients with primary or r-CDI.

Detailed description: This is a Phase III, multicenter, controlled and open label clinical trial in which patients who suffered an episode of Clostridioides difficile infection (either the first episode or subsequent recurrences) will be randomly assigned (1:1) to one of the following arms:

* Fidaxomicin
* MBK-01 (heterologous lyophilized fecal microbiota)

Objective: To assess the efficacy of FMT with capsules of lyophilized fecal microbiota (MBK-01), compared to the control (fidaxomicin) at 8 weeks after the start of the treatment. Also, assess the safety of MBK-01 and the quality of life of patients participating in the study.

Follow up: participants will return for clinic visits at 72 hours, week 3 and week 8 after the start of the treatment, and will receive follow-up phone calls at month 3 and month 6 after the start of the treatment. Stool samples will be collected from participants for further studies at time 0 and week 8 after the start of the treatment. Study Outcomes are detailed in the specific section of this website.

Rationale: The transferred microbiota restores the recipient's intestinal microbiota by reintroducing bacterial taxa that were absent or in low proportion in the recipient before the FMT. This supports the expansion of the recipient's own commensal microbiota and re-establishing a microbiota community with a high biodiversity.

Donors: All donors are screened to ensure they meet the strict requirements necessary to maintain the safety of the MBK-01.

Justification: The treatment of Clostridioides difficile infections (CDI) with antibiotics is usually effective for acute symptoms, but after the initial treatment, the probability of recurrence at 8 weeks ranges from 10-20 % of cases, and once a patient has a recurrence, the probability of further recurrences increases up to 40-65 %. In recent years, Fecal Microbiota Transfer (FMT) has emerged as the preferred non-pharmacological treatment to manage CDI with multiple recurrences and recent clinical trials have evaluated its potential efficacy and safety in the treatment of patients with primary CD infection. Although antibiotics are the recommended therapy for the first episode of CDI, treatment with oral vancomycin and/or metronidazole often results in significant treatment failure, with recurrences occurring in up to 30-40% of patients. Furthermore, antibiotic treatment does not correct deficiencies in the intestinal microbiota that facilitate CD infection and is associated with the risk of the emergence of antibiotic-resistant bacteria. Moreover, the treatment of recurrences is not adequately standardized. In recent years, although the most widely used alternatives have been fidaxomicin and bezlotoxumab, their efficacy in patients who already suffer from r-CDI is not proven. The administration of the FMT through oral capsules, although it is not standardized, has proven to be effective in the restoration of intestinal microbiota of patients with r-CDI. In addition, the use of lyophilized formulas facilitates the concentration of bacteria and further optimizes the donors' sample and reduces the amount of capsules that the patient has to ingest.

Eligibility criteria: Inclusion Criteria:

1. Patients of both genders, over 18 years.
2. Patients that undergo an episode of CD infection (either the first episode or subsequent recurrences).
3. Presence of an episode of diarrhea defined as ≥3 stools/24 hours, at the beginning of the episode.
4. Confirmation of the presence of CD toxin A and/or B in faeces, by a direct toxin detection test or by the PCR technique for the detection of toxin/s producing genes, at the start of the episode that is going to be treated in the clinical trial (the toxin test must be positive within 7 days prior to the enrolment of the patient in the trial).

Exclusion Criteria:

1. Previous faecal microbiota transfer.
2. Transplanted patients, except those with a solid organ transplant of more than 2 years, with good organ function.
3. Absolute neutrophil count \<500 cells /μL at the time of the enrollment in the study.
4. Pregnancy, breastfeeding, or pregnancy intentions over the course of the study.
5. Active treatment with bile acid sequestrants (for instance: cholestyramine).
6. Positive patients for the human immunodeficiency virus (HIV) except those with lymphocytes T CD4 count \> 200 cells/μL and viral load less than 20 copies.
7. Swallowing dysfunction or no oral motor coordination.
8. Patient admitted in an intensive care unit or expected to be admitted in an intensive care unit due to serious illness.
9. History of significant medical conditions that, in the opinion of the investigator, would not allow an adequate evaluation or follow-up of the patient.

Primary outcomes:
measure: Global Absence of Diarrhea Due to Clostridiodes Difficile 8 Weeks After the Start of the Treatment
timeFrame: 8 weeks after the start of the treatment
measure: Absence of Diarrhea: Number of Episodes of Diarrhea (3 or More Stools/24 Hours) 72 Hours After the Start of the Treatment
timeFrame: 72 hours after the start of the treatment
measure: Absence of Diarrhea: Number of Episodes of Diarrhea (3 or More Stools/24 Hours) 3 Weeks After the Start of the Treatment
timeFrame: 3 weeks after the start of the treatment
measure: Absence of Diarrhea: Number of Episodes of Diarrhea (3 or More Stools/24 Hours) 3 Months After the Start of the Treatment
timeFrame: 3 months after the start of the treatment
measure: Absence of Diarrhea: Number of Episodes of Diarrhea (3 or More Stools/24 Hours) 6 Months After the Start of the Treatment
timeFrame: 6 months after the start of the treatment
Secondary outcomes:
measure: Duration of Hospitalisation
timeFrame: Up to 8 weeks after the start of the treatment
measure: Good/Bad Progress of the Patient
timeFrame: Up to 72 hours after the start of the treatment
measure: Time to Recurrence Depending on Randomisation Groups
timeFrame: Up to 6 months after the start of the treatment
measure: Duration of Treatment
timeFrame: Up to 10 days
measure: Overall Survival
timeFrame: Up to 6 months after the start of the treatment
measure: Number of Adverse Events Per Randomisation Group
timeFrame: Up to 6 months after the start of the treatment
measure: Type of Adverse Events Per Ramdomisation Group
timeFrame: Up to 6 months after the start of the treatment
measure: Number of Serious Adverse Events Per Ramdomisation Group
timeFrame: Up to 6 months after the start of the treatment
measure: Type of Serious Adverse Events Per Ramdomisation Group
timeFrame: Up to 6 months after the start of the treatment
measure: Adverse Events Related to the Treatment
timeFrame: Up to 6 months after the start of the treatment
measure: Adverse Event Seriousness
timeFrame: Up to 6 months after the start of the treatment
measure: Adverse Events Related to the CDI
timeFrame: Up to 6 months after the start of the treatment
measure: Mortality Associated With CDI
timeFrame: Up to 6 months after the start of the treatment
measure: Intensive Care Unit Admissions (ICU)
timeFrame: Up to 6 months after the start of the treatment
measure: Adverse Events of Special Interest
timeFrame: Up to 6 months after the start of the treatment
measure: SF36 Questionnaire (The Short Form-36 Health Survey) to Evaluate the Quality of Life
timeFrame: Day 0, 8 weeks and 6 months after the start of the treatment
Other outcomes:
Locations:
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
state: Cantabria
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Barakaldo
country: Spain
facility: Hospital Universitario de Cruces
city: Barcelona
country: Spain
facility: Hospital Quirónsalud Barcelona
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitario de Bellvitge
city: Bilbao
country: Spain
facility: Hospital Universitario de Basurto
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofía
city: Donostia
country: Spain
facility: Hospital Universitario de Donostia
city: Girona
country: Spain
facility: Hospital Josep Trueta de Gerona
city: Logroño
country: Spain
facility: Hospital San Pedro
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro
city: Madrid
country: Spain
facility: Hospital Universitario Quirónsalud Madrid
city: Palma De Mallorca
country: Spain
facility: Hospital Universitario Son Espases
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico La Fe
city: Vitoria-Gasteiz
country: Spain
facility: Hospital Universitario de Araba
city: Zaragoza
country: Spain
facility: Hospital Clínico Universitario Lozano Blesa
Study officials:
affiliation: Hospital Universitario Ramon y Cajal
name: Javier Cobo, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Reigadas E, Bouza E, Olmedo M, Vazquez-Cuesta S, Villar-Gomara L, Alcala L, Marin M, Rodriguez-Fernandez S, Valerio M, Munoz P. Faecal microbiota transplantation for recurrent Clostridioides difficile infection: experience with lyophilized oral capsules. J Hosp Infect. 2020 Jun;105(2):319-324. doi: 10.1016/j.jhin.2019.12.022. Epub 2019 Dec 26.
citation: Reigadas E, Olmedo M, Valerio M, Vazquez-Cuesta S, Alcala L, Marin M, Munoz P, Bouza E. Fecal microbiota transplantation for recurrent Clostridium difficile infection: Experience, protocol, and results. Rev Esp Quimioter. 2018 Oct;31(5):411-418. Epub 2018 Sep 14.