E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Recurrent infection with Clostridium Difficile |
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E.1.1.1 | Medical condition in easily understood language |
Recurrent infection with the bacteria Clostridium Difficile |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10072994 |
E.1.2 | Term | Clostridium difficile infection recurrence |
E.1.2 | System Organ Class | 100000004862 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate the treatment effect of rectal bacteriotherapy instillation (RBI) and faecal microbiota transplantation /FMT) against the standard antibotic treatment with vancomycin for patients with recurrent Clostridium Difficile infection in a randomised controlled trial |
At undersøge effekten af rektal bakterieinstillation (RBI) og fækal mikrobiotisk transplantation (FMT) over for standard antibiotisk behandling til patienter med rekurrent CDI i et randomiseret klinisk forsøg |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age ≥ 18 years
- Recurrent Clostridium Difficile infection with diarrhea (or toxic megacolon) and verified presence of Clostridium difficile in faeces, and/or pseudomembranoues colitis, diagnosed within 90 days of the last episode of Clostridium difficile infection
- Having received at least one earlier specific treatment for Clostridium difficile infection (at least 10 days of vancomycin with at least 125 mg 4 times daily or at least 10 days of metronidazol with at least 500 mg 3 times a day)
- The patient is allowed to have started treatment with oral vancomycin within 7 days, but does not need to have started treatment with oral vancomycin
- Being able to give informed consent after information in danish |
- Alder ≥ 18 år.
- Rekurrent CDI med diarré (eller toksisk megacolon), samt mikrobiologisk verificeret tilstedeværelse af CD i fæces (ved PCR analyse for toxiner) og/eller fund af pseudomembranøs colitis (ved endoskopi/histopatologi), påvist indenfor 90 dage efter det seneste tilfælde af CDI.
- Have modtaget én eller flere tidligere specifikke behandlinger for CDI (mindst 10 dages vancomycin med dosis af mindst 125 mg x 4 daglig eller mindst 10 dages behandling med metronidazol i dosis 500 mg x 3 daglig).
- Patienten kan være startet behandling med peroral vancomycin af behandlende læge (indenfor 7 dage), men behøver ikke være startet behandling med peroral vancomycin.
- Patienten skal være i stand til at give informeret samtykke ud fra dansksproget deltagerinformation.
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E.4 | Principal exclusion criteria |
- Terminal illness with a life expectancy less than 3 months.
- Allergy to vancomycin.
- Other clinically significant gastrointestinal infections.
- Other antibacterial treatment planned for a duration of more than 14 days from time of inclusion (for example for spondylodiscitis, endocarditis or tuberculosis).
- Gastrointestinal disease, which can cause diarrhea or in other way affects symptom reporting, including patients that have undergone colectomy.
- Severely compromised immune system, which makes faecal microbiota transplantation/rectal bacteriotherapy releatively contraindicated by clinical judgement.
- Pregnancy, planned pregnancy or breast feeding. |
- Terminal sygdom med forventet levetid <3 måneder.
- Allergi overfor vancomycin.
- Anden klinisk betydende gastrointestinal infektion.
- Anden antibakteriel behandling, der er planlagt til over 14 dages varighed fra inklusionstidspunktet (f.eks. i forbindelse med spondylodiskit, endocarditis eller tuberkulose).
- Gastrointestinal sygdom, der forårsager diarré eller kan påvirke symptom rapportering, herunder kolektomerede patienter.
- Svær immunsvækkelse, som gør FMT/RBI relativt kontraindiceret ved klinisk bedømmelse.
- Graviditet, planlagt graviditet og amning.
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E.5 End points |
E.5.1 | Primary end point(s) |
Clinical cure, defined as the absence of Clostridium Difficile infection, in 90 days after the end of treatment |
Klinisk behandlingssucces, defineret som fravær af Clostridium Difficile infektion, i perioden op til 90 dage efter endt behandling i de tre arme. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
A interim analysis will be done when 30 patients in each treatment group has been followed for 90 days.
Final evaluation will be done after 180 days of follow-up after treatment on all patients. |
Vi planlægger en interimanalyse af cure rate (efter 90 dages opfølgning) i de tre behandlingsarme efter 30 patienter i hver behandlingsarm. Endelig evaluering foretages efter 180 dages opfølgning af alle patienter. |
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E.5.2 | Secondary end point(s) |
- Early (Between 14-30 days after) and late (after 31-180 days) recurrence of CDI after end of treatment.
- Days with diarrhea in week 1, 4, 8, 12 after end of treatment.
- CDI-associated hospitalization and hospitalization of other causes in the 180 days of follow-up after end of treatment.
- CDI-associated outpatient hospital contact and outpatient hospital contact of other causes in the 180 days of follow-up after end of treatment.
- CDI-associated mortality and all-cause mortality 30, 90 and 180 days after end of treatment.
- CDI-associated morbidity, CDI-associated mortality and all-cause mortality 3 years and 5 years after end of treatment (as part of a prospective registerbased study after end of trial).
Subgroup analyzes:
- The effect of treatment (primary endpoint) in the three treatment arms by stratification of patients in groups with 1 recurrence and with ≥2 recurrences.
- The effect of treatment (primary endpoint), depending on the CD strain - respectively toxin B CDI cases, toxin B plus binary toxin CDI cases and CD027 CDI cases.
- Treatment effect (primary endpoint), depending on the patients' serum level of antibodies to Toxin A and B, anti-TcdA and anti-TcdB, at inclusion.
Other analyzes:
- Registration of antibiotic treatments and temporal association with new recurrences of CDI in 180 days after the end of treatment.
- Identification of demographic and clinical factors associated with treatment success / failure.
- Characterization of the intestinal microbiota before and after FMT / RBI, in conjunction with characterization of intestinal microbiota in donors / RBI mixture. This will only be carried out in a subset of patients.
- Measurement of the bile acid composition before and after FMT / RBI. Comparing with microbiota composition and treatment efficacy. Will be conducted on the same subset of patients as above.
- Characterization of the CD strain in the case of recurrence after treatment to determine whether it is a relapse (same strain) or a reinfection (with new strain).
- Side effects in the three treatment arms for 14 days after treatment. |
- Tidlig (inden for 14-30 dage) og sen (inden for 180 dage) rekurrent CDI efter endt behandling.
- Dage med diarré i uge 1, 4, 8 og 12 efter endt behandling.
- CDI-associeret hospitalsindlæggelse og hospitalsindlæggelse af anden årsag i opfølgningsperioden på 180 dage efter endt behandling.
- CDI-associeret ambulant kontakt og ambulant kontakt af anden årsag i opfølgningsperioden på 180 dage efter endt behandling.
- CDI-associeret mortalitet og all-cause mortalitet ved henholdsvis 30, 90 og 180 dage efter afsluttet behandling.
- 3 års og 5 års opfølgning af CDI-associeret morbiditet og mortalitet, samt all-cause mortalitet(som led i efterfølgende prospektivt registerstudie). .
Subgruppeanalyser:
- Behandlingseffekt (primære effektmål) i de tre behandlingsarme ved stratificering af patienterne i grupper med 1. recurrente tilfælde og med ≥2 recurrente tilfælde.
- Behandlingseffekt (primære effektmål) afhængigt af CD stamme – hhv. toxin B CDI cases, toxin B plus binært toxin CDI cases og CD027 CDI cases.
- Behandlingseffekt (primære effektmål) afhængig af patienternes serumniveau af antistoffer mod toxin A og B, anti-TcdA og anti-TcdB, ved inklusion.
Øvrige analyser:
- Registrering af antibiotiske behandlinger og sammenhæng med eventuelle recurrente tilfælde af CDI i 180 dage efter endt behandling.
- Identifikation af demografiske og kliniske faktorer associeret til behandlingssucces/behandlingssvigt.
- Karakterisering af den intestinale mikrobiota før og efter FMT/RBI sammenholdt med karakterisering af den intestinale mikrobiota hos donorer/RBI-blandingen. Foretages i en undergruppe af patienterne.
- Bestemmelse af galdesyresammensætningen før og efter FMT/RBI. Sammenholdes med mikrobiota-sammensætningen og behandlingseffekt. Foretages i samme undergruppe som ovenstående.
- Karakterisering af stammer ved rekurrent CDI efter behandling for at fastslå, om der er tale om recidiv eller re-infektion (med ny stamme).
- Opgørelse af bivirkninger i de tre behandlingsarme i 14 dage efter endt behandling.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluation after 180 days of follow-up |
Evaluering foretages efter 180 dages opfølgning |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LVLS (i.e. 180 days follow-up on the last subject) |
Sidste patients sidste opfølgning, dvs. sidste patients 180 dages opfølgning |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |