| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Colon cancer in track 1.
Colon adenoma in track 2. |
Koloncancer i spor 1.
Kolonadenom i spor 2. |
|
| E.1.1.1 | Medical condition in easily understood language |
Colon cancer in track 1.
Colon adenoma in track 2. |
Tyktarmskræft i spor 1.
Tyktarmsadenom i spor 2. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009944 |
| E.1.2 | Term | Colon cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10048832 |
| E.1.2 | Term | Colon adenoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| The aim of this study is to investigate the effect of local antibiotic treatment with fosfomycin and metronidazole on tumor characteristics and the colonic biofilm in patients with right-sided colon cancer or right-sided colon adenomas. |
| Formålet med dette studie er at undersøge effekten af lokal antibiotisk behandling med fosfomycin og metronidazol hos patienter med højresidig tyktarmskræft eller højresidig tyktarmsadenom. |
|
| E.2.2 | Secondary objectives of the trial |
| • Safety assessment of the spraying of the right hemicolon with fosfomycin/metronidazol gel. |
| Sikkerhedsvurdering af det at spraye højre tyktarmsafsnit med fosfomycin/metronidazol gel |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Male and female patients above 18 years of age with either:
• right-sided colon cancer tumor with adenocarcinoma histologically verified scheduled for open or laparoscopic resection at the Department of Surgery, Herlev Hospital or Zealand University Hospital (track 1)
• right-sided adenomas ≥2cm in diameter endoscopically verified scheduled for endoscopic mucosal resection at the Department of Surgery, Herlev Hospital or Zealand University Hospital (track 2a)
Written informed consent must be obtained.
|
Mænd og kvinder over 18 år med enten:
• Højresidig tyktarmskræfttumor, som er patologisk verificeret adenocarcinom, der skal have foretaget en åben eller laparoskopisk resektion ved Kirurgisk Afdeling, Herlev Hospital eller Sjællands Universitetshospital (track 1)
• Højresidig tyktarmsadenom ≥2cm i diameter, som er endoskopisk verificeret,, der skal have foretaget en endoskopisk mukosaresektion ved Kirurgisk Afdeling, Herlev Hospital eller Sjællands Universitetshospital (track 2a)
Informeret samtykke skal foreligge for alle deltagende patienter.
|
|
| E.4 | Principal exclusion criteria |
• Patients with previous allergic reaction to fosfomycin and/or metronidazole
• Patients under current antibiotic treatment or patient who had the last dose of antibiotics 30 days prior to inclusion
• Patients with a non-passable tumor or patients where a part of the tumor is not visible during endoscopy (Track 1)
• Patients with neoadjuvant chemotherapy or radiation 12 months prior to the resection
• Patients with a history of familial adenomatous polyposis (FAP) or hereditary nonpolyposis colorectal cancer (HNPCC)
• Patients with a history of inflammatory bowel disease (IBD)
• Patients under current treatment with warfarin (Marevan) and phenprocoumon (Marcoumar), or NOAK such as dabigatran (Pradaxa®), rivaroxiban (Xarelto®), edoxaban (Lixiana®) or apixaban (Eliquis®)
• Patients under current treatment with Fenemal (Phenobarbital)
• Patients who previously have received a fecal transplantation
• Patients who have previously had colorectal cancer, and are now presenting with a secondary colon tumor
• Patients with a current alcohol use disorder (AUD): defined as a patient who are currently drinking 8 or more drinks/week for women and 15 or more drinks/week for men
• Predictable poor compliance (psychiatric disease, not speaking fluent Danish, mentally impaired etc)
• Patients with an American Society of Anaesthesiologists physical status Classification (ASA score) of IV
• Patients unable to be sedated
• Pregnancy or lactation (fertile women must have a negative serum or urine pregnancy test to participate)
• Fertile women who do not use safe contraception during the study period
Following contraceptive methods are acceptable when used consistently and in accordance with both the product label and the instructions of the physician are:
- Oral contraceptive, either combined or progestogen alone
- Injectable progestogen
- Implants of levonorgestrel
- Estrogenic vaginal ring
- Percutaneous contraceptive patches
- Intrauterine device or intrauterine system with a documented failure rate < 1% per year
- Male partner sterilization (vasectomy with documented azoospermia) prior to female patient´s entry into the study, and this male is the sole partner for that patient
- Double barrier method: condom with spermicidal agent (foam/gel/film/cream/suppository), condom and occlusive cap (diaphragm or cervical/vault cap) with vaginal spermicidal agent (foam/gel/film/cream/suppository) |
• Patienter med tidligere allergisk reaktion overfor fosfomycin og eller metronidazol
• Patienter under antibiotisk behandling eller patienter med sidste antibiotikadosis 30 dage inden inklusion
• Patienter, hvis tumor ej er passabel for endoskopet, eller hvor man ikke kan se hele tumor under endoskopien
• Patienter med neoadjuverende kemoterapi eller stråling 12 måneder før operationen
• Patienter, der er tidligere diagnosticeret med arvelige tyktarmskræftformer såsom familiær adenomatøs polypose (FAP) eller hereditær non-polypose coloncancer (HNPCC)
• Patienter med tidligere inflammatorisk tarmsygdom (IBD)
• Patienter i behandling med warfarin (Marevan) og phenprocoumon (Marcoumar), eller NOAK såsom dabigatran (Pradaxa®), rivaroxiban (Xarelto®), edoxaban (Lixiana®) eller apixaban (Eliquis®)
• Patienter i behandling med Fenemal (phenobarbital)
• Patienter, der tidligere har modtaget et fæcestransplantat
• Patienter, der tidligere har haft en tyktarmskræft og som nu præsenterer sig med en sekundær (metakron) tyktarmstumor
• Patienter med aktuel alkoholafhængighedssygdom (AUD): defineret som en patient, der aktuelt har et højt forbrug af på alcohol: 8 eller flere genstande per uge for kvinder og 15 eller flere genstande per uge for mænd
• Patienter med forudset dårlig compliance (psykiatrisk lidelse,ej flydende dansk sprog etc)
• Patienter med ASA klasse IV
• Patienter, der ej kan sederes
• Patienter, der er gravide eller ammende (fertile kvinder skal have en negativ serum-HCG eller urin-HCG inden deltagelse)
• Fertile kvindelige patienter, der ikke anvender sikker prævention under studieperioden:
o Oral prævention, enten kombinationspræparat eller progestogen
o Injektion af progestogen
o Implantat af levonorgestrel
o Vaginal ring med østrogen
o Perkutan præventionsplastre
o Intrauterin prævention eller et intrauterint system med en dokumenteret failure rate < 1% pr år
o Mandlig partner er steriliseret (vasektomi med dokumenteret azoospermi) inden deltagelse i studiet, og at denne partner er eneste partner for patienten
o Dobbelt-barriere metode: kondom med spermicid agens (skum/gel/film/creme/suppositorie), kondom og kvindelig barriere (diaphragma eller cervical cap) med vaginal spermicid agens (skum/gel/film/creme/suppositorie) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome
• A quantitative change in the bacterial biomass adherent to the colonic epithelium of the resected colon adjusted for baseline level found before the intervention through fluorescence in situ (FISH) technique. The specific measurement variable is biofilm depth and 2D and 3D biofilm mass. The method of aggregation will be means.
The exploratory primary outcomes
• The determination of differences in translational markers present in the resected tumor tissue adjusted for the level seen at the baseline (the therapeutic colonoscopy) through a principal component analysis (PCA). The translational markers of interest are tumor markers, and markers of the microenvironment and the immune response. The analyses will be performed using the PanCancer IO 360TM Gene Expression Panel (nanoString).
• The determination of a change in the bacterial composition adjusted for the bacteria found at baseline before the intervention through fluorescence in situ (FISH) technique and sequencing with Metagenome. |
Primære outcome:
• En kvantitativ ændring af den bakterielle biomasse, der adhærerer til det resecerede tyktarmenafsnits epitel ved tumor justeret for baseline niveau inden antibiotikainterventionen ved fluorescence in situ hybridisering (FISH) teknik. De specifikke variable er biofilm tykkelse og 2D og 3D biofilm masse.
Eksplorerende primære outcomes:
• Det primære outcome er forskelle i translationelle markører tilstede i det resecerede tumor væv justeret for baseline niveau (inden den terapeutiske kikkertundersøgelse) gennem en principal component analyse (PCA). De translationelle markører er tumormarkører, markører for mikromiljøet og for immunresponset. Analyserne bliver foretaget med PanCancer IO 360TM Gene Expression Panel (nanoString).
• En ændring i den bakterielle komposition i tumor justeret for baseline niveau inden antibiotikainterventionen ved fluorescence in situ hybridisering (FISH) teknik og vævssekventering med Metagenome. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary outcome
A report with results from the biofilm depth analyses will be delivered when all samples have been analyzed.
Exploratory primary outcome
The results of the gene expression analysis of 770 genes will be delivered in a report. A report with results from the biofilm analyses will be delivered when all samples have been analyzed. |
| Primære outcome: en raport med resultater for analyser af biofilmtykkelse og biomasse vil blive leveret når alle samples er analyseret. |
|
| E.5.2 | Secondary end point(s) |
Track 1: colon cancer
• Differences in the presence of known bacterial drivers such as Fusobacterium nucleatum, Enterococcus faecalis, Bacteroides Fragilis, Escherischia coli, and Porphyromonas in the tumor samples from preoperative biopsies and the resected colon.
• Differences in gene expression in the normal mucosa from preoperative biopsies and the resected colon using the PanCancer IO 360TM Gene Expression Panel (nanoString).
• Differences in gene expression in the preoperative and operative blood samples determined by the nCounter® PanCancer Immune Profiling Panel (nanoString).
• The pathological assessment of tumor: tumor type, grade of dysplasia, TNVM-stage, MSI-status along with an assessment of the immunological response using the Immunoscore and an assessment of the biofilm present on the tumor.
• The pathological assessment of the normal mucosa of the right hemicolon: presence of biofilm, dysplasia and inflammation.
• Safety assessment of the spraying of the right hemicolon with fosfomycin/metronidazole gel. This will be assessed through adverse events at least 19 days after the intervention (postoperative day 14).
Track 2: colon adenoma
• Differences in gene expression in the normal mucosa from preoperative biopsies and the operative biopsies using the PanCancer IO 360TM Gene Expression Panel (nanoString).
• Differences in gene expression in the tumor tissue from the mucosal resection compared with archived FFPE tumor tissue from patients with colon adenoma using the PanCancer IO 360TM Gene Expression Panel (nanoString).
• Differences in gene expression in the preoperative blood samples and the blood samples taken on the operation day using the nCounter® PanCancer Immune Profiling Panel (nanoString).
• The pathological assessment of polyp: type and size, along with an assessment of the immunological response and an assessment of the biofilm present on the polyp.
• The pathological assessment of the normal mucosa of the right hemicolon: presence of biofilm, dysplasia and inflammation.
• Safety assessment of the spraying of the right hemicolon with fosfomycin/metronidazole gel. This will be assessed through adverse events at least 19 days after the intervention (postoperative day 14). |
Track 1: colon cancer
• Forskelle i tilstedeværelsen af kræftfremmende bakterier såsom Fusobacterium nucleatum, Enterococcus faecalis, Bacteroides Fragilis, Escherischia coli, og Porphyromonas fra biopsier taget før antibiotikainterventionen og efter, i form af vævsprøver tarmresektat .
• Forskelle i genekspression i den raske tyktarmsslimhinde (mukosa) fra biopsier taget før interventionen og vævsprøver fra tarmresektatet ved analyse PanCancer IO 360TM Gene Expression Panel (nanoString).
• Forskelle i genekspression i blod opsamlet før interventionen og efter interventionen (på operationsdagen) ved analyse med nCounter® PanCancer Immune Profiling Panel (nanoString).
• Patologisk undersøgelse af kræfttumor: tumortype, dysplasigrad , TNVM-stadie, MSI-status, vurdering af immunologisk respons vha Immunoscore og om biofilm er tilstede på tumor.
• Patologisk undersøgelse af rask tyktarmsslimhinde (mukosa): tilstedeværelse af biofilm, dysplasi, og inflammation
• Sikkerhedsvurdering af det at spraye højre tyktarmsafsnit med fosfomycin/metronidazol gel
Track 2: tyktarmsadenom
• Forskelle i tilstedeværelsen af kræftfremmende bakterier såsom Fusobacterium nucleatum, Enterococcus faecalis, Bacteroides Fragilis, Escherischia coli, og Porphyromonas fra biopsier taget før antibiotikainterventionen og efter, i form af vævsprøver fra slimhinde og slimhinderesektat.
• Forskelle i genekspression i den raske tyktarmsslimhinde (mukosa) fra biopsier taget før interventionen og de operative biopsier ved analyse med PanCancer IO 360TM Gene Expression Panel (nanoString).
• Forskelle i genekspression i tumorvæv fra de den resercerede tyktarmsslimhinde sammenlignet med arkiveret FFPE tumorvæv fra patienter med tyktarmsadenom ved analyse med PanCancer IO 360TM Gene Expression Panel (nanoString).
• Forskelle i genekspression i blod opsamlet før interventionen og efter interventionen (på operationsdagen) ved analyse med nCounter® PanCancer Immune Profiling Panel (nanoString).
• Patologisk undersøgelse af adenoma: type og størrelse, vurdering af immunologisk respons og om biofilm er tilstede på adenomet
• Patologisk undersøgelse af rask tyktarmsslimhinde (mukosa): tilstedeværelse af biofilm, dysplasi, og inflammation
• Sikkerhedsvurdering af det at spraye højre tyktarmsafsnit med fosfomycin/metronidazol gel |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The study will collect demographic and baseline information from the patient files through Sundhedsplatformen (EPIC). The results of the gene expression analysis of 770 genes will be delivered in a report. A report with results from the biofilm analyses will be delivered when all samples have been analyzed. Immunoscore data will be delivered in a report. Data from pathology reports of the resected colon and resected mucosa will be collected from the pathology reports in Sundhedsplatformen. The results of the blood sample analyses will be collected through Sundhedsplatformen Safety assessment of the gel will be based on patient files as well as through the postoperative interview on postoperative day 14+/-2. |
| Demografi og baseline information fra patientjournaler indsamles løbende fra Sundhedsplatformen sammen med patologisvar og blodprøvesvar. Resultater fra genekspressionsanalyserne af 770 gener og fra analyser af biofilm vil blive leveret når alle samples er analyseret. Sikkerhedsvudering af gelen vil blive foretaget løbende baseret på opslag i patientjournaler samt gennem de postoperative interviews på postoperative dag 14. |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| translational biomarkers |
| translationelle biomarkører |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Der er en matched retrospektiv kohorte af patienter med colonadenom, spor 2a |
| There is a matched retrospective cohort of patients with colon adenoma, track 2a |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | Yes |
| 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
|
| Last visit of the 24th fully evaluable patient |
| Sidste besøg for den 24. fuldt evaluerbare patient |
|
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | 14 |
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