Primerjava bolnikov v redni klinični praksi in tistih, vključenih v randomizirana klinična preskušanja tarčnih zdravil za Crohnovo bolezen: pomen vključitvenih in izključitvenih kriterijev

Kodrič, Tina (author), Vovk, Tomaž (mentor), Hanžel, Jurij (comentor)

Crohnova bolezen (CB) je ena od kroničnih vnetnih črevesnih bolezni (KVČB). Gre za progresivno bolezen, ki povzroča poškodbe črevesja in lahko prizadane vse segmente prebavil, pri čemer sta najpogosteje prizadeta terminalni ileum in debelo črevo. V zadnjih letih se je na področju raziskav KVČB pojavil izrazit napredek, ki je povzročil vse večje težave pri vključevanju bolnikov v klinična preskušanja. Izvedli smo neintervencijsko, retrospektivno raziskavo, v katero smo vključili 155 bolnikov, ki so bili v letu 2022 zdravljeni za CB z zdravili ali kirurškimi posegi na kliničnem oddelku za gastroenterologijo, Univerzitetnega kliničnega centra Ljubljana. Namen raziskave je bil raziskati delež bolnikov z zmerno do hudo CB, ki bi izpolnjevali pogoje za vključitev v klinične študije novih tarčnih zdravil za CB in ugotoviti najpogostejše razloge in omejitve, zaradi katerih bolniki s CB v klinični praksi ne ustrezajo kriterijem za sodelovanje v kliničnih preskušanjih. Vključitvene in izključitvene kriterije smo pridobili iz petih protokolov tretje faze kliničnih preskušanj za tarčna zdravila za CB: risankizumab, upadacitinib, ozanimod, guselkumab in guselkumab/golimumab soformulacijo. Ob predpostavki, da so ocene točkovnika SES-CD (enostavni endoskopski točkovnik za Crohnovo bolezen) pri bolnikih z manjkajočimi podatki neustrezne, bi se v vsaj eno od petih študij uvrstilo 34,2 % bolnikov, medtem ko bi se v primeru ustreznih ocen SES-CD vključilo 36,1 % bolnikov. Večina pacientov se je uspešno vključila v študijo za ozanimod, ki je imela najmanj stroge vključitvene in izključitvene kriterije, medtem ko je bil odstotek vključitve v preostalih študijah, ki so imele strožja merila za vključitev, precej nižji. Za potrebe magistrske naloge smo predpostavili, da bi lahko bolniki, ki so pred konzilijem (posvetovanjem strokovnjakov) prejemali biološko terapijo in niso bili hospitalizirani, med študijo namesto bioloških zdravil prejemali kortikosteroide. Ta predpostavka izhaja iz dejstva, da bi sicer 51,6 % bolnikov bilo izključenih zaradi zahtevanega dolgega obdobja izpiranja med zadnjim prejemom predhodnega biološkega zdravila in preskušanim zdravilom. Med raziskavo smo identificirali glavne vzroke za izključitev bolnikov, med katerimi so bila neskladja med endoskopsko in klinično oceno (51,0 %), bolniki, ki še niso prejemali bioloških zdravil (biološko naivni bolniki) (46,5 %), posamezniki z zapleti CB (30,3 %), sočasna uporaba aminosalicilatov, kortikosteroidov ali imunomodulatorjev (20,0 %), bolniki, ki so že prejeli učinkovine, ki ciljajo na IL-12/23 ali IL-23 (21,9 %) in tisti z zgodovino pomembnih zdravstvenih težav (20,6 %) ali s prisotnostjo neustreznih laboratorijskih vrednosti (16,8 %). Skrb za varnost pacientov se je odražala v izključitvenih kriterijih, ki so zajemali prisotnost okužb, omejitve glede starosti, prisotnost komorbiditet, zgodovino kirurških posegov ter zgodovino ali prisotnost malignih obolenj.

• Language: Slovenian
• Keywords: Crohnova bolezen, biološka zdravila, majhne molekule, kronična vnetna črevesna bolezen, retrospektivna raziskava
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2024
• PID: 20.500.12556/RUL-160258
• Publication date in RUL: 24.08.2024

Secondary language

• Language: English
• Title: Comparison between patients in regular clinical practice and those enrolled in randomized clinical trials of target drugs for Crohn's disease: importance of inclusion and exclusion criteria

Abstract

Crohn's disease (CD) is one of the chronic inflammatory bowel diseases (IBD). It's a progressive disease that causes damage to the intestine and can affect all segments of the gastrointestinal tract, with the terminal ileum and colon being the most commonly affected. In recent years, there have been clear developments in the field of IBD research, which have led to increasing difficulties in enrolling patients in clinical trials. We conducted a non-interventional, retrospective study including 155 patients treated for CD with medication or surgery at the Gastroenterology Department, University Medical Centre Ljubljana in 2022 to investigate the proportion of patients with moderate to severe CD encountered in the course of routine clinical practice, who would be eligible for inclusion in clinical trials of new target drugs for CD and to identify the most common reasons and limitations for which patients with CD in clinical practice do not meet the criteria for participation in clinical trials. Inclusion and exclusion criteria were obtained from five phase III clinical trial protocols for CD target drugs: risankizumab, upadacitinib, ozanimod, guselkumab and guselkumab/golimumab co-formulation. Assuming that SES-CD (Simple Endoscopic Score for Crohn's Disease) estimates are inadequate in patients with missing data, 34.2 % of patients would be enrolled in at least one of the five studies, while 36.1 % of patients would be enrolled if SES-CD estimates were adequate. The majority of patients were successfully enrolled in the ozanimod study that had the least stringent inclusion and exclusion criteria, whereas the inclusion rates were much lower in the remaining studies that had more stringent inclusion criteria. For the purpose of this thesis, we assumed that patients who were receiving biologic therapy before the consilium (consultation of experts) and were not hospitalised could receive corticosteroids instead of biologics during the study. This assumption is based on the fact that 51.6 % of patients would otherwise have been excluded due to the required long washout period between the last receipt of the prior biologic and the investigational drug. During the study, we identified the main reasons for patient exclusion, which included non-compliance with the prescribed endoscopic and clinical assessment criteria (51.0 %), patients who have not yet received biological medicines (biologically naive patients) (46.5 %), individuals with CD complications (30.3 %), concomitant use of aminosalicylates, corticosteroids or immunomodulators (20.0 %), patients already receiving active agents targeting IL-12/23 or IL-23 (21.9 %) and those with a history of significant health problems (20.6 %) or inadequate laboratory values (16.8 %). Patient safety concerns were reflected in exclusion criteria, which included the presence of infections, age restrictions, presence of comorbidities, history of surgical procedures and history or presence of malignancies.

• Keywords: Crohn's disease, biologics, small molecules, chronic inflammatory bowel disease, retrospective study