Clinical Trial Design Considerations for Hospitalised Patients With Ulcerative Colitis Flares and Application to Study Hyperbaric Oxygen Therapy in the NIDDK HBOT-UC Consortium.
Journal
Alimentary pharmacology & therapeutics
ISSN: 1365-2036
Titre abrégé: Aliment Pharmacol Ther
Pays: England
ID NLM: 8707234
Informations de publication
Date de publication:
15 Oct 2024
15 Oct 2024
Historique:
revised:
19
07
2024
received:
30
06
2024
accepted:
23
09
2024
medline:
15
10
2024
pubmed:
15
10
2024
entrez:
15
10
2024
Statut:
aheadofprint
Résumé
Patients with ulcerative colitis (UC) who are hospitalised for acute severe flares represent a high-risk orphan population. To provide guidance for clinical trial design methodology in these patients. We created a multi-centre consortium to design and conduct a clinical trial for a novel therapeutic intervention (hyperbaric oxygen therapy) in patients with UC hospitalised for moderate-severe flares. During planning, we identified and addressed specific gaps for inclusion/exclusion criteria; disease activity measures; pragmatic trial design considerations within care pathways for hospitalised patients; standardisation of care delivery; primary and secondary outcomes; and sample size and statistical analysis approaches. The Truelove-Witt criteria should not be used in isolation. Endoscopy is critical for defining eligible populations. Patient-reported outcomes should include rectal bleeding and stool frequency, with secondary measurement of urgency and nocturnal bowel movements. Trial design needs to be tailored to care pathways, with early intervention focused on replacing and/or optimising responsiveness to steroids and later interventions focused on testing novel rescue agents or strategies. The PRECIS-2 framework offers a means of tailoring to local populations. We provide standardisation of baseline testing, venous thromboprophylaxis, steroid dosing, discharge criteria and post-discharge follow-up to avoid confounding by usual care variability. Statistical considerations are provided given the small clinical trial nature of this population. We provide an outline for framework decisions made for the hyperbaric oxygen trial in patients hospitalised for UC flares. Future research should focus on the remaining gaps identified.
Sections du résumé
BACKGROUND
BACKGROUND
Patients with ulcerative colitis (UC) who are hospitalised for acute severe flares represent a high-risk orphan population.
AIM
OBJECTIVE
To provide guidance for clinical trial design methodology in these patients.
METHODS
METHODS
We created a multi-centre consortium to design and conduct a clinical trial for a novel therapeutic intervention (hyperbaric oxygen therapy) in patients with UC hospitalised for moderate-severe flares. During planning, we identified and addressed specific gaps for inclusion/exclusion criteria; disease activity measures; pragmatic trial design considerations within care pathways for hospitalised patients; standardisation of care delivery; primary and secondary outcomes; and sample size and statistical analysis approaches.
RESULTS
RESULTS
The Truelove-Witt criteria should not be used in isolation. Endoscopy is critical for defining eligible populations. Patient-reported outcomes should include rectal bleeding and stool frequency, with secondary measurement of urgency and nocturnal bowel movements. Trial design needs to be tailored to care pathways, with early intervention focused on replacing and/or optimising responsiveness to steroids and later interventions focused on testing novel rescue agents or strategies. The PRECIS-2 framework offers a means of tailoring to local populations. We provide standardisation of baseline testing, venous thromboprophylaxis, steroid dosing, discharge criteria and post-discharge follow-up to avoid confounding by usual care variability. Statistical considerations are provided given the small clinical trial nature of this population.
CONCLUSION
CONCLUSIONS
We provide an outline for framework decisions made for the hyperbaric oxygen trial in patients hospitalised for UC flares. Future research should focus on the remaining gaps identified.
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIDDK NIH HHS
ID : DK134321
Pays : United States
Investigateurs
Kirk B Russ
(KB)
Matthew P Kelly
(MP)
Michael W Winter
(MW)
Ahmad AlhajHusain
(A)
Ashwin Ananthakrishnan
(A)
Adina Gutium
(A)
Marvin Heyboer
(M)
Ganesh Aswath
(G)
Udayakumar Navaneethan
(U)
Walter Conlan
(W)
Anne G Tuskey
(AG)
Brittany J Behar
(BJ)
Oriana M Damas
(OM)
Juan O Bravo
(JO)
Jenny S Sauk
(JS)
Gerald H Markovitz
(GH)
Juan Jimenez
(J)
Jamie Heffernan
(J)
Jeffrey M Dueker
(JM)
Kevin O'Toole
(K)
M Anthony Sofia
(MA)
Robert B McLafferty
(RB)
Gerald W Dryden
(GW)
Benjamin D Rogers
(BD)
M Hassan Murad
(MH)
Raymond Shields
(R)
Hussam Tabaja
(H)
Jayanth Adusumalli
(J)
Aaron Cohn
(A)
Richard S Viglione
(RS)
Jamie B Wabich
(JB)
Informations de copyright
© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.
Références
M. Fumery, S. Singh, P. S. Dulai, C. Gower‐Rousseau, L. Peyrin‐Biroulet, and W. J. Sandborn, “Natural History of Adult Ulcerative Colitis in Population‐Based Cohorts: A Systematic Review,” Clinical Gastroenterology and Hepatology 16, no. 3 (2018): 343–356.e3, https://doi.org/10.1016/j.cgh.2017.06.016.
S. Samuel, S. B. Ingle, S. Dhillon, et al., “Cumulative Incidence and Risk Factors for Hospitalization and Surgery in a Population‐Based Cohort of Ulcerative Colitis,” Inflammatory Bowel Diseases 19, no. 9 (2013): 1858–1866, https://doi.org/10.1097/MIB.0b013e31828c84c5.
M. J. Buie, J. Quan, J. W. Windsor, et al., “Global Hospitalization Trends for Crohn's Disease and Ulcerative Colitis in the 21st Century: A Systematic Review With Temporal Analyses,” Clinical Gastroenterology and Hepatology 21, no. 9 (2023): 2211–2221, https://doi.org/10.1016/j.cgh.2022.06.030.
C. Ma, M. K. Smith, L. Guizzetti, et al., “Assessing National Trends and Disparities in Ambulatory, Emergency Department, and Inpatient Visits for Inflammatory Bowel Disease in the United States (2005‐2016),” Clinical Gastroenterology and Hepatology 18, no. 11 (2020): 2500–2509.e1, https://doi.org/10.1016/j.cgh.2020.01.023.
N. H. Nguyen, J. Koola, P. S. Dulai, L. J. Prokop, W. J. Sandborn, and S. Singh, “Rate of Risk Factors for and Interventions to Reduce Hospital Readmission in Patients With Inflammatory Bowel Diseases,” Clinical Gastroenterology and Hepatology 18 (2019): 1939–1948.e7, https://doi.org/10.1016/j.cgh.2019.08.042.
D. Laharie, A. Bourreille, J. Branche, et al., “Long‐Term Outcome of Patients With Steroid‐Refractory Acute Severe UC Treated With Ciclosporin or Infliximab,” Gut 67, no. 2 (2018): 237–243, https://doi.org/10.1136/gutjnl‐2016‐313060.
I. Ordás, E. Domènech, M. Mañosa, et al., “Long‐Term Efficacy and Safety of Cyclosporine in a Cohort of Steroid‐Refractory Acute Severe Ulcerative Colitis Patients From the ENEIDA Registry (1989‐2013): A Nationwide Multicenter Study,” American Journal of Gastroenterology 112, no. 11 (2017): 1709–1718, https://doi.org/10.1038/ajg.2017.180.
J. L. Opstelten, I. Vaartjes, M. L. Bots, and B. Oldenburg, “Mortality After First Hospital Admission for Inflammatory Bowel Disease: A Nationwide Registry Linkage Study,” Inflammatory Bowel Diseases 25, no. 10 (2019): 1692–1699, https://doi.org/10.1093/ibd/izz055.
J. Allison, L. J. Herrinton, L. Liu, J. Yu, and J. Lowder, “Natural History of Severe Ulcerative Colitis in a Community‐Based Health Plan,” Clinical Gastroenterology and Hepatology 6, no. 9 (2008): 999–1003, https://doi.org/10.1016/j.cgh.2008.05.022.
J. G. Williams, M. F. Alam, L. Alrubaiy, et al., “Infliximab Versus Ciclosporin for Steroid‐Resistant Acute Severe Ulcerative Colitis (CONSTRUCT): A Mixed Methods, Open‐Label, Pragmatic Randomised Trial,” Lancet Gastroenterology & Hepatology 1, no. 1 (2016): 15–24, https://doi.org/10.1016/s2468‐1253(16)30003‐6.
M. G. Thomas, C. Bayliss, S. Bond, et al., “Trial Summary and Protocol for a Phase II Randomised Placebo‐Controlled Double‐Blinded Trial of Interleukin 1 Blockade in Acute Severe Colitis: The IASO Trial,” BMJ Open 9, no. 2 (2019): e023765, https://doi.org/10.1136/bmjopen‐2018‐023765.
N. Narula, J. K. Marshall, J. F. Colombel, et al., “Systematic Review and Meta‐Analysis: Infliximab or Cyclosporine as Rescue Therapy in Patients With Severe Ulcerative Colitis Refractory to Steroids,” American Journal of Gastroenterology 111, no. 4 (2016): 477–491, https://doi.org/10.1038/ajg.2016.7.
D. Laharie, A. Bourreille, J. Branche, et al., “Ciclosporin Versus Infliximab in Patients With Severe Ulcerative Colitis Refractory to Intravenous Steroids: A Parallel, Open‐Label Randomised Controlled Trial,” Lancet 380, no. 9857 (2012): 1909–1915, https://doi.org/10.1016/s0140‐6736(12)61084‐8.
K. Leung, G. Rhee, S. Parlow, et al., “Absence of Day 3 Steroid Response Predicts Colitis‐Related Complications and Colectomy in Hospitalized Ulcerative Colitis Patients,” Journal of the Canadian Association of Gastroenterology 3, no. 4 (2020): 169–176, https://doi.org/10.1093/jcag/gwz005.
G. G. Kaplan, E. P. McCarthy, J. Z. Ayanian, J. Korzenik, R. Hodin, and B. E. Sands, “Impact of Hospital Volume on Postoperative Morbidity and Mortality Following a Colectomy for Ulcerative Colitis,” Gastroenterology 134, no. 3 (2008): 680–687, https://doi.org/10.1053/j.gastro.2008.01.004.
S. de Silva, C. Ma, M. C. Proulx, et al., “Postoperative Complications and Mortality Following Colectomy for Ulcerative Colitis,” Clinical Gastroenterology and Hepatology 9, no. 11 (2011): 972–980, https://doi.org/10.1016/j.cgh.2011.07.016.
S. Singh, A. Al‐Darmaki, A. D. Frolkis, et al., “Postoperative Mortality Among Patients With Inflammatory Bowel Diseases: A Systematic Review and Meta‐Analysis of Population‐Based Studies,” Gastroenterology 149, no. 4 (2015): 928–937, https://doi.org/10.1053/j.gastro.2015.06.001.
P. S. Dulai and V. Jairath, “Acute Severe Ulcerative Colitis: Latest Evidence and Therapeutic Implications,” Therapeutic Advances in Chronic Disease 9, no. 2 (2018): 65–72, https://doi.org/10.1177/2040622317742095.
J. A. Berinstein, J. L. Sheehan, M. Dias, et al., “Tofacitinib for Biologic‐Experienced Hospitalized Patients With Acute Severe Ulcerative Colitis: A Retrospective Case‐Control Study,” Clinical Gastroenterology and Hepatology 19, no. 10 (2021): 2112–2120.e1, https://doi.org/10.1016/j.cgh.2021.05.038.
R. Gilmore, L. Tan, R. Fernandes, Y. K. An, and J. Begun, “Upadacitinib Salvage Therapy for Infliximab Experienced Patients With Acute Severe Ulcerative Colitis,” Journal of Crohn's & Colitis 17 (2023): 2033–2036, https://doi.org/10.1093/ecco‐jcc/jjad115.
A. Singh, M. K. Goyal, V. Midha, et al., “Tofacitinib in Acute Severe Ulcerative Colitis (TACOS): A Randomized Controlled Trial: Tofacitinib in ASUC,” American Journal of Gastroenterology 119 (2023): 1365–1372, https://doi.org/10.14309/ajg.0000000000002635.
Institute of Medicine (US) Committee on Strategies for Small‐Number‐Participant Clinical Research Trials, Small Clinical Trials: Issues and Challenges, eds. C. H. Evans, Jr. and S. T. Ildstad (Washington, DC: National Academies Press, 2001).
N. J. Butcher, A. Monsour, E. J. Mew, et al., “Guidelines for Reporting Outcomes in Trial Reports: The CONSORT‐Outcomes 2022 Extension,” JAMA 328, no. 22 (2022): 2252–2264, https://doi.org/10.1001/jama.2022.21022.
K. Loudon, S. Treweek, F. Sullivan, P. Donnan, K. E. Thorpe, and M. Zwarenstein, “The PRECIS‐2 Tool: Designing Trials That Are Fit for Purpose,” British Medical Journal 350 (2015): h2147, https://doi.org/10.1136/bmj.h2147.
C. Ha, T. A. Ullman, C. A. Siegel, and A. Kornbluth, “Patients Enrolled in Randomized Controlled Trials Do Not Represent the Inflammatory Bowel Disease Patient Population,” Clinical Gastroenterology and Hepatology 10, no. 9 (2012): 1002–1007; quiz e78., https://doi.org/10.1016/j.cgh.2012.02.004.
A. Barnes, P. Spizzo, and R. Mountifield, “Corticosteroid Exposure Prior to Admission and Predicting Need for Rescue Therapy in Acute Severe Ulcerative Colitis,” Internal Medicine Journal 52, no. 5 (2022): 828–833, https://doi.org/10.1111/imj.15131.
S. C. Truelove and L. J. Witts, “Cortisone in Ulcerative Colitis; Preliminary Report on a Therapeutic Trial,” British Medical Journal 2, no. 4884 (1954): 375–378, https://doi.org/10.1136/bmj.2.4884.375.
D. T. Rubin, A. N. Ananthakrishnan, C. A. Siegel, B. G. Sauer, and M. D. Long, “ACG Clinical Guideline: Ulcerative Colitis in Adults,” American Journal of Gastroenterology 114, no. 3 (2019): 384–413, https://doi.org/10.14309/ajg.0000000000000152.
J. D. Feuerstein, K. L. Isaacs, Y. Schneider, S. M. Siddique, Y. Falck‐Ytter, and S. Singh, “AGA Clinical Practice Guidelines on the Management of Moderate to Severe Ulcerative Colitis,” Gastroenterology 158, no. 5 (2020): 1450–1461, https://doi.org/10.1053/j.gastro.2020.01.006.
F. Magro, P. Gionchetti, R. Eliakim, et al., “Third European Evidence‐Based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra‐Intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo‐Anal Pouch Disorders,” Journal of Crohn's & Colitis 11, no. 6 (2017): 649–670, https://doi.org/10.1093/ecco‐jcc/jjx008.
C. Corte, N. Fernandopulle, A. M. Catuneanu, et al., “Association Between the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and Outcomes in Acute Severe Ulcerative Colitis,” Journal of Crohn's and Colitis 9, no. 5 (2015): 376–381, https://doi.org/10.1093/ecco‐jcc/jjv047.
V. Gupta, W. Mohsen, T. P. Chapman, and J. Satsangi, “Predicting Outcome in Acute Severe Colitis—Controversies in Clinical Practice in 2021,” Journal of Crohn's and Colitis 15, no. 7 (2021): 1211–1221, https://doi.org/10.1093/ecco‐jcc/jjaa265.
A. Adams, V. Gupta, W. Mohsen, et al., “Early Management of Acute Severe UC in the Biologics Era: Development and International Validation of a Prognostic Clinical Index to Predict Steroid Response,” Gut 72, no. 3 (2023): 433–442, https://doi.org/10.1136/gutjnl‐2022‐327533.
R. K. Grant, G. R. Jones, N. Plevris, et al., “The ACE (Albumin, CRP and Endoscopy) Index in Acute Colitis: A Simple Clinical Index on Admission That Predicts Outcome in Patients With Acute Ulcerative Colitis,” Inflammatory Bowel Diseases 27, no. 4 (2021): 451–457, https://doi.org/10.1093/ibd/izaa088.
P. S. Dulai, L. E. Raffals, D. Hudesman, et al., “A Phase 2B Randomised Trial of Hyperbaric Oxygen Therapy for Ulcerative Colitis Patients Hospitalised for Moderate to Severe Flares,” Alimentary Pharmacology & Therapeutics 52, no. 6 (2020): 955–963, https://doi.org/10.1111/apt.15984.
P. S. Dulai, J. C. Buckey, Jr., L. E. Raffals, et al., “Hyperbaric Oxygen Therapy Is Well Tolerated and Effective for Ulcerative Colitis Patients Hospitalized for Moderate‐Severe Flares: A Phase 2A Pilot Multi‐Center, Randomized, Double‐Blind, Sham‐Controlled Trial,” American Journal of Gastroenterology 113, no. 10 (2018): 1516–1523, https://doi.org/10.1038/s41395‐018‐0005‐z.
Y. Dehghan and S. B. Hanauer, “S892 Outpatient Biologic Therapy Is Associated With Worse Outcomes During and After Admissions for Acute Severe Ulcerative Colitis,” American Journal of Gastroenterology 118, no. 10S (2023): S665, https://doi.org/10.14309/01.ajg.0000953208.61016.dc.
S. Hanauer, R. Panaccione, S. Danese, et al., “Tofacitinib Induction Therapy Reduces Symptoms Within 3 Days for Patients With Ulcerative Colitis,” Clinical Gastroenterology and Hepatology 17, no. 1 (2019): 139–147, https://doi.org/10.1016/j.cgh.2018.07.009.
P. S. Dulai, S. Singh, V. Jairath, E. Wong, and N. Narula, “Integrating Evidence to Guide Use of Biologics and Small Molecules for Inflammatory Bowel Diseases,” Gastroenterology 166 (2023): 396–408.e2, https://doi.org/10.1053/j.gastro.2023.10.033.
K. Gottlieb, J. Requa, W. Karnes, et al., “Central Reading of Ulcerative Colitis Clinical Trial Videos Using Neural Networks,” Gastroenterology 160, no. 3 (2021): 710–719.e2, https://doi.org/10.1053/j.gastro.2020.10.024.
B. G. Feagan, R. Khanna, W. J. Sandborn, et al., “Agreement Between Local and Central Reading of Endoscopic Disease Activity in Ulcerative Colitis: Results From the Tofacitinib OCTAVE Trials,” Alimentary Pharmacology & Therapeutics 54, no. 11–12 (2021): 1442–1453, https://doi.org/10.1111/apt.16626.
G. C. Nguyen, S. K. Murthy, B. Bressler, et al., “Quality of Care and Outcomes Among Hospitalized Inflammatory Bowel Disease Patients: A Multicenter Retrospective Study,” Inflammatory Bowel Diseases 23, no. 5 (2017): 695–701, https://doi.org/10.1097/mib.0000000000001068.
P. S. Dulai, V. Rai, L. E. Raffals, et al., “Recommendations on the Appropriate Management of Steroids and Discharge Planning During and After Hospital Admission for Moderate‐Severe Ulcerative Colitis: Results of a RAND Appropriateness Panel,” American Journal of Gastroenterology 117, no. 8 (2022): 1288–1295, https://doi.org/10.14309/ajg.0000000000001775.
W. J. Sandborn, M. Ferrante, B. R. Bhandari, et al., “Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Ulcerative Colitis,” Gastroenterology 158, no. 3 (2020): 537–549.e10, https://doi.org/10.1053/j.gastro.2019.08.043.
A. Bitton, D. Buie, R. Enns, et al., “Treatment of Hospitalized Adult Patients With Severe Ulcerative Colitis: Toronto Consensus Statements,” American Journal of Gastroenterology 107, no. 2 (2012): 179–194; author reply 195, https://doi.org/10.1038/ajg.2011.386.
A. C. Moore and B. Bressler, “Acute Severe Ulcerative Colitis: The Oxford Criteria No Longer Predict In‐Hospital Colectomy Rates,” Digestive Diseases and Sciences 65, no. 2 (2020): 576–580, https://doi.org/10.1007/s10620‐019‐05668‐6.
S. Pola, D. Patel, S. Ramamoorthy, et al., “Strategies for the Care of Adults Hospitalized for Active Ulcerative Colitis,” Clinical Gastroenterology and Hepatology 10, no. 12 (2012): 1315–1325.e4, https://doi.org/10.1016/j.cgh.2012.07.006.
C. Le Berre and L. Peyrin‐Biroulet, “Selecting End Points for Disease‐Modification Trials in Inflammatory Bowel Disease: The SPIRIT Consensus From the IOIBD,” Gastroenterology 160, no. 5 (2021): 1452–1460.e21, https://doi.org/10.1053/j.gastro.2020.10.065.
M. Cole, S. Speer, B. Davis, I. C. Strug, and M. Schwartz, P0680—Endoscopy Recording in Inflammatory Bowel Disease Clinical Trial Recruitment, ACG 2023 Annual Scientific Meeting Abstracts (Vancouver, BC: American College of Gastroenterology, 2023).
N. Narula, H. Hamam, J. Liu, et al., “Adaptive Steroid Tapering Impedes Corticosteroid‐Free Remissions Compared to Forced Tapering in Clinical Trials of Ulcerative Colitis,” Journal of Crohn's & Colitis (2024), https://doi.org/10.1093/ecco‐jcc/jjae092. Online ahead of print.
S. Honap, V. Jairath, B. E. Sands, P. S. Dulai, S. Danese, and L. Peyrin‐Biroulet, “Acute Severe Ulcerative Colitis Trials: The Past, the Present and the Future,” Gut 73, no. 10 (2024): 1763–1773, https://doi.org/10.1136/gutjnl‐2024‐332489.
N. Narula, H. Hamam, F. Peerani, T. Bessissow, B. Bressler, and P. S. Dulai, “Resolution of Rectal Bleeding by Day 7 in Acute Severe Ulcerative Colitis Is Prognostic for Post‐Discharge Corticosteroid Free Clinical Remission and Endoscopic Improvement,” American Journal of Gastroenterology 119 (2024): 1939–1942, https://doi.org/10.14309/ajg.0000000000002860.
C. Ma, J. Hanzel, R. Panaccione, et al., “CORE‐IBD: A Multidisciplinary International Consensus Initiative to Develop a Core Outcome Set for Randomized Controlled Trials in Inflammatory Bowel Disease,” Gastroenterology 163, no. 4 (2022): 950–964, https://doi.org/10.1053/j.gastro.2022.06.068.
P. Ranganathan, C. S. Pramesh, and R. Aggarwal, “Common Pitfalls in Statistical Analysis: Intention‐To‐Treat Versus Per‐Protocol Analysis,” Perspectives in Clinical Research 7, no. 3 (2016): 144–146, https://doi.org/10.4103/2229‐3485.184823.
M. Ghadessi, R. Tang, J. Zhou, et al., “A Roadmap to Using Historical Controls in Clinical Trials—By Drug Information Association Adaptive Design Scientific Working Group (DIA‐ADSWG),” Orphanet Journal of Rare Diseases 15, no. 1 (2020): 69, https://doi.org/10.1186/s13023‐020‐1332‐x.
C. R. Mehta and S. J. Pocock, “Adaptive Increase in Sample Size When Interim Results Are Promising: A Practical Guide With Examples,” Statistics in Medicine 30, no. 28 (2011): 3267–3284, https://doi.org/10.1002/sim.4102.