Crohn’s disease is a chronic form of inflammatory bowel disease that can affect any part of the gastrointestinal tract but most commonly affects the ileum, colon, and rectum. Common gastrointestinal symptoms experienced by patients with Crohn’s disease include abdominal pain, rectal bleeding, fatigue, vomiting, diarrhea, perianal disease, weight loss, and bloating.^1–3 According to Crohn’s and Colitis Canada, there are approximately 129,000 Canadians living with Crohn’s disease (one in 150 people), and it is estimated that 5,700 new cases of Crohn’s disease are diagnosed each year.¹

Ustekinumab (Stelara) is a fully human immunoglobulin G1 kappa monoclonal antibody that binds to the shared p40 subunit of interleukin (IL)-12 and IL-23.⁴ Ustekinumab is already approved by Health Canada for the treatment of adults with chronic moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy, and for the treatment of adult patients with active psoriatic arthritis, alone or in combination with methotrexate.⁴

The current indication under review is for the treatment of adult patients with moderately to severely active Crohn’s disease, who have had an inadequate response with, loss of response to, or intolerance to either immunomodulators or one or more tumour necrosis factor (TNF) alpha antagonists, or have had an inadequate response with, intolerance to, or demonstrated dependence on corticosteroids. The recommended dosage for ustekinumab in the treatment of Crohn’s disease is an initial single intravenous (IV) induction dose based on body weight (approximating 6 mg/kg), followed by a 90 mg subcutaneous (SC) maintenance dose eight weeks later, then one dose every eight weeks thereafter as maintenance treatment. For some patients (e.g., “those with low inflammatory burden,” per the product monograph), an alternative maintenance regimen of ustekinumab 90 mg SC every 12 weeks may be administered at the discretion of the treating physician. Patients who inadequately respond to the 90 mg SC every 12 weeks regimen may be switched to the every eight weeks regimen. Immunomodulators and/or corticosteroids may be continued during treatment with ustekinumab. The product monograph recommends that, in patients who have responded to treatment with ustekinumab, corticosteroids may be reduced or discontinued in accordance with standard of care.⁴

The objective of this report is to perform a systematic review of the beneficial and harmful effects of ustekinumab in accordance with the Health Canada–approved indication for the treatment of Crohn’s disease. Only Health Canada–approved dosage regimens for ustekinumab for Crohn’s disease were included in this review. Ustekinumab has been previously reviewed through the CADTH Common Drug Review (CDR) for the treatment of plaque psoriasis and psoriatic arthritis.^5,6

Contents

• Clinical Review Report
  • ABBREVIATIONS
  • EXECUTIVE SUMMARY
    • Introduction
    • Results and Interpretation
    • Potential Place in Therapy
    • Conclusions
  • 1. INTRODUCTION
    • 1.1. Disease Prevalence and Incidence
    • 1.2. Standards of Therapy
    • 1.3. Drug
    • 1.4. Key Comparators
    • 1.5. Previous Reviews by CADTH Common Drug Review
  • 2. OBJECTIVES AND METHODS
    • 2.1. Objectives
    • 2.2. Methods
  • 3. RESULTS
    • 3.1. Findings from the Literature
    • 3.2. Included Studies
    • 3.3. Patient Disposition
    • 3.4. Exposure to Study Treatments
    • 3.5. Critical Appraisal
    • 3.6. Efficacy
    • 3.7. Harms
  • 4. DISCUSSION
    • 4.1. Summary of Available Evidence
    • 4.2. Interpretation of Results
    • 4.3. Potential Place in Therapy
  • 5. CONCLUSIONS
  • APPENDIX 1. PATIENT INPUT SUMMARY
    • 1. Brief Description of Patient Groups Supplying Input
    • 2. Condition-Related Information
    • 3. Current Therapy-Related Information
    • 4. Expectations About the Drug Being Reviewed
  • APPENDIX 2. LITERATURE SEARCH STRATEGY
  • APPENDIX 3. EXCLUDED STUDIES
  • APPENDIX 4. DETAILED OUTCOME DATA
    • Clinical Remission Subgroup Analyses
    • Clinical Response Subgroup Analyses
    • Inflammatory Bowel Disease Questionnaire and Short Form (36) Health Survey Additional Data
  • APPENDIX 5. VALIDITY OF OUTCOME MEASURES
    • Aim
    • Findings
    • Conclusion
  • APPENDIX 6. SUMMARY OF THE IM-UNITI EXTENSION STUDY
    • Objective
    • Findings
    • Limitations
    • Summary
  • APPENDIX 7. SUMMARY OF INDIRECT COMPARISONS
    • Background
    • Methods for Manufacturer’s Indirect Comparison
    • Results
    • Critical Appraisal of Manufacturer’s IDC
    • Critical Appraisal of Mocko et al. Indirect Comparison
    • Critical Appraisal of Singh et al. Indirect Comparison
    • Conclusions
  • REFERENCES
• Pharmacoeconomic Review Report
  • ABBREVIATIONS
  • EXECUTIVE SUMMARY
    • Background
    • Summary of Identified Limitations and Key Results
    • Conclusions
  • INFORMATION ON THE PHARMACOECONOMIC SUBMISSION
    • 1. SUMMARY OF THE MANUFACTURER’S PHARMACOECONOMIC SUBMISSION
    • 2. MANUFACTURER’S BASE CASE
    • 3. SUMMARY OF MANUFACTURER’S SENSITIVITY ANALYSES
    • 4. KEY LIMITATIONS OF MANUFACTURER’S SUBMISSION
    • 5. CADTH COMMON DRUG REVIEW REANALYSES
    • 6. ISSUES FOR CONSIDERATION
    • 7. PATIENT INPUT
    • 8. CONCLUSIONS
  • APPENDIX 1. COST COMPARISON
  • APPENDIX 2. ADDITIONAL INFORMATION
  • APPENDIX 3. REVIEWER WORKSHEETS
    • Manufacturer’s Model Structure
    • Manufacturer’s Results
    • Manufacturer’s Sensitivity Analyses
    • Manufacturer’s Probabilistic Sensitivity Analysis
    • Manufacturer’s Alternative Costing Scenarios
    • CADTH Common Drug Review Reanalyses
  • REFERENCES
• CDEC FINAL RECOMMENDATION
  • Recommendation
  • Reasons for the Recommendation
  • Of Note
  • Background
  • Summary of CDEC Considerations

This review report was prepared by the Canadian Agency for Drugs and Technologies in Health (CADTH). In addition to CADTH staff, the review team included a clinical expert in gastroenterology who provided input on the conduct of the review and the interpretation of findings

The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.

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