Infliximab (Remicade) for paediatric ulcerative colitis - second line

Transcription

1 Infliximab (Remicade) for paediatric ulcerative colitis - second line September 2011 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research

2 Infliximab (Remicade) for paediatric ulcerative colitis - second line Target group Ulcerative colitis (UC) in children aged 6-17 years: moderate to severe second line after failure of conventional therapy. Technology description Infliximab (Remicade) is a chimeric human-murine monoclonal antibody that binds with high affinity to both soluble and transmembrane forms of tumour necrosis factor-α (TNF-α), neutralising its biological effects 1. Infliximab is administered intravenously at a dose of 5mg/kg in weeks 0, 2 and 6, and every 8 weeks thereafter. Infliximab is licensed in the EU for 2 : Ulcerative colitis treatment of moderately to severely active disease in adult patients who have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine or azathioprine, or who are intolerant to or have medical contraindications for such therapies. Adult Crohn s disease: o Treatment of moderately to severely active Crohn's disease, in patients who have not responded to a corticosteroid and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies. o Treatment of fistulising, active Crohn's disease, in patients who have not responded to conventional treatment (including antibiotics, drainage and immunosuppressive therapy). Paediatric Crohn s disease in children and adolescents aged 6-17 years, who have not responded to conventional therapy including a corticosteroid, an immunomodulator and primary nutrition therapy; or who are intolerant to or have contraindications for such therapies. Rheumatoid arthritis in combination with methotrexate for: o Adult patients with active disease when the response to disease-modifying antirheumatic drugs (DMARDS), including methotrexate, has been inadequate. o Adult patients with severe, active and progressive disease not previously treated with methotrexate or other DMARDs. Ankylosing spondylitis treatment of severe, active disease, in adult patients who have responded inadequately to conventional therapy. Psoriatic arthritis treatment of active and progressive disease in adult patients with an inadequate response to previous DMARD therapy. Psoriasis treatment of moderate to severe plaque psoriasis in adult patients who have failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or PUVA a. Common reported side-effects of infliximab include upper respiratory tract infections, headache, sinusitis, abdominal pain, nausea and infusion-related reactions 2. a PUVA - Psoralen plus UVA phototherapy 2

3 Infliximab is also in phase III development for Crohn s disease (prevention of relapse), treatment of hepatitis C infection (treatment naive patients), plaque psoriasis (in combination with methotrexate), ulcerative colitis (combination therapy), and phase II development for pyoderma. Innovation and/or advantages Infliximab represents the first licensed anti-tnf medication for the paediatric population, with moderate to severe disease, providing an additional treatment option where corticosteroids and other immunosuppressive agents are inadequate to control disease. Developer MSD/Janssen Biologics. Availability, launch or marketing dates, and licensing plans In phase III clinical trials. NHS or Government Priority Area None identified Relevant guidance NICE technology appraisal in development. Ulcerative colitis (moderate to severe, second line) adalimumab. Expected date of issue to be confirmed 3. NICE technology appraisal. Infliximab for the treatment of acute exacerbations of 4 ulcerative colitis NICE technology appraisal. Infliximab for subacute manifestations of ulcerative 5 colitis NICE clinical guideline in development. Management of ulcerative colitis. Expected 6 July NICE interventional procedure guidance. Leukapheresis for inflammatory bowel disease British Society of Gastroenterology. Guidelines for the management of inflammatory bowel disease in adults European Crohn's and Colitis Organisation (ECCO), European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN), Pediatric Porto Inflammatory Bowel Disease Working group of ESPGHAN. Consensus for managing acute severe ulcerative colitis in children: A systematic review and joint statement 9 from ECCO, ESPGHAN, and the Porto IBD Working Group of ESPGHAN British Society of Paediatric Gastroenterology, Hepatology, and Nutrition. Guidelines for the management of inflammatory bowel disease in children in the United 10 Kingdom European Crohn's and Colitis Organisation (ECCO). European evidence-based consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis Clinical need and burden of disease UC is a form of chronic inflammatory bowel disease (IBD) affecting the colon and rectum. The most common symptoms are abdominal cramping, faecal urgency and bloody diarrhoea 7. Patients with IBD are at an increased risk of developing colorectal cancer, thought to be the result of chronic inflammation of the gastrointestinal mucosa 12. 3

4 Patients with UC have approximately 20% lifetime risk of colorectal cancer, with the risk increasing with the duration of the disease 13. Colorectal cancer is rarely encountered in patients experiencing colitis for less than seven years. Thereafter the risk is estimated to increase at a rate of % per year 12. The clinical course of UC is marked by exacerbation and remission, with around 50% of patients experiencing a relapse in any year 8. Flare-ups can significantly affect patients quality of life; around 55% of patients report flare-ups every few months, 9% have monthly flare-ups, and a further 9% experience weekly problems 14. A prospective survey of IBD in children aged under 16 years carried out in the UK and Ireland during 1998 and 1999 reported the incidence of UC in England and Wales as 1.4 and 1.7 per 100,000 per year respectively 15. A more recent prospective study of paediatric IBD conducted in South Wales over an eight year period ( ) found the incidence of UC in children under 16 years of age to be 1.5 cases per 100,000 per year 16. The prevalence of paediatric IBD in South Wales has been reported as 20 per 100,000 childhood population (children aged 0-16 years) with a 3:1 preponderance of Crohn s disease compared to UC 17. Although presentation of UC symptoms during adolescence is common, as many as 40% of children present before the age of In there were 909 finished consultant episodes for UC in patients aged up to 14 years (inclusive) in England and a total of 34,096 admissions and 80,584 bed days within the total population 19 (ICD10 K51). UC has a slight excess of mortality in the first two years after diagnosis, but little subsequent difference from the general population thereafter 8. A severe attack of UC can be potentially life threatening, however in England and Wales in 2009 there was only 1 registered death in patients aged up to 19 years (inclusive) 20. Existing comparators and treatments Treatment of UC involves induction of remission in patients with active disease and subsequent maintenance of remission. Paediatric treatments include 4, 8, 9, 10, 11 : Aminosalicylates mild to moderate UC. Available as oral preparations, retention enemas, rectal foam preparation and suppositories (examples include mesalazine, balsalazide sodium and sulphasalazine). Corticosteroids moderate to severe relapsing UC. Available as oral preparations, parenteral preparations, retention enemas and rectal foam preparations (examples include prednisolone, beclometasone dipropionate, hydrocortisone). Unlicensed immunosuppressants are often used for second line treatment, including azathioprine (the most commonly used), 6-mercaptopurine, methotrexate and, rarely, tacrolimus. In severe acute UC, short-term ciclosporin (IV) is occasionally used in children not responding to IV corticosteroids b. Trials of exclusive polymeric liquid diet e.g. Modulen b. Colectomy b. b Expert personal communication 4

5 Efficacy and safety Trial Sponsor Status Source of information Location Design Participants and schedule Follow-up Primary outcomes Secondary outcomes Key results Adverse effects (AEs) NCT , CR012388, C0168T72; children and adolescents; infliximab; phase III. Centocor, Inc. Published in abstract. Abstract 21. EU, USA and Canada. Randomised, dose-ranging. n=60; children aged 6-17; moderately to severely active UC; receiving, failed to respond to, or adverse effects from aminosalicylates, immunomodulators or corticosteroids. Following induction regimen of infliximab 5mg/kg at week 0, 2 and 6, patients randomised to 5mg/kg every 8 weeks through week 46, or 5mg/kg every 12 weeks through week 42. Active treatment period 54 weeks. Efficacy of induction regimen in inducing clinical response as measured by Mayo score; safety of infliximab during induction and maintenance dosing regimens. Efficacy of maintenance regimens in maintaining remission as measured by Paediatric Ulcerative Colitis Activity Index (PUCAI) score; efficacy of induction regimen in inducing clinical remission as measured by Mayo and PUCAI score; efficacy of induction regimen in inducing mucosal healing. At week 8, 73.3% of patients experienced a clinical response, 40% (Mayo score) and 33.3% (PUCAI score) experienced clinical remission, 68.3% achieved mucosal healing and 33.3% had normal or inactive disease as measured by endoscopy; at week 54, a greater proportion were in remission (PUCAI score) in the 5mg/kg every 8 weeks treatment group (38.1%) than in the 5mg/kg every 12 weeks treatment group (18.2%); no deaths, malignancies, serious neurologic events, opportunistic infections, tuberculosis or congestive heart failure were reported. Through week 54 the proportion of subjects experiencing serious AEs was similar across treatment groups; all subjects in both treatment groups reported one or more AEs; more subjects in the 5mg/kg every 12 weeks group discontinued treatment than the 5mg/kg every 8 weeks treatment group; similar numbers of subjects reported infections requiring oral or parenteral treatment across each group; antibodies to infliximab developed in 4 subjects. Estimated cost and cost impact The cost of infliximab for this indication is not yet known. However, the cost of infliximab 100mg vial for its licensed indications is Claimed or potential impact speculative Patients Reduced mortality or increased length of survival Other: Reduction in associated morbidity or Improved quality of life for patients and/or carers Quicker, earlier or more accurate diagnosis or identification of disease None identified 5

6 Services Increased use: requirement for IV infusion. Service organisation Staff requirements Decreased use Other: None identified Costs Increased unit cost compared to alternative Increased costs: more patients coming for treatment Increased costs: capital investment needed New costs: Savings: Other: Dependent upon dosing regimen. Other issues Clinical uncertainty or other research question identified: None identified References 1 Tracey D, Klareskog L, Sasso EH et al. Tumour necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacology and therapeutics 2008;117(2): Electronic Medicines Compendium. Infliximab 100mg powder for infusion (SPC). tion+for+infusion/ Accessed 6 September National Institute for Health and Clinical Excellence. Ulcerative colitis (moderate to severe, second line) - adalimumab. Technology appraisal in development. Expected date of issue to be confirmed. 4 National Institute for Health and Clinical Excellence. Infliximab for the treatment of acute exacerbations of ulcerative colitis. Technology appraisal TA163. London: NICE; December National Institute for Health and Clinical Excellence. Infliximab for subacute manifestations of ulcerative colitis. Technology appraisal TA140. London: NICE; April National Institute for Health and Clinical Excellence. Management of ulcerative colitis. Clinical guideline in development. Expected July National Institute for Health and Clinical Excellence. Leukapheresis for inflammatory bowel disease. Interventional procedure guidance IPG126. London: NICE; June Mowat C, Cole A, Windsor A et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60: Turner D, Travis SPL, Griffiths AM et al. Consensus for managing acute severe ulcerative colitis in children: A systematic review and joint statement from ECCO, ESPGHAN, and the Porto IBD Working Group of ESPGHAN. American Journal of Gastroenterology 2011;106(4): Sandhu BK, Fell JM, Beattie RM et al. Guidelines for the management of inflammatory bowel disease in children in the United Kingdom. Journal of Paediatric Gastroenterology and Nutrition 2008;55:S1-S Stange EF, Travis SPL, Vermeire S et al for the European Crohn's and Colitis Organisation (ECCO). European evidence-based consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis. Journal of Crohn's and Colitis 2008;2: Ullman TA and Itzkowitz SH. Intestinal inflammation and cancer. Gastroenterology 2011;140: Brentnall TA. Molecular underpinnings of cancer in ulcerative colitis. Current Opinion in Gastroenterology 2003;19(1): National Association for Colitis & Crohn s Disease - Press Information. New European survey of people with Colitis and Crohn s disease highlights that brits needs to communicate better. Accessed 4 August Sawczenko A, Sandhu BK, Logan RF et al. Prospective survey of childhood inflammatory bowel disease in the British Isles. The Lancet 2001;357: Ahmed M, Davies IH, Hood K et al. Incidence of paediatric inflammatory bowel disease in South Wales. Archives of Disease in Childhood 2006;91: Hassan K, Cowan FJ, Jenkins HR. The incidence of childhood inflammatory bowel disease in Wales. European Journal of Pediatrics 2000;159: Hyams S, Davis P, Grancher K et al. Clinical outcome of ulcerative in children. The Journal of Pediatrics 1996;129:

7 19 NHS Hospital episode statistics. NHS England HES data Office for National Statistics. Mortality statistics deaths registered in 2009, series DR ClinicalTrials.gov. A study of the safety and efficacy of infliximab (Remicade) in pediatric patients with moderately to severely active ulcerative colitis Clinical Study Report (Final) Accessed 6 September British Medical Association and Royal Society of Great Britain. British National Formulary. BNF 61. London: BMJ Group and RPS Publishing, March The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are not necessarily those of the NHS, the NIHR or the Department of Health The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B15 2SP, England Tel: +44 (0) Fax +44 (0)