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

September 2011


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-
(TNF-), 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 Crohns 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 Crohns 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 anti-
rheumatic 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
September 2011


3
Infliximab is also in phase III development for Crohns 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/J anssen 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
ulcerative colitis. 2008
.
4
NICE technology appraisal. Infliximab for subacute manifestations of ulcerative
colitis. 2008
.
5
NICE clinical guideline in development. Management of ulcerative colitis. Expected
J uly 2013
.
6
NICE interventional procedure guidance. Leukapheresis for inflammatory bowel
disease. 2005
.
7

.
British Society of Gastroenterology. Guidelines for the management of inflammatory
bowel disease in adults. 2011
8
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
from ECCO, ESPGHAN, and the Porto IBD Working Group of ESPGHAN. 2011
.
9
British Society of Paediatric Gastroenterology, Hepatology, and Nutrition. Guidelines
for the management of inflammatory bowel disease in children in the United
Kingdom. 2008
.
10
European Crohn's and Colitis Organisation (ECCO). European evidence-based
consensus on the diagnosis and management of ulcerative colitis: definitions and
diagnosis. 2008
.
11

.
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
.
September 2011


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 0.5-1.0% 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 (1996-2003) 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 Crohns
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 10
18

.
In 2009-2010 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
September 2011


5



Efficacy and safety

Trial NCT00336492, CR012388, C0168T72; children and adolescents; infliximab; phase
III.
Sponsor Centocor, Inc.
Status Published in abstract.
Source of
information
Abstract
21
Location
.
EU, USA and Canada.
Design Randomised, dose-ranging.
Participants
and schedule

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.
Follow-up Active treatment period 54 weeks.
Primary
outcomes
Efficacy of induction regimen in inducing clinical response as measured by Mayo
score; safety of infliximab during induction and maintenance dosing regimens.
Secondary
outcomes
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.
Key results 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.
Adverse effects
(AEs)
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 419.62
22

.
Claimed or potential impact speculative

Patients
Reduced mortality or increased
length of survival
Reduction in associated morbidity
or Improved quality of life for
patients and/or carers
Quicker, earlier or more accurate
diagnosis or identification of
disease

Other: None identified


September 2011


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):244-279.
2
Electronic Medicines Compendium. Infliximab 100mg powder for infusion (SPC).
http://www.medicines.org.uk/EMC/medicine/3236/SPC/Remicade+100mg+powder+for+concentrate+for+solu
tion+for+infusion/ Accessed 6 September 2011.
3
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 2008.
5
National Institute for Health and Clinical Excellence. Infliximab for subacute manifestations of ulcerative
colitis. Technology appraisal TA140. London: NICE; April 2008.
6
National Institute for Health and Clinical Excellence. Management of ulcerative colitis. Clinical guideline in
development. Expected J uly 2013.
7
National Institute for Health and Clinical Excellence. Leukapheresis for inflammatory bowel disease.
Interventional procedure guidance IPG126. London: NICE; J une 2005.
8
Mowat C, Cole A, Windsor A et al. Guidelines for the management of inflammatory bowel disease in adults.
Gut 2011;60: 71-607.
9
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 J ournal of Gastroenterology 2011;106(4):574-588.
10
Sandhu BK, Fell J M, Beattie RM et al. Guidelines for the management of inflammatory bowel disease in
children in the United Kingdom. J ournal of Paediatric Gastroenterology and Nutrition 2008;55:S1-S13.
11
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. J ournal of Crohn's and Colitis 2008;2:1-23.
12
Ullman TA and Itzkowitz SH. Intestinal inflammation and cancer. Gastroenterology 2011;140:1807-1816.
13
Brentnall TA. Molecular underpinnings of cancer in ulcerative colitis. Current Opinion in Gastroenterology
2003;19(1):64-68.
14
National Association for Colitis & Crohns Disease - Press Information. New European survey of people with
Colitis and Crohns disease highlights that brits needs to communicate better.
https://www.nacc.org.uk/downloads/media/EuropeanSurvey.pdf Accessed 4 August 2011.
15
Sawczenko A, Sandhu BK, Logan RF et al. Prospective survey of childhood inflammatory bowel disease in
the British Isles. The Lancet 2001;357:1093-1094.
16
Ahmed M, Davies IH, Hood K et al. Incidence of paediatric inflammatory bowel disease in South Wales.
Archives of Disease in Childhood 2006;91:344-345.
17
Hassan K, Cowan FJ , J enkins HR. The incidence of childhood inflammatory bowel disease in Wales.
European J ournal of Pediatrics 2000;159:261-263.
18
Hyams S, Davis P, Grancher K et al. Clinical outcome of ulcerative in children. The J ournal of Pediatrics
1996;129:81-88.
September 2011


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19
NHS Hospital episode statistics. NHS England 2009-10 HES data. 2010. www.hesonline.nhs.uk
20
Office for National Statistics. Mortality statistics deaths registered in 2009, series DR 2009
www.statistics.gov.uk
21
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)
http://download.veritasmedicine.com/PDF/CR012388_CSR.pdf Accessed 6 September 2011.
22
British Medical Association and Royal Society of Great Britain. British National Formulary. BNF 61. London:
BMJ Group and RPS Publishing, March 2011.































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The views expressed in this publication are not necessarily those of the NHS, the NIHR or the
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