What was the aim of this review?
This Cochrane Review aimed to find out if long-term use of certolizumab pegol (CZP) is an effective and safe treatment for people with Crohn's disease (CD) compared to placebo. We collected and analyzed all relevant studies to answer this question.
What is Crohn's disease?
CD is a chronic disease that causes inflammation of the gastrointestinal tract such as the small and large intestines. The common symptoms of CD are chronic diarrhoea, abdominal pain, fever, and weight loss. The exact cause and mechanism of CD are not clear, but it is known that a chemical messenger called tumour necrosis factor-alpha (TNFα) is involved in the inflammation of the intestines.
What is certolizumab pegol?
CZP is a medicine that is injected under the skin and suppresses the activity of TNFα. CZP can suppress ongoing inflammation in people with CD. However, the effectiveness and safety of long-term use of CZP in people with CD who do not have an ongoing inflammation are not well understood, and it is important to clarify this point.
What did we do?
We searched for studies that investigated CZP compared with placebo (a dummy treatment) in people with CD. We searched the medical literature up to 23 March 2022.
What did we find?
We found one relevant study involving 428 people with CD. The study focused on people with CD aged 18 years and older who showed a positive response to three doses of CZP. It compared the effectiveness and side effects of long-term use of CZP against placebo.
Key results
We found that CZP use likely contributed to better control of CD. Of 216 people with CD who were given CZP, 103 had control of the disease for 26 weeks. In contrast, of the 212 people with CD who were given a placebo, 60 had control of their disease. In addition, there were no obvious side effects of either CZP or placebo over the 26 weeks.
Certainty in the evidence
We used a general four-level rating scale method (i.e. high, moderate, low, or very low) for evaluating our certainty in the evidence of the results (GRADE). We found that the certainty of the evidence for the effects of CZP was moderate because the number of participants was insufficient in the included study. For safety evidence of CZP, the certainty of the evidence was low due to the small number of participants who experienced side effects.
Conclusions
CZP is likely an effective and safe treatment to suppress inflammation in people with CD; however, the current studies are limited to 26 weeks of follow-up (monitoring) and only in adults. Therefore, these conclusions cannot be used to guide longer-term treatment or for children at present.
Read the full abstract
Crohn's disease (CD) is a disease with an impaired immune response characterized by chronic, relapsing-remitting, and progressive inflammation mainly affecting the gastrointestinal tract. Certolizumab pegol (CZP) is a biological agent that regulates the impaired immune response by controlling tumour necrosis factor-α (TNFα). However, the efficacy and safety of long-term administration of CZP for people with CD with inflammation under control are not well understood.
Objectives
To assess the efficacy and safety of CZP for maintenance of remission in people with CD.
Search strategy
We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, WHO ICTRP, and conference abstracts from inception to 23 March 2022. We contacted pharmaceutical companies involved with the production of CZP for further relevant information.
Selection criteria
We included randomized controlled trials (RCTs) comparing CZP with placebo in adults with CD.
Data collection and analysis
Two review authors independently selected studies and extracted data. The main outcomes were failure to maintain clinical remission at week 26, failure to maintain clinical response at week 26, and serious adverse events. We planned to perform meta-analyses including all available studies if similar enough for pooling to be appropriate and calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences with 95% CIs for continuous outcomes. We analyzed the number needed to treat for an additional beneficial outcome (NNTB) and the number needed to treat for an additional harmful outcome (NNTH) to indicate the magnitude of treatment effects. The same two review authors independently evaluated the risk of bias by using the Cochrane RoB 2 tool and evaluated the certainty of evidence using the GRADE framework.
Main results
We identified one study meeting our prespecified eligibility criteria. The included study enrolled 428 adults with CD who responded to induction therapy with CZP 400 mg at weeks 0, 2, and 4. The study evaluated long-term efficacy and safety of CZP administered subcutaneously every four weeks compared with placebo.
The proportion of participants who failed to maintain clinical remission at week 26 was 52.3% (113/216) in the CZP group compared to 71.7% (152/212) in the placebo group. Treatment of CZP probably results in a large reduction in failure to maintain clinical remission at week 26 (RR 0.73, 95% CI 0.63 to 0.85). The NNTB was 5 (95% CI 4 to 9). We judged this outcome at low risk of bias. Using the GRADE assessment, we judged the certainty of evidence as moderate due to the low number of events occurred.
The proportion of participants who failed to maintain clinical response at week 26 was 37.5% (81/216) in the CZP group compared to 64.2% (136/212) in the placebo group. Treatment of CZP probably results in a large reduction in failure to maintain clinical response at week 26 (RR 0.58, 95% CI 0.48 to 0.71). The NNTB was 4 (95% CI 3 to 5). We judged this outcome at low risk of bias. Using the GRADE assessment, we judged the certainty of evidence as moderate due to the low number of events occurred.
The proportion of participants who developed serious adverse events was 5.6% (12/216) in the CZP group compared to 6.6% (14/212) in the placebo group. Treatment of CZP may lead to no difference in serious adverse events compared to placebo when used as a remission maintenance treatment (RR 0.84, 95% CI 0.40 to 1.78). The NNTB was 95 (95% CI NNTH 19 to NNTB 25). We evaluated the risk of bias for this outcome as low. We evaluated the certainty of evidence as low due to the low number of events occurred and the CIs were not sufficiently narrow.
Authors' conclusions
CZP probably results in a large reduction in failure to maintain clinical remission and response at week 26 in people with CD. The evidence suggests that CZP may lead to no difference in serious adverse events compared to placebo when used as a remission maintenance treatment. However, the current studies are limited to 26 weeks of follow-up and only included adults. Therefore, these conclusions cannot be used to guide longer term treatment or for treatment in children at present.
