Natalizumab for treatment of active Crohn's disease

Background

Crohn's disease (CD) is a chronic inflammatory disease of the intestines. CD frequently occurs in the lower part of the small intestine, called the ileum, but it can affect any part of the digestive tract. Common symptoms include abdominal pain, often in the lower right area, and diarrhea. When people with CD are experiencing symptoms, the disease is called 'active'. When the symptoms stop, it is called 'remission'. Natalizumab and infliximab are biologic medications. These medications are directly infused into a vein (intravenous). Biologics suppress the immune system and reduce the inflammation associated with CD. Biologics are often given to people with moderate to severe CD who are unable to achieve remission despite treatment with standard drugs.

Study characteristics

We performed a comprehensive literature review and identified five randomized controlled trials (an experiment in which participants are randomly assigned to receive two or more interventions and the results are compared) that involved a total of 1771 participants. Four studies (1692 participants) compared one, two or three intravenous infusions of natalizumab (300 mg or 3 mg/kg or 6mg/kg) to placebo (a sham infusion - an infusion that was identical in appearance to natalizumab but did not contain any active medicine). These studies followed participants for 12 weeks. One study (79 participants) compared three intravenous infusions of natalizumab (300 mg) and infliximab (5 mg/kg) to infliximab and placebo. The participants in this study were unable to achieve remission despite treatment with the biologic drug infliximab. This study followed participants for 10 weeks. All of the studies were high quality.

Key results

Depending upon the study, intravenous infusions of natalizumab or placebo were administered at weeks zero, four and eight. One, two and three infusions of natalizumab were superior to placebo for induction of remission and clinical response (improvement in symptoms of active CD). The rates of side effects, study withdrawals due to side effects and serious side effects were similar across the natalizumab and placebo groups at 4, 8 and 12 weeks. Common side effects included headache, nausea, nasopharyngitis (common cold), abdominal pain, fatigue, vomiting and worsening of Crohn's disease.

The study comparing combination therapy with natalizumab and infliximab to infliximab and placebo demonstrated similar remission rates at 10 weeks. The rates of side effects, withdrawals due to side effects and serious side effects were similar across groups at 10 weeks. Common adverse events included headache, worsening of Crohn's disease, nausea, and nasopharyngitis.

The included trials were not designed to detect serious side effects that occur infrequently. Natalizumab is associated with the development of progressive multifocal leukoencephalopathy (PML) resulting in some patient deaths. PML is a serious infection of the nervous system that can often be fatal. There are currently no tests which can reliably predict those at risk of developing PML.

Quality of evidence

Overall, the quality of evidence for each outcome was generally high.

Conclusions

High quality data suggest that natalizumab is effective for induction of clinical remission and response in some patients with moderately to severely active Crohn's disease. Due to the association with PML, and the availability of alternative agents that are not associated with PML, natalizumab is not likely to be used in patients who fail currently available medical therapy for Crohn's disease. The use of natalizumab in select patients (e.g. people allergic to different biologics) needs to be carefully considered against the potential risk of developing PML. Futher studies of natalizumab are not likely to be done.

Authors' conclusions: 

High quality data suggest that natalizumab is effective for induction of clinical remission and response in some patients with moderately to severely active CD. However, none of the included studies had the power to detect rare but serious adverse events such as PML. Due to the association with PML, and the availability of alternative agents that are not associated with PML, natalizumab is not likely to be used in patients who fail currently available medical therapy. The use of natalizumab in select patients (e.g. patients allergic to different biologics) needs to be carefully considered against the potential risk of developing PML. Futher studies of natalizumab are not likely to be done.

Read the full abstract...
Background: 

This systematic review update summarizes the current evidence on the use of natalizumab for induction of remission in Crohn's disease (CD).

Objectives: 

To determine the efficacy and safety of natalizumab for induction of remission in CD.

Search strategy: 

We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD Group Specialized Trials Register, and clinicaltrials.gov from inception to 10 May 2018.

Selection criteria: 

We included randomized controlled trials (RCTs) comparing natalizumab to a placebo or control therapy for induction of remission in CD.

Data collection and analysis: 

Two authors independently screened studies, extracted data and assessed methodological quality using the Cochrane risk of bias tool. The primary outcome was failure to enter clinical remission. Secondary outcomes included clinical response, mean change in Crohn's Disease Activity Index (CDAI), adverse events (AEs), withdrawal due to AEs and serious AEs. For dichotomous outcomes, we calculated the risk ratio (RR) and 95% confidence interval (95% CI). For continuous outcomes we calculated the mean difference (MD) and 95% CI. Data were pooled for meta-analysis when the interventions, patient groups and outcomes were sufficiently similar (determined by consensus). We used GRADE to assess the overall quality of the evidence.

Main results: 

A total of five RCTs (1771 participants) were included. Four studies (1692 participants) compared one, two or three infusions of natalizumab (300 mg or 3 mg/kg or 6mg/kg) to placebo. One study (79 participants) compared three infusions of natalizumab (300 mg) and infliximab (5 mg/kg) to infliximab and placebo. Four studies were rated as low risk of bias. One study was rated as unclear risk of bias for selective reporting.

One, two and three infusions of natalizumab were superior to placebo for induction of remission and clinical response. Infusions were administered at weeks zero, four and eight. After one infusion, 76% (849/1117) of natalizumab participants failed to enter remission at 4 weeks compared to 83% (411/494) of placebo participants (RR 0.91, 95% CI 0.86 to 0.96, 3 studies, GRADE high quality). At 4 weeks, the RR for clinical response was 0.78 (95% CI 0.66 to 0.92, 3 studies, 1611 participants, GRADE moderate quality). After two infusions, after 8 weeks, 66% (693/1049) of natalizumab participants failed to enter remission compared to 77% (382/494) of placebo participants (RR 0.85, 95% CI 0.76 to 0.95; 3 studies, GRADE moderate quality). At 8 weeks, the RR for clinical response was 0.73 (95% CI 0.58 to 0.91, 3 studies, 1543 participants, GRADE low quality). After three infusions, at 12 weeks, 61% (596/983) of natalizumab participants failed to enter remission compared to 73% (313/431) of placebo participants (RR 0.85, 95% CI 0.78 to 0.92, 2 studies, GRADE high quality). At 12 weeks, the RR for clinical response was 0.76 (95% CI 0.67 to 0.86, 2 studies, 1414 participants, GRADE high quality). One study (507 participants) reported on change in CADI from baseline. Natalizumab participants had a larger drop in mean CDAI scores than placebo participants at 4, 8 and 12 weeks.

The rates of AEs, withdrawals due to AEs and serious AEs were similar across groups at 4, 8 and 12 weeks. After one infusion, 74% (50/68) of natalizumab participants experienced an AE compared to 81% (51/63) of placebo participants (RR 0.91, 95% CI 0.75 to 1.09, GRADE moderate quality). Withdrawal due to an AE occurred in 1% (1/68) of natalizumab participants and 3% of placebo participants (RR 0.46, 95% CI 0.04 to 4.98, GRADE low quality). SAEs occurred in 10% (7/68) of natalizumab participants compared to 11% (7/63) of placebo participants (RR 0.93, 95% CI 0.34 to 2.49, GRADE low quality). After two infusions, 86% (57/66) of natalizumab participants experienced an AE compared to 81% (51/63) of placebo participants (RR 1.07, 95% CI 0.92 to 1.24, GRADE moderate quality). Withdrawal due to an AE occurred in 3% (2/66) natalizumab participants compared to 3% (2/63) placebo participants (RR 0.95, 95% CI 0.14 to 6.57, GRADE low quality). SAEs occurred in 9% (6/66) of natalizumab participants and 11% (7/63) of placebo participants (RR 0.82, 95% CI 0.29 to 2.30, GRADE low quality). After three infusions, 86% (848/984) of natalizumab participants experienced an AE compared to 83% (359/431) placebo participants (RR 1.03, 95% CI 0.98 to 1.08, GRADE high quality). Withdrawals due to AEs occurred in 8% (82/984) of natalizumab participants compared to 10% (45/431) of placebo participants (RR 0.86, 95% CI 0.59 to 1.26, GRADE moderate quality). SAEs occurred in 7% (65/983) of natalizumab participants and 8% (36/431) of placebo participants (RR 0.76. 95% CI 0.37 to 1.56, GRADE low quality). Adverse events included headache, nausea, nasopharyngitis, abdominal pain, fatigue, vomiting, and exacerbation of CD.

The study comparing combination therapy with natalizumab and infliximab to infliximab and placebo demonstrated similar remission rates at 10 weeks. Sixty-four per cent (33/52) of participants assigned to natalizumab and infliximab failed to achieve remission compared to 70% (19/27) assigned to placebo and infliximab (RR 0.90, 95% CI 0.65 to 1.24, GRADE moderate quality). The rates of AEs (moderate quality evidence), withdrawals due to AEs (low quality evidence) and serious AEs (low quality evidence) were similar across groups at 10 weeks. Adverse events included headache, exacerbation of CD, nausea, and nasopharyngitis.

Natalizumab is associated with the development of progressive multifocal leukoencephalopathy (PML) resulting in some patient deaths. There are currently no tests which can reliably predict those at risk of developing PML.

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