Adalimumab for children with Crohn’s disease

While adalimumab has been used in children with refractory Crohn’s disease, there has not been a lot of available data.  However, this situation has improved with the publication of the “IMAgINE 1” study (Hyams JS et al, Gastroenterology 2012; 143: 365-74).

This study enrolled 192 pediatric (6-17 yr-old) patients with moderate to severe Crohn’s disease; patients had PCDAI >30 and had failed conventional therapy with the exception of infliximab.  Approximately 45% in both groups had received prior treatment with infliximab.  The study started as an open-label induction followed by double-blind randomization into either a high-dose or low-dose maintenance phase.

Dosing:  For open label, patients >40 kg received 160 mg at week 0 and 80 mg at week 2.; patients <40 kg, received 80 mg at week 0 and 40 mg at week 2.

For maintenance, high dose was considered 40 mg every other week (eow) if >40 kg, and 20 mg eow if <40 kg.  Low dose was 20 mg and 10 mg respectively based on weight.

Results: 152 of 188 patients completed 26 week study period; 4 patients did not complete induction period.  At week 26, 63 patients (33.5%) were in clinical remission.  The high-dose remission response was 38.7% which was not statistically different from the 28.4% response in the low-dose group.

At week 52, there was a statistically improved response rate in the high-dose group 41.9% compared with low-dose group 28.4%; at the week 52 point, the remission rates were 33.3% compared with 23.2% respectively (p=0.1).  Among patients who were at least 13, it is noted that the overall CDAI clinical remission rate was 51% (week 26) and 36% (week 52) which are comparable to adult data from CHARM study.

Based on previous infliximab: Patients who had prior infliximab did not respond as favorably as infliximab-naive patients.  In the high dose group, the clinical remission at week 26 was 56.9% for infliximab-naive group compared to 16.7% for infliximab-experienced.  Similarly, the infliximab-naive response was higher, 68.6% compared with 47.6% for the infliximab-experienced.

Safety: “No new safety signals were detected.” Yet, 101 of 192 patients had adverse events during open label period, including 2 serious infections (which resolved & patients completed study).  Eight serious infections were noted during double-blind period.  Other safety problems included hepatic-related events in 9 of 188 patients, injection site reactions in 19 patients, hematologic adverse events in 8 patients, and 8 allergic reactions.  There were no reports of malignancy, congestive heart failure, lupus-like syndrome or demyelinating disease.

In both the high-dose and low-dose group, switching to weekly therapy instead of eow was allowed and commonly occurred: 48/95 in low-dose & 35/93 in high-dose.

Reasons for discontinuation: In both groups, drug discontinuation was frequent.  In the low-dose group, 37 patients stopped therapy.  In 18, this was due to lack of efficacy.  The other reasons included adverse effects in 10, protocol violation in 4, withdrew consent in 4, and lost to followup in 1.  In the high-dose group, 27  stopped therapy.  In 11, this was due to lack of efficacy; 12 had adverse effects, 2 withdrew consent, and 1 had protocol violation.

Another recent article (Inflamm Bowel Dis 2012; 18: 685-90) indicates that the annual risk of loss of response to adalimumab was 18% per year of followup.  This study involved 380 CD patients with an average age of 38 years.  This study also showed that there was a significant difference between patients naive to anti-TNF therapy and those who had prior anti-TNF therapy:  8% loss of response per year of followup compared with 22% respectively.

Related blog entries:

TNF-α antagonists and infections

CHOOSE TNF TRIAL

Disease modifying treatment in IBD

Only one chance to make first impression

TNF antagonists and UC

Adalimumab references:

  • -Gut 2011:  Gut doi:10.1136/gut.2010.221127. Use in induction of remission in UC. Reinisch W, et al. Adalimumab for induction of clinical remission in … – Gut – BMJ
  • -Aliment Pharmacol Ther 2010; 32: 1228-39. CHOICE trial. adalimumab effective in pts failing prior IFX.
  • -Gastroenterol 2009; 137: 1628. n=168.  71% & 67% of pts responded by weeks 4 & 12.  61% demonstrated sustained benefit. (in IFX failure pts). Of 156 pts, 65% needed to step up to 40mg weekly and 60 eventually stopped adalimumab due to loss of response.  Lower trough levels associated with loss of effectiveness & often with antibodies to adalimumab (present in 9.2% of pts).
  • -IBD 2011; 17: 2512.  n=50.  62% of pts develop skin reactions: eczema, acne-like dermatitis, psoriasis-like (6 of 50).  Adalimumab d/c’d in 22%.  Message -see dermatologist
  • -Lofberg et al. Am J Gastro 2008; 103: S418 (abstract 1069) Care study. -n=945. Humira at week 20 -remissions in 52% of pts naive to biologics, in 46% who prev responded to IFX & became intolerant, in 40% who prev responded to IFX and lost response, and 36% of pts with primary non-response to IFX.
  • -IBD 2008; 14: S1 Abrstarct 0002. Humira in TNF-naive patients with Crohn’s disease. Decreases hospitalizations. (12 month: 12.7% vs 20.3% in placebo group) Adult dosing: Induction 160mg, then 80mg in 2 weeks, then 40mg every 2 weeks.
  • -IBD 2008; 14: 1683. Response to adalimumab in 10 children.
  • -Gastro 2008; 135: 1493. n=778. mod-to severe Crohn had less hospitalizations (decreased ~60%) and surgery if Rx’d w Humira. 40mg eo week or qweek post 80/40 induction
  • -NEJM 2008; 359: 810. Use in pediatric JRA -helpful.
  • -JPGN 2008; 47: 19. n=15 pediatric patients. Complete or partial response in 64%.
  • -Gastro 2007; 132: 52. CHARM Trial. n=778. 40mg weekly c 47% response at week 26 (17% placebo) & 41% @ week 52 (12% placebo); works nearly as well in pts c prev inliximab as naive pts. Rapid onset ~c/in 2 weeks
  • -Clin Gastro & Hep 2006; 4: 1199-1213. Excellent review. Suggested dosing: 20mg every other week if 20-25kg, 25mg every other week if 25-30kg, 30mg every other week if 30-40kg, 35mg every other week if 40-55kg,  40mg every other week if >55kg, and increase to weekly dosing if needed
  • -JPGN 2008; 46: 1208, 226. pediatric case report and review of CHARM
  • -Gastro 2006; 130: 323-333. CLASSIC-I Trial, n=299. 36% 4-week response to 160mg/80mg week 0/subsequent week 2 (vs. 12% of placebo) All pts naive to anti-TNF Rx.

Adalimumab Injection Pain

  • Suggestions from GI bulletin board. 1)you let the Humira Pen sit out for about 30 minutes prior to administering the medication, so that it appears clear and not foggy, that it greatly reduces pain at the site. 2) the pain disappeared after adding bicarbonate to the Humira. By trial and error, our nurse found that 0.15cc of bicarbonate is the minimum amount that yields a good effect.
  • -Lidocaine with adalimumab. Abstract reference: AF Ayala, Rosanne S.Groh, Brandt P.Robbins, Lisa M.Scalzi, Lizabeth Bingham, C. April TI The addition of injectable lidocaine to adalimumab results in decreased injection site pain and increased acceptance of therapy. 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals. CY OCT 24-29, 2008 CL San Francisco, CA. They used 0.2 ml 1% lidocaine into prefilled adalimumab syringe. We’ve tried this with a few patients and it seems to work well.
  • -Pt developed a “shot blocker” that is a bristle brush with a central hole for the syringe. The brush diffuses the pain from the Humira injection. Click the link below for a youtube video he created.
  • -http://www.youtube.com/watch?v=nfL95YRlTjY

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