Maintenance Tacrolimus 0.03% Ointment Reduces Major Flares in Children With Atopic Dermatitis

Deborah Brauser

March 19, 2010

March 19, 2010 (Miami Beach, Florida) — Tacrolimus 0.03% ointment applied twice weekly is effective and safe for children with moderate to severe atopic dermatitis (AD), according to a post hoc analysis of a phase 3 European study presented here at the American Academy of Dermatology 68th Annual Meeting.

In fact, results showed that the patients treated with the tacrolimus maintenance regimen over 12 months had significantly fewer major flares than those treated with standard therapy, applied in reaction to disease flares. In addition, maintenance therapy was associated with a prolonged time to first flare.

"We think these are really exciting data because long-term treatment for these patients is quite challenging," said investigational team member Shevani Naidoo, PharmD, from Astellas Pharma Europe in Middlesex, United Kingdom, during her presentation here.

"Offering patients up to a year of control of their disease, where they're flare-free longer, and improving their AD symptoms shows that this could be a good option for physicians," added Dr. Naidoo.

Evaluating Data From CONTROL

In this analysis, the investigators examined data from 153 of the children (aged 2 to 15 years) from the Pediatric CONTROL trial after their moderate to severe AD was stabilized on twice-daily treatment with the tacrolimus ointment for up to 6 weeks. Of the entire CONTROL population, this was the subgroup with the most severe disease.

These patients were then randomized to apply either tacrolimus 0.03% ointment twice weekly on areas of usual flare (maintenance therapy, n = 78), or to a standard reactive tacrolimus regimen (standard therapy, n = 75).

"This was not a placebo-controlled trial," Dr. Naidoo pointed out. She also noted that her company was able to gain a license in Europe to evaluate the twice-weekly usage of 0.03% ointment in children for their studies.

Disease flares were treated with the ointment twice daily for 1 to 6 weeks until an Investigator's Global Assessment (IGA) of 2 or less was achieved. Once the flare was controlled, the patients returned to the randomized study.

The primary end point was the number of major flares occurring during the study period, defined as "exacerbations requiring tacrolimus ointment treatment for more than 7 days to treat an IGA of 3 to 5."

Fewer Flares With Maintenance Therapy

At the end of the study, the children in the maintenance group experienced significantly fewer major flares than those in the standard group (P < .001), with 46.2% experiencing no major flares at all (compared with 21.3% of those in the standard group).

The maintenance group also had fewer exacerbation treatment days than the standard group (42.3 days vs 68.9 days), and a significantly longer time to first major flare (P < .001).

"Interestingly, when we looked at the ointment usage by the patients, we noted that it did not increase with the twice-weekly application and was similar in both arms" (mean use, 1.29 vs 1.42 g/day for the maintenance and standard groups, respectively), reported Dr. Naidoo.

"Therefore, we were able to gain a significantly better response in patients with an equivalent amount of ointment," she added.

Both groups showed similar overall tolerability to the tacrolimus ointment. "Adverse events thought to be treatment related were seen in 33 patients in the twice-weekly group, compared with 27 patients in the flare-only group," reported Dr. Naidoo.

The most common adverse events were application-site reactions, and there were 2 cases of serious adverse events reported: 1 of eczema herpeticum and 1 of infected eczema.

When asked during the Q&A session if the restrictions in Europe are similar to those in the United States regarding duration of use for this agent, Dr. Naidoo said that their patients only used it for a year because that was the length of the trial upon which their license was based.

"I know that physicians here tend to use [tacrolimus], [discontinue treatment], then reassess the patient after 12 months [to see] if their skin is responding to treatment, and then continue [treatment] after assessment if everything is alright," she explained. "In Europe, there isn't a specific restriction that patients have to come off treatment for a certain period of time, just that the skin needs to be reassessed."

However, "because of the natural progression of AD, there's a likelihood that children may grow out of the disease. So there is a trend to actually suspend treatment for a period of time to see whether or not the eczema is still active," said Dr. Naidoo.

When asked if she had any tips to minimize the stinging and burning that often occurs after applying the ointment, Dr. Naidoo said that with ongoing treatment, as the lesions heal, "patients don't experience the burning as much."

"It's only on the acute lesions that they have the burning and irritation," she reported. "Our physicians will sometimes give oral analgesics if the flare's really bad, but that's an off-label use."

Convincing, but Doesn't Address Black Box Warning

"This study was an interesting attempt to try to decrease disease flare in patients with [AD]. From a clinical point of view, there is a strong need to find ways to prevent relapses and this, I think, is a good one," said session moderator Youwen Zhou, MD, PhD, associate professor in the Department of Dermatology and Skin Science at the University of British Columbia in Vancouver.

"There are always different philosophies as to how to handle potential flares, and I think this study demonstrated the feasibility and effectiveness of doing regular twice-per-week treatments. They've shown some interesting data that support that this potentially could be a viable approach for decreasing flares," said Dr. Zhou, who was not involved with this study. "The data are quite convincing."

However, "I don't think it addresses the issue of the [US Food and Drug Administration]'s black box warning for this treatment and the malignancy concern, which is always a practical concern, whether it is real or perceived," he cautioned. "Of course, one can argue that the twice-weekly application over the long term may actually result in limited or less cumulative use of medication because there would be less need to use it for an extended period of time."

"Overall, I would say this is an option worth thinking about," concluded Dr. Zhou.

This study was supported by Astellas Pharma Europe, which employs Dr. Naidoo. Dr. Zhou reports participating in other Astellas-sponsored studies, although he had no involvement with this one.

American Academy of Dermatology (AAD) 68th Annual Meeting: Abstract P503. Presented March 8, 2010.

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