EXPERT ANALYSIS FROM WCD 2015
VANCOUVER, B.C. (FRONTLINE MEDICAL NEWS) – A persuasive case can be made for ivermectin 1% cream as the new treatment of choice for papulopustular rosacea, Dr. Leon Kircik asserted at the World Congress of Dermatology.
He cited the results of a large recent head-to-head randomized trial in which ivermectin 1% cream (Soolantra), approved last December by the Food and Drug Administration, proved superior to metronidazole 0.75% cream (Metrocream), which is the market leader and until now the topical agent most physicians have considered their first-line treatment for papulopustular rosacea.
The study, known as ATTRACT (Assessment of a Topical Treatment in Rosacea: Activity, Compliance, Tolerability), was a 962-patient, phase III, single-blind, European randomized trial. Ivermectin demonstrated faster onset of action, a greater clinical success rate, delayed time to relapse following treatment discontinuation, a lower relapse rate, and better tolerability ( Br. J. Dermatol. 2015;172:1103-10 ).
Dr. Kircik, a Louisville dermatologist in private practice, and a clinical trialist, was not involved in the ATTRACT study but was impressed that it was undertaken by Galderma, which markets both drugs.
“We don’t get many head-to-head studies in dermatology. Those are typically studies no one wants to sponsor. And most of what few head-to-head studies are done are designed as noninferiority studies. In this case, ATTRACT was designed as a superiority study. That’s a higher bar to reach,” noted Dr. Kircik, a consultant to, and member of the speakers bureau for, Galderma and other pharmaceutical companies.
ATTRACT was a two-part study. In part A, 962 patients with moderate to severe rosacea were randomized to ivermectin 1% cream once daily or metronidazole 0.75% cream b.i.d. for 16 weeks. As early as the first assessment at 3 weeks, a significant difference in favor of ivermectin was evident in terms of reduction in inflammatory lesion count. At week 16, the ivermectin group showed an 83% reduction from baseline in inflammatory lesions, significantly better than the 73.7% reduction with metronidazole. Moreover, 84.9% of the ivermectin group was rated clear or almost clear by Investigator’s Global Assessment (IGA) compared with 75.4% of the metronidazole group.
In addition, 34.9% of ivermectin-treated patients achieved an IGA of 0 by 16 weeks, meaning they were totally lesion free, compared with 21.7% of the metronidazole group. That “completely clear” status is really important psychosocially to a significant proportion of patients, said Dr. Kircik.
“How many times have you had a patient come in asking for an intralesional steroid injection for their single remaining lesion after months of topical treatment?” he asked rhetorically.
Ivermectin was better tolerated than was metronidazole. The rate of treatment-related adverse events leading to discontinuation – typically for skin irritation, redness, or itching – was 0.6% in the ivermectin group compared with 2.1% with metronidazole.
Part B of the ATTRACT study was an unusually designed 36-week extension study.
“In my mind, part B is much more important and much more relevant because rosacea is a chronic disease. It doesn’t last for just 16 weeks. Part B asks what happens after we stop therapy. This is the rare clinical trial that actually mimics real life,” Dr. Kircik said.
Despite physicians’ standard advice to continue with maintenance therapy after clearing, the reality is that most patients stop treatment once they clear, figuring they’ll resume if they relapse, he asserted. Part B of ATTRACT reflected that approach. Seven hundred fifty-seven patients who were clear/almost clear as defined by an IGA of 0/1 at the end of 16 weeks enrolled in the 36-week extension study. They surrendered their medication and returned to their physician monthly. If they had relapsed during that month, meaning they showed up with an IGA of 2 or more, they got their medication back; if they were still IGA 0/1, they did not.
The median time to relapse off treatment in the ivermectin group was 115 days, a full month later than the 85 days for the metronidazole group. Also, the relapse rate in the ivermectin group was significantly lower: 62.7% compared with 68.4% in the metronidazole group.
“The impact on both clinical practice and pharmacoeconomic practice is huge here. It makes sense to switch from metronidazole to ivermectin as first-line therapy because you know that your patients will do better and will relapse later and less,” Dr. Kircik declared.
He was a coinvestigator in the twin pivotal phase III randomized Galderma-funded trials that led to FDA approval of ivermectin for papulopustular rosacea. Although those studies have been published ( J. Drugs Dermatol. 2014;13:1380-6 ), Dr. Kircik highlighted a couple of findings he said haven’t drawn the attention they deserve. Both came from the long-term 40-week extension that followed the initial 12-week, double-blind stage.
One of these underappreciated findings concerned safety. The rate of treatment-related dermatologic adverse events during the double-blind first 3 months of the study was 2.5% in the ivermectin group compared with 6.3% in vehicle-treated controls.
“That’s pretty impressive. That the active treatment arm of the study had less treatment-related dermatologic adverse events than placebo has never been seen before in any other topical study. It tells you something: The assumption here is that the potent inherent anti-inflammatory activity of ivermectin is overwhelming,” the dermatologist said.
The other particularly noteworthy finding came in the long-term, 40-week extension study that followed the initial 12-week, double-blind stage. What was impressive here was the way the proportion of patients who were IGA clear/almost clear rose steadily throughout, he noted. At the end of the initial 3-month phase of the two studies, 38%-40% of ivermectin-treated patients were clear/almost clear. At 12 months, nearly 70% were.
“In most studies, efficacy sort of plateaus at some point. Here it keeps going up through 12 months. So if somebody comes to your office after 3 months using ivermectin and says, ‘Eh, I’m okay, but I’m not clear or almost clear,’ there’s no reason to switch to another medication, because if they continue you know there’s a high chance they will become clear/almost clear,” Dr. Kircik said.
On the other hand, study participants who were still IGA ‘severe’ after 3 months remained severe after 12 months on the drug. So the message here is if a patient still has severe rosacea after 3 months on ivermectin it’s time to change drugs, he added.