Effectiveness of Oral Ivermectin and Malathion Lotion for Difficult-to-Treat Head LiceIvermectin and Malathion Lotion and Head Lice

Chosidow O, Giraudeau B, Cottrell J, et al

N Engl J Med. 2010;362(10):896-905

Question: In patients with difficult-to-treat head lice, is oral ivermectin more effective than topical malathion lotion?

Design: Multicenter, cluster-randomized, double-blind, double-dummy, active-controlled trial.

Setting: Community-recruited patients from 7 study centers (4 in the United Kingdom and 1 each in Ireland, France, and Israel) by means of advertising or outreach by nurses.

Patients: People older than 2 years, with weight greater than 15 kg and with difficult-to-treat head lice infestation, defined as the persistence of live lice 2 to 6 weeks after topical application of a pyrethroid-based or malathion insecticide.

Intervention: Cluster-randomization, with households as clusters. Randomization was stratified according to the number of persons with infestation within a household. In randomly assigned households (1:1 ratio), all persons from the same household received either ivermectin, 400 μg/kg, or 0.5% malathion lotion on days 1 and 8. Patients who were still infested with head lice on day 15 entered an extension stage in which the randomized treatment was switched to the alternative treatment, used in the same dose as in the primary stage.

Main Outcome Measures: The primary end point was the absence of live head lice on day 15. Secondary outcomes were the absence of head lice on days 2 and 8, as well as on days 22 and 29 for patients who entered the extension stage. Patients' treatment preferences for oral tablets or lotion was also recorded.

Results: Of the 1209 patients assessed for eligibility, 812 in 376 households (clusters) were randomized as follows: 398 patients in 185 households to receive ivermectin and 414 patients in 191 households to receive malathion. In the intention-to-treat population, 95.2% of patients receiving ivermectin and 85.0% of those receiving malathion were lice-free on day 15 (absolute difference, 10.2 percentage points; 95% confidence interval [CI], 4.6-15.7; P < .001; number needed to treat [NNT] with ivermectin 9.8; 95% CI, 6.4-21.7). In the per-protocol population, 97.1% and 89.8% of patients receiving ivermectin and malathion, respectively, were lice-free on day 15 (absolute difference, 7.3 percentage points; 95% CI, 2.8-11.8; P < .001; NNT with ivermectin, 13.9; 95% CI, 8.5-35.7). There were no significant differences in the frequency of adverse events in the 2 treatment groups.

Authors' Conclusions: For difficult-to-treat head-lice infestations, oral ivermectin, given twice at a 7-day interval, had superior efficacy compared with topical 0.5% malathion lotion, a finding that suggests that it could be an alternative treatment.

The quality of this trial was high. It used cluster randomization, with households as clusters, a design that is more appropriate than individual randomization in this setting, because it prevents contamination between the 2 treatment groups and increases the power of the study.

Once an eligible patient was identified and recruited as an index patient, his or her household was randomly assigned to a treatment group, so that all the other members in that household received the same treatment. Randomization was stratified according to the number of infested persons within a household (≤3 or ≥4).

The method of generation of the randomization sequence (permuted blocks of 4) was adequate. Allocation concealment was ensured by using a randomization schedule generated by a third party, delivered to the contractor who provided the treatment kits and not revealed to the investigators until after the database was finalized.

Patients in the 2 treatment groups were similar at baseline with respect to age, sex, weight, race/ethnicity, hair density, hair length, and intensity of infestation (defined as number of live lice on visual inspection)—variables that might have influenced the outcome. Studied households in the 2 groups were similar with respect to household size, number of members and infested members per household, and severity of infestation. Patients and outcome assessors were adequately masked to treatment. The a priori sample size calculation is reported and an appropriate intention-to-treat analysis using the last observation carried forward approach and per-protocol analysis were performed.

This was a 2-step trial, with the first objective of establishing noninferiority and the second objective of establishing superiority. In the first step, the noninferiority hypothesis is that the new treatment (ivermectin) is noninferior to the active treatment (malathion) by a prespecified noninferiority margin. If after this step inferiority can be rejected, the superiority hypothesis is tested. If the superiority test is positive, one can conclude superiority of ivermectin treatment over malathion; otherwise, noninferiority without superiority is concluded.¹ This type of trial design implies particular planning, analysis, and reporting: the test of noninferiority has to be prospectively specified in the protocol, the noninferiority margin has to be rigorously prespecified and taken into account in the formulation of the sample size calculation, both intent-to-treat and per-protocol analyses should be performed, and results should be presented as CIs around the observed differences in responses.² All those details were adequately performed and reported.

The main outcome—the absence of live head lice—is clinically relevant and the timing of its assessment (day 15) is clinically important, because the study drugs have little ovocidal activity and nits can continue to hatch until 11 days after the first administration.

This outcome was measured by trained staff using a standardized procedure for fine-toothed combing. Confounding factors such as adherence to treatment and correct application of a sufficient amount of malathion lotion were controlled for, as both ivermectin and malathion were administered on site by the investigators.

In the intention-to-treat population, 95.2% of patients receiving ivermectin and 85.0% of those receiving malathion were lice-free on day 15 (absolute difference, 10.2 percentage points; 95% CI, 4.6-15.7; P < .001; NNT with ivermectin, 9.8; 95% CI, 6.4-21.7). In the per-protocol population, 97.1% and 89.8% of patients receiving ivermectin and malathion, respectively, were lice-free on day 15 (absolute difference, 7.3 percentage points; 95% CI, 2.8-11.8; P < .001; NNT with ivermectin 13.9; 95% CI, 8.5-35.7). These results indicate that in both the intention-to-treat and per-protocol populations, ivermectin was superior to malathion.

The secondary outcomes were the absence of live head lice on days 2 and 8 as well as on days 22 and 29 (for those patients who entered the extension stage). The superiority of ivermectin was seen at both days 2 and day 8 with an absolute difference of 10.1 (95% CI, 4.3-15.8) and 29.8 (95% CI, 22.4-37.3) percentage points, respectively. This effect remained stable at day 29, favoring ivermectin with an absolute difference of 8.3 percentage points (95% CI, 3.1-13.5). In a real clinical setting it might be possible for ivermectin to be even more effective that malathion, as it is known that in general adherence to topical treatments is lower than adherence to systemic treatments.³ In terms of patients' reported outcome measures, 78.3% of patients preferred tablets, 13.0% preferred the lotion, and 8.7% had no preference.

The frequency of adverse events was similar in both groups. The use of oral ivermectin comes with a caveat: the risk of anaphylaxis. However, anaphylactic reactions have been reported only when ivermectin was used to treat onchocerciasis and other internal parasitoses⁴ but would not be expected when treating ectoparasites.⁵

The main limitations of this study, as acknowledged by its authors, are the self-reporting of previous treatment failure and the lack of parasitologic testing. The results of this trial are clinically useful, being both feasible and generalizable. Because the study was performed in a community setting in 4 countries and involved a large number of participants, one could infer that similar results could be achieved in the general population.

Although topical insecticides (pyrethrins, pyretrhoids, malathion) have been considered to be the gold standard of treatment, head lice resistance to these drugs, especially to pyrethrins, became increasingly common in the early 1990s and prompted health authorities to reintroduce malathion into the US market. A few randomized trials^{6 - 7} evaluated methods that attempt to suffocate the lice. However, major and minor flaws of those studies limit our ability to draw firm conclusions about the efficacy of such methods. Under these circumstances, gathering good evidence about an effective treatment for resistant head lice is of utmost importance, and the authors of this study should be applauded for choosing to study 2 drugs for this indication in a randomized controlled trial (RCT).

This is the first RCT evaluating the efficacy of ivermectin orally vs malathion lotion for difficult-to-treat head lice. Its findings are important because pyrethroid pediculocide resistance of head lice is increasingly common, with studies estimating that the frequency of the permethrin-resistant kdr allele can be as high as 97.1% in some populations.⁸ Roughly, 95% and 85% of patients who failed previous insecticide treatment for head lice were lice-free at day 15 when treated with ivermectin and malathion, respectively. The effect lasted, with 96% and 88% of patients treated with ivermectin and malathion, respectively, being lice-free at day 29. There were no clinically significant adverse events in the 2 groups. To date, only a few cases of in vivo⁹ and in vitro¹⁰ ivermectin resistance have been reported, despite its being used for mass treatment for scabies and pediculosis. Data from this study suggest that oral ivermectin can be used as an effective alternative treatment for difficult-to-treat head lice.

Correspondence: Catalin Mihai Popescu, MD, PhD, Department of Dermatology, Carol Davila University of Medicine and Pharmacy, Colentina Hospital, Sos Stefan cel Mare 19-21, Bucharest 020125, Romania (catalin.m.popescu@gmail.com).

Accepted for Publication: September 5, 2010.

Author Contributions: Both authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of data analysis. Analysis and interpretation of data: C. M. Popescu and R. Popescu. Drafting of the manuscript: C. M. Popescu. Critical revision of the manuscript for important intellectual content: C. M. Popescu and R. Popescu. Statistical analysis: C. M. Popescu.

Financial Disclosure: Dr C. M. Popescu has received travel grants and honoraria from Astellas and travel grants from Schering AG, Sanofi-Aventis, Janssen-Cilag, Servier Pharma, Hoffman La Roche, and L’Oréal. Dr R. Popescu has received travel grants from Astellas, Sanofi-Aventis, and L’Oréal.