Study Population

Figure 1. Figure 1. Study Sites in Fiji. The figure shows the locations of the three island communities that were included in the study. The yellow pin indicates the site of the standard-care group, the red pin the sites of the permethrin group, and the blue pin the sites of the ivermectin group.

We conducted SHIFT in Fiji from September 2012 through September 2013. After consultation with health authorities, we identified three island communities as study groups (Figure 1), on the basis of relative isolation, population size (small enough to be manageable but large enough to provide study power), and cultural similarities.25 One community occupies a single island, the second occupies two neighboring islands, and the third occupies three islands. Each community has one nurse-staffed clinic.

Study Procedures

The three island communities were randomly assigned, through the drawing of lots, to one of three different interventions for scabies control: standard care involving the administration of permethrin to affected persons and their contacts (standard-care group), mass administration of permethrin (permethrin group), or mass administration of ivermectin (ivermectin group). The study procedures were the same across communities and involved visits at baseline and at 12 months for all residents and a visit at 3 months for a random sample of 20% of each group. Each visit took place during a scheduled week.

All residents were eligible to participate. The residents were identified with the use of a 2012 population list provided by the study nurse; they were invited by letter to participate and then visited by the local district nurse if they were present in the community. When the study team arrived for the baseline visit, all residents who were present at the time were invited to enroll in the study. Those who provided consent to participate gave basic sociodemographic information and a brief medical history. When the study team returned for the 12-month visit, all residents who were present in the community were again approached by the study team. The residents who had enrolled in the study at baseline were reexamined and asked about any absences from the community since enrollment. The residents who were present but had not enrolled in the study at baseline were invited to enroll. At the baseline, 3-month, and 12-month visits, a skin examination of consenting participants was performed by the study nurse.

For the groups that underwent mass drug administration, data on adverse events were obtained through direct questioning of participants 7 to 14 days after the drug was administered. During the periods before and after the drug was administered, we used routinely collected health service data to record the number of patients who presented to community clinics with any skin condition and the number of clinic referrals to major health centers.

In accordance with the Integrated Management of Childhood Illness (IMCI) guidelines,13 scabies was defined as the presence of pruritic inflammatory papules with a typical anatomical distribution (e.g., on the webs of the fingers, hands, wrists, or ankles).26 Examination of the breasts and genitals was performed only when requested by participants and in a separate, private space. Determination of the severity of scabies was based on the number of lesions, in categories of mild (≤10), moderate (11 to 49), and severe (≥50). Infected scabies was defined as scabies plus the presence of pus-filled or crusted papules. If crusted (“Norwegian”) scabies was suspected, a scraping of the skin was obtained for microscopic examination for mites, and a photograph was sent to the team’s clinical advisors (the second and last authors). Impetigo was defined as the presence of a papular, pustular, or ulcerative lesion surrounded by erythema.

Interventions

Standard-Care Group

Participants in the standard-care group who had scabies at baseline were referred to the local clinic for guideline-recommended treatment with one dose of topical permethrin cream, with a second dose provided after 14 days if symptoms persisted. The guidelines also recommended a single dose of permethrin for the patient’s contacts.13 We provided permethrin cream to the local clinics to ensure that the supply would be adequate.

Permethrin Group

All participants in the permethrin group were offered one dose of topical permethrin cream followed by a second dose 7 to 14 days later if scabies had been observed at baseline. For younger children, parents were asked to apply the cream under the direct observation of study staff. Older children and adults were encouraged to apply the cream in the clinic but could apply it at home. Participants were asked to apply the cream from neck to toes and to leave it on for 8 to 24 hours (or for 4 hours in the case of participants <2 months of age). In infants, the cream was also applied to the scalp.

Ivermectin Group

All participants in the ivermectin group were offered one dose of oral ivermectin (200 μg per kilogram of body weight), which was taken under the direct observation of study staff. Ivermectin was replaced with topical permethrin cream in the following participants: children who weighed less than 15 kg, women who were pregnant or breast-feeding,27 persons with neurologic disease, and persons taking medications that are metabolized by the cytochrome P-450 pathway, including warfarin and some anticonvulsant agents. For participants who had scabies at baseline, a second dose of the medication that had been provided at baseline was distributed by study staff 7 to 14 days after the initial dose was administered.

Treatment for crusted scabies consisted of the administration of two doses of ivermectin 1 week apart and the administration of permethrin cream twice a week for 1 month, with follow-up at 1, 2, 3, and 12 months.28 All participants with crusted or purulent impetigo lesions were referred to clinics in order to receive antibiotic agents, in accordance with Fiji IMCI guidelines.13 Participants in all groups could present to their community clinic at any time and receive standard care with permethrin.

Study Outcomes

The primary outcome was the change in the prevalence of scabies and of impetigo from baseline to 12 months. Prevalence was calculated at baseline and 12 months with the use of data from the entire sample of participants at each time point.

Safety outcomes were based on adverse events, which were classified as serious if they were immediately life threatening, led to hospitalization, or resulted in persistent or substantial disability or death. We established an independent safety committee that consisted of academic physicians, including a Fijian representative. Adverse events were reviewed by the local study doctor, with subsequent referral to the safety committee.

Study Oversight

The trial was approved by the Fijian National Research Ethics Committee and the Royal Children’s Hospital Human Research Ethics Committee. There was a delay in meeting registration deadlines for the study because the investigators initially were of the understanding that community-intervention studies of this kind, as opposed to individually randomized trials, do not require registration. Written informed consent was obtained from all participants. Merck Sharp and Dohme (Australia) provided the ivermectin but had no other role in the study. The Fiji Ministry of Health and Medical Services provided paid personnel. The study was designed by the authors. All the authors vouch for the integrity and completeness of the data and analyses and for the fidelity of the study to the protocol (available with the full text of this article at NEJM.org).

Statistical Analysis

We calculated the change in prevalence of scabies and of impetigo in each of the three study groups. We calculated both the absolute reduction (the difference between the prevalence at 12 months and the prevalence at baseline) and the relative reduction (the ratio of the prevalence at 12 months to the prevalence at baseline). Confidence intervals for the reductions were calculated with the use of the variance of the binomial distribution.29 To compare the study groups, we calculated the ratio of the prevalence at 12 months to the prevalence at baseline in each group and then tested the null hypothesis that these ratios were equal.30 All tests were two-sided. Among participants who were examined at both baseline and 12 months, we calculated the rates of the appearance of scabies (the proportion of persons without scabies at baseline who had scabies at 12 months) and the disappearance of scabies (the proportion of persons with scabies at baseline who did not have scabies at 12 months). Safety outcomes were summarized as proportions of participants in each group who had adverse events.

Study power and sample size were based on estimates from previous research conducted in Fiji. We estimated that the prevalence of scabies would be 23% at baseline and that the prevalence would fall to 5% in the groups that underwent mass drug administration6-8 and to 10% in the standard-care group.16,31 Assuming an 80% response rate in each group and a 20% loss to follow-up at 12 months, we estimated that a sample of 1920 participants would give the study more than 90% power to detect the estimated differences at a two-sided significance level of 0.05.