Community control strategies for scabies: A cluster randomised noninferiority trial.

BACKGROUND: Scabies is a neglected tropical disease hyperendemic to many low- and middle-income countries. Scabies can be successfully controlled using mass drug administration (MDA) using 2 doses of ivermectin-based treatment. If effective, a strategy of 1-dose ivermectin-based MDA would have substantial advantages for implementing MDA for scabies at large scale. METHODS AND
FINDINGS: We did a cluster randomised, noninferiority, open-label, 3-group unblinded study comparing the effectiveness of control strategies on community prevalence of scabies at 12 months. All residents from 35 villages on 2 Fijian islands were eligible to participate. Villages were randomised 1:1:1 to 2-dose ivermectin-based MDA (IVM-2), 1-dose ivermectin-based MDA (IVM-1), or screen and treat with topical permethrin 5% for individuals with scabies and their household contacts (SAT). All groups also received diethylcarbamazine and albendazole for lymphatic filariasis control. For IVM-2 and IVM-1, oral ivermectin was dosed at 200 μg/kg and when contraindicated substituted with permethrin. We designated a noninferiority margin of 5%. We enrolled 3,812 participants at baseline (July to November 2017) from the 35 villages with median village size of 108 (range 18 to 298). Age and sex of participants were representative of the population with 51.6% male and median age of 25 years (interquartile range 10 to 47). We enrolled 3,898 at 12 months (July to November 2018). At baseline, scabies prevalence was similar in all groups: IVM-2: 11.7% (95% confidence interval (CI) 8.5 to 16.0); IVM-1: 15.2% (95% CI 9.4 to 23.8); SAT: 13.6% (95% CI 7.9 to 22.4). At 12 months, scabies decreased substantially in all groups: IVM-2: 1.3% (95% CI 0.6 to 2.5); IVM-1: 2.7% (95% CI 1.1 to 6.5); SAT: 1.1% (95% CI 0.6 to 2.0). The risk difference in scabies prevalence at 12 months between the IVM-1 and IVM-2 groups was 1.2% (95% CI -0.2 to 2.7, p = 0.10). Limitations of the study included the method of scabies diagnosis by nonexperts, a lower baseline prevalence than anticipated, and the addition of diethylcarbamazine and albendazole to scabies treatment.
CONCLUSIONS: All 3 strategies substantially reduced prevalence. One-dose was noninferior to 2-dose ivermectin-based MDA, as was a screen and treat approach, for community control of scabies. Further trials comparing these approaches in varied settings are warranted to inform global scabies control strategies. TRIAL REGISTRATION: Clinitrials.gov NCT03177993 and ANZCTR N12617000738325.

Introduction

Scabies is a pruritic, papular rash caused by the mite Sarcoptes scabiei var. hominis. The infestation is transmitted by human-to-human skin contact and therefore is more common in crowded dwellings, which arise most often in resource-limited areas [1]. Itching and associated scratching due to scabies can lead to considerable morbidity ranging from sleep disturbance through to secondary bacterial infections and their sequelae [1]. For these reasons, and because of emerging evidence of successful control interventions, scabies was included on the World Health Organization’s (WHO) list of neglected tropical diseases in 2017 [2]. Multiple studies have documented a high burden of scabies in Pacific island countries, including in Fiji [3-5].

For several key neglected tropical diseases, mass drug administration (MDA) is the primary control strategy in endemic settings. For scabies, the Skin Health Intervention Fiji Trial (SHIFT) showed that 2-dose ivermectin-based MDA (with permethrin treatment for individuals where ivermectin was contraindicated) was a highly effective intervention for scabies and was superior to MDA using only permethrin [5]. After 1 round of 2-dose ivermectin-based MDA, scabies prevalence reduced from 32.1% at baseline to 1.9% at 12 months and was sustained out to 24 months [6]. This finding was replicated on a larger scale in the Solomon islands, in the Azithromycin Ivermectin MDA (AIM) trial, in which ivermectin-based MDA was coadministered with azithromycin for trachoma in a study population of over 26,000 [7,8].

Ivermectin is active against the adult scabies mite but not its eggs [9], and, therefore, 2 doses of ivermectin 7 to 14 days apart are recommended for treatment of individuals with scabies [10]. The WHO Informal Consultation on a Framework for Scabies Control recommends a 2-dose ivermectin-based MDA for community control based on evidence from the SHIFT and AIM trials [5,7,11]. However, the requirement for 2 doses greatly increases programme costs and duration, participation burden for the community, and is difficult to integrate with other neglected tropical disease MDA programmes, which are all 1-dose.

A retrospective study in Zanzibar found a substantial reduction in scabies presentations to clinics following single, annual rounds of ivermectin (with albendazole) for lymphatic filariasis [12]. However, there has been no previous study specifically comparing 1-dose versus 2-dose ivermectin-based MDA for scabies. This research gap was highlighted as a priority in the WHO consultation on scabies control [11].

The Fiji Integrated Therapy (FIT) study was an open-label, cluster randomised trial, implemented as one component of a 5-country trial comparing the safety and efficacy of MDA for lymphatic filariasis using diethylcarbamazine and albendazole, adding ivermectin to the combination [13,14]. For the Fiji component, we adapted the international study design for filariasis to nest a trial for scabies control.

Methods

Study design

This was a 3-group, open-label, cluster randomised, noninferiority trial comparing the effectiveness of 3 community interventions for scabies control (S1 Fig), with the village as unit of randomisation or cluster, nested within a safety and efficacy study for control of lymphatic filariasis, as described previously [13,14]. Participants in the first group (IVM-2) were offered ivermectin-based treatment plus diethylcarbamazine and albendazole followed by a second dose of ivermectin-based treatment 8 days later. Participants in the second group (IVM-1) were offered the same treatment as IVM-2, without the second dose of ivermectin-based treatment. In the third group (screen and treat, or SAT), participants were offered diethylcarbamazine and albendazole and screened for scabies by clinical examination. Those with scabies, and their household contacts, were provided 1 dose of topical permethrin, the current standard of care for case treatment in Fiji [15].

The study protocol (S1 Protocol) was approved by relevant Fijian governmental departments, the Fiji National Health Research and Ethics Review Committee (reference 2016.81.MC), and the Royal Children’s Hospital Melbourne Human Research Ethics Committee (reference 36205).

Participants

The trial was conducted in 2017 and 2018 in 35 villages on Rotuma and Gau, 2 remote islands within the Eastern Division of Fiji (Fig 1). MDA using ivermectin or permethrin has not previously been implemented on these islands. All residents were eligible to participate and approached through their local village administrative structures. Community engagement was undertaken in each village, including an interactive presentation explaining the study, facilitated by village leaders and local health staff. Key points included treatment allocation, individual consent, screening for infections, exclusion criteria for treatment, the need for directly observed treatment for oral medication, and study visit schedules. All residents were invited to the community central meeting place to participate. Written consent was required from all participants aged over 12 years, and written parental/guardian consent for those aged less than 18 years.

Fig 1

Map of study sites, village locations, and treatment allocation.

IVM-1, one-dose ivermectin-based MDA; IVM-2, two-dose ivermectin-based MDA; MDA, mass drug administration; SAT, screen and treat with 1-dose permethrin to index cases of scabies and their household contacts. Made with reference to Natural Earth (naturalearthdata.com) and The Pacific Community (SPC) Statistics for Development Division (pacificdata.org/data/dataset/2017_fji_phc_admin_boundaries).

A second enrolment of residents took place 12 months after MDA. In order to measure the prevalence of scabies and impetigo in the entire community, residents not present at baseline were eligible.

Randomisation and masking

All 17 villages on Rotuma and 18 villages on Gau agreed to participate prior to treatment allocation. Randomisation of the 35 villages (clusters) was generated and allocated by an independent statistician using Stata software in a 1:1:1 ratio stratified by island. Stratification by island was implemented by randomising villages on an island equally to the treatment arms and separately for each island. No villages dropped out after allocation. There was no allocation concealment and no blinding of participants or the study team involved in recruitment, clinical examination, treatment assessment, or analysis.

Procedures

At the baseline and 12-month visits, all participants underwent skin examination by one of 2 trained nurses. Both nurses were recruited from the Dermatology Hospital in Fiji and completed half-day, classroom-based training in the clinical diagnosis of scabies. Supervision was provided by a paediatrician during the initial fieldwork at both time points. All exposed skin areas were assessed. Unexposed areas were examined in a separate, private area if the nurse suspected scabies or at the participant’s request. Scabies was diagnosed by identification of typical scabies lesions [5,16]. Impetigo was defined as skin sores that were pus filled, had overlying crusted pus, or had surrounding erythema [16]. Individuals with impetigo were referred to the local health clinic for treatment.

Oral ivermectin was dosed according to weight aiming for 200 μg/kg using whole 3 mg tablets only and administered under direct observation by a study team member (S1 Table). Exclusion criteria for ivermectin treatment were the following: age less than 5 years, weight under 15 kg, pregnancy, breastfeeding within 7 days of delivery, severe illness, or known allergy to ivermectin. For those excluded from ivermectin, treatment with topical permethrin cream 5% (Glenmark Pharmaceuticals) was substituted as 2 doses in IVM-2 or 1 dose in IVM-1. In the SAT group, 1 dose of permethrin cream was dispensed to participants diagnosed with scabies and each of their household contacts. Participants treated with permethrin in all groups were advised by study staff to apply over the whole body for 8 hours overnight (4 hours for children aged less than 2 months) before washing off, but application was not directly observed. Diethylcarbamazine and albendazole were given to eligible participants in all groups, according to schedules and inclusion criteria described previously (S1 Table) [13,14].

The procedures at the 12-month visit were similar to those at baseline. Changes included surveying participants as to whether they had left the island during the preceding year. All eligible were offered coadministered treatment with 1 dose of ivermectin, diethylcarbamazine, and albendazole, which had by then become the Fijian control strategy for lymphatic filariasis based on updated WHO guidelines [17]. Individuals with scabies and their household contacts were provided with 1 dose of permethrin cream.

Outcomes and statistical analysis

The primary outcome measure was the absolute reduction in community prevalence of scabies and impetigo between baseline and 12 months. We assumed an estimated scabies prevalence range of 25% to 35% across clusters, based on previous Fijian surveys [4,5], inducing an intracluster correlation (ICC) between 0.03–0.06 adopting the Fleiss-Cuzick estimator for ICC (S1 Methods) [18]. We assumed an absolute reduction of scabies of 29% in IVM-2 group, 22% in IVM-1 group, and 15% in the SAT group, based on findings from SHIFT [5]. Utilising a Monte Carlo simulation tool with 1,000 simulations and Bonferroni-adjusted one-sided confidence intervals (CIs) that maintain a global type I error of 5%, we estimated that 24 clusters of 100 with balanced random allocation of exposure would be sufficient to achieve at least 80% power for comparison of treatment effect between any of the 2 groups.

We used the number of participants examined at baseline and 12 months as the denominators for scabies community prevalence calculations. Participants’ data were analysed in the treatment group of their village they were resident in. Overall point prevalence estimates with 95% CI at baseline and 12 months were calculated, taking account of clustering by village using Taylor series linearization of complex sample variance and stratification by island. To calculate the absolute reduction in prevalence between the 2 time points, the 12-month prevalence was subtracted from the baseline prevalence for every village, before calculating the mean of the difference for each treatment group. Since the aim was to compare strategies for community control of scabies, we used the 2-dose ivermectin-based treatment group as the reference group for most of the analyses, with the rationale that this is the current recommendation for scabies MDA. Risk differences of scabies prevalence at 12 months between any 2 groups were calculated using generalised linear models with binomial distribution and identity link that adjusted for clustering by village and stratification by island. We considered a treatment approach to be noninferior if the upper limit of the two-sided 95% CI for risk difference between any 2 groups was 5% or less. We calculated the population attributable risk of impetigo from scabies and used bootstrapping with repetitions of 5,000 to generate 95% CIs.

The broader trial included evaluation of the safety of ivermectin, diethylcarbamazine, and albendazole compared to diethylcarbamazine and albendazole, as well as the impact of these treatments on lymphatic filariasis at 12 and 24 months, which have been reported previously [13,14]. In addition, the effect on soil-transmitted helminths at 12 months and the acceptability of MDA in Fiji will be reported separately.

Data were analysed using Stata software version 14.2. The trial was prospectively registered (Clinitrials.gov NCT03177993 and ANZCTR N12617000738325).

Results

We enrolled 3,812 participants at baseline between 13 July to 14 November 2017, and 3,898 at 12 months between 24 July to 19 November 2018 (Fig 2), covering 82% of the recorded resident population at both visits, similar between groups (Table 1, S2 and S3 Tables). The age and sex distribution of participants was representative of the resident population (S2 and S3 Tables).

Fig 2

Trial profile detailing village cluster randomisation, enrolment, and treatment at baseline and enrolment at 12-month follow-up.

IVM-1, one-dose ivermectin-based MDA; IVM-2, two-dose ivermectin-based MDA; MDA, mass drug administration; SAT, screen and treat with 1-dose permethrin to index cases of scabies and their household contacts. aLess than 5 years old and weight equal to or greater than 15 kilograms. bTreatment violation due to misclassification of participant’s resident village.

Table 1

Participant demographics at baseline and 12-month visits by treatment group.

	IVM-2				IVM-1				SAT
	Baseline		12 monthsa		Baseline		12 monthsa		Baseline		12 monthsa
	n	%	n	%	n	%	n	%	n	%	n	%
Population	1,618		1,630		1,376		1,443		1,616		1,679
Consented	1,337	82.6	1,279	78.5	1,182	85.9	1,196	82.9	1,293	80.0	1,423	84.8
Sex
Male	694	51.9	693	54.2	599	50.7	617	51.6	673	52.0	751	52.8
Female	643	48.1	586	45.8	583	49.3	579	48.4	620	48.0	672	47.2
Age (years)
Median (IQR)	25	(9–46)	28	(10–47)	22	(11–46)	23	(11–47)	27	(10–48)	26	(10–47)
<2	35	2.6	30	2.3	20	1.7	38	3.2	38	2.9	44	3.1
2–4	94	7.0	73	5.7	74	6.3	64	5.4	80	6.2	87	6.1
5–9	210	15.7	202	15.8	149	12.6	143	12.0	182	14.1	212	14.9
10–14	201	15.0	166	13.0	158	13.4	156	13.0	172	13.3	193	13.6
15–24	121	9.1	110	8.6	207	17.5	214	17.9	134	10.4	149	10.5
25–34	140	10.5	166	13.0	124	10.5	121	10.1	154	11.9	181	12.7
35–49	257	19.2	238	18.6	192	16.2	197	16.5	236	18.3	245	17.2
50–64	188	14.1	195	15.2	170	14.4	170	14.2	207	16.0	218	15.3
≥65	91	6.8	99	7.7	88	7.4	93	7.8	90	7.0	94	6.6

IQR, interquartile range; IVM-1, one-dose ivermectin-based MDA; IVM-2, two-dose ivermectin-based MDA; MDA, mass drug administration; SAT, screen and treat with 1-dose permethrin to index cases of scabies and their household contacts.

aParticipants allocated to treatment group of their current resident village in 2018.

The median village size at baseline was 108 (range 18 to 298) and median household size of 5 (interquartile range 4 to 7). At the 12-month visit, 418 (9.1%) baseline residents had permanently left the study sites, and 591 (12.4%) were newly arrived residents (Fig 2). A further 138 residents moved to a village in a different study group between visits. Of 3,884 participants surveyed at the 12-month visit, 2,089 (53.8%) reported having left the island at least once in the preceding 12 months.

Treatment coverage of the recorded resident population in the IVM-2 group was 82.1% for at least 1 dose and 80.2% for 2 doses. Two doses of ivermectin were given to 1,170 (87.5% of enrolled participants) and 2 doses of permethrin to 128 (9.6%) participants. In the IVM-1 group, resident population treatment coverage was 85.9%. In this group, ivermectin was given to 1,079 participants (91.3% of enrolled participants) and permethrin to 103 (8.7%; S2 Table). In the SAT group, there were 176 people found to have scabies with 340 uninfected household contacts, resulting in 516 participants receiving permethrin treatment (resident population treatment coverage of 31.9%, corresponding to 39.9% of enrolled participants; Fig 2).

Scabies was found in 513 individuals (13.5%) at baseline with similar prevalence between groups: IVM-2: 11.7%; IVM-1: 15.2%; SAT: 13.6% (Table 2). Scabies prevalence across villages ranged from 1.2% to 31.4% (S4 Table). Children aged less than 15 years had a higher prevalence compared to adults (S6 Table). There were no cases of crusted scabies.

Table 2

Scabies and impetigo prevalence at baseline and 12-month visits by treatment group.

	Prevalence at baselinea				Prevalence at 12 monthsa				Absolute reductionb
	N	n	%	(95% CI)	N	n	%	(95% CI)	%	(95% CI)
IVM-2
Scabies	1,337	157	11.7	(8.5–16.0)	1,279	16	1.3	(0.6–2.5)	10.7	(6.4–14.9)
Impetigo	1,337	25	1.9	(1.1–3.3)	1,279	13	1.0	(0.5–2.0)	1.1	(−0.4–2.5)
IVM-1
Scabies	1,182	180	15.2	(9.4–23.8)	1,196	32	2.7	(1.1–6.5)	11.1	(4.5–17.7)
Impetigo	1,182	27	2.3	(1.5–3.4)	1,196	9	0.8	(0.3–1.8)	1.6	(0.4–2.7)
SAT
Scabies	1,293	176	13.6	(7.9–22.4)	1,423	16	1.1	(0.6–2.0)	10.1	(4.7–15.4)
Impetigo	1,293	30	2.3	(1.3–4.1)	1,423	5	0.4	(0.2–0.7)	2.0	(0.7–3.2)

CI, confidence interval; IVM-1, one-dose ivermectin-based MDA; IVM-2, two-dose ivermectin-based MDA; MDA, mass drug administration; SAT, screen and treat with 1-dose permethrin to index cases of scabies and their household contacts.

aAdjusted for clustering by village and stratification by island.

bAdjusted for clustering by village.

At 12 months, the prevalence of scabies was substantially lower in all treatment groups: IVM-2: 1.3%; IVM-1: 2.7%; SAT: 1.1% (Table 2). The risk difference in scabies prevalence at 12 months for IVM-1 compared to IVM-2 group: 1.2%; for SAT compared to IVM-2: 0.2%; and IVM-1 compared to SAT: 1.3% (Fig 3). All villages except one (allocated to IVM-1) had a decrease in prevalence, and 16 out of 35 had no scabies cases detected at 12 months (S4 Table). Of the 64 cases detected at 12 months, 20 (31%) were in newly enrolled participants, 15 were in people who had scabies at baseline, and the remainder were in previously enrolled people without scabies at baseline.

Fig 3

Scabies prevalence risk difference and 95% CI between any 2 groups at 12 months.

CI, confidence interval; IVM-1, one-dose ivermectin-based MDA; IVM-2, two-dose ivermectin-based MDA; MDA, mass drug administration; SAT, screen and treat with 1-dose permethrin to index cases of scabies and their household contacts. Whiskers represent 95% CI around risk difference. aReference treatment group.

At baseline, 82 (2.2%) participants had impetigo. The prevalence was similar across treatment groups (Table 2, S5 Table) and more prevalent in children aged less than 15 years (S7 Table). At 12 months, there was a decrease in impetigo prevalence in all groups to 1.0% or less. The risk difference in impetigo prevalence at 12 months for IVM-1 compared to IVM-2 group: −0.2%; for SAT compared to IVM-2: −0.2%; and IVM-1 compared to SAT: 0.0% (Fig 3). Of the 82 participants with impetigo at baseline, 62 (75.6%) had concurrent scabies, representing a population risk of impetigo attributable to scabies of 72.7% (95% CI 61.8 to 83.7). At 12 months, 9 of 27 cases of impetigo (33.3%) had scabies, representing a population risk of impetigo attributable to scabies of 28.6% (95% CI 7.7 to 49.4).

Discussion

In our study of MDA for scabies in an endemic island setting, there was a significant reduction in the community prevalence of scabies and impetigo at 12 months in all 3 groups. One-dose ivermectin-based MDA and also a screen and treat approach using permethrin were not inferior to 2-dose ivermectin-based MDA.

The results from the MDA groups in our study are consistent with those of other studies in the Pacific in which ivermectin-based MDA led to substantially reduced prevalence of scabies and impetigo [5,8,19]. However, these previous studies used a 2-dose ivermectin-based MDA approach, and our study is the first randomised trial, to our knowledge, to demonstrate that community-wide treatment with a single dose is able to substantially reduce both burden and transmission, despite ivermectin having minimal ovicidal activity.

We also observed that screening for scabies and then providing 1 dose of permethrin treatment to individuals with clinical signs and their household contacts was highly effective in reducing community prevalence at 12 months. Direct comparison between our study and SHIFT is difficult because of higher baseline scabies prevalence in SHIFT study sites [5]. Nonetheless, the effectiveness of our screen and treat approach was higher than that reported for the corresponding standard care group in SHIFT, possibly because our study team dispensed permethrin, rather than referring to the local clinic for treatment as done in SHIFT [5,20].

While the effectiveness of all 3 groups was similar, we believe that a screen and treat approach would be impractical to implement as a large-scale public health strategy. This approach would be labour intensive and expensive, requiring a large workforce of highly skilled clinical examiners to screen all individuals within a population [20,21]. Furthermore, in high prevalence settings, identification and treatment of infected individuals and their household contacts may result in community treatment coverage approaching that of MDA.

There are a number of limitations to our study. First, diagnosis of scabies and impetigo was made by trained but nonexpert clinical examiners, without parasitological or microbiological confirmation, and these examiners were not blinded to treatment received. Nonexperts have been reported to be less sensitive in the diagnosis of mild cases of scabies compared to experts [21], and so it is possible that a proportion of cases of scabies may have been missed. Second, all participants in the study also received diethylcarbamazine and albendazole as MDA for lymphatic filariasis; however, neither of these medications have activity against the scabies mite or bacterial pathogens [13]. Third, while this study comparing MDA regimens was a nested trial, it was designed from the outset to be a stand-alone 3-arm, cluster randomised trial. Fourth, the baseline scabies prevalence in our study was lower than anticipated, likely due to geographical variation in prevalence, but this did not impact the statistical power of the trial.

This study was conducted on 2 small Pacific islands and may not be generalizable to larger populations and higher density settings. Another trial comparing 1 and 2 doses of ivermectin-based MDA for scabies is currently underway in the Solomon Islands [22], and before–after studies of the impact of filariasis MDA programmes that include a single dose of ivermectin on scabies are being conducted in a number of countries including Timor-Leste [23]. In addition, these results are limited to the first 12 months after MDA. Previous studies have demonstrated that 1 round of MDA may have a prolonged and sustained benefit, but we will not have data to determine if this will be replicated at our study sites [6,8].

Our study provides evidence from a randomised trial that 1-dose ivermectin-based MDA is noninferior to 2-dose and, therefore, may be adequate as a strategy for controlling scabies in endemic settings. More research is needed to support our finding, including in larger populations and in non-island settings. While we also found that the screen and treat strategy was equivalent, this approach would be impractical to implement at scale.

Medication dosing schedule by weight or age.

(PDF)

Click here for additional data file.

Baseline population and participant demographics and treatment coverage by village.

IQR, interquartile range; IVM-1, one-dose ivermectin-based MDA; IVM-2, two-dose ivermectin-based MDA; MDA, mass drug administration; SAT, screen and treat with 1-dose permethrin to index cases of scabies and their household contacts. aVillages 1–17 are on Rotuma; Villages 18–35 are on Gau; median village size 108. bPercentage of census population treated.

(PDF)

Click here for additional data file.

Population and participant demographics at 12-month follow-up.

IQR: interquartile range; IVM-1, one-dose ivermectin-based MDA; IVM-2, two-dose ivermectin-based MDA; MDA, mass drug administration; SAT, screen and treat with 1-dose permethrin to index cases of scabies and their household contacts. aVillages 1–17 are on Rotuma; Villages 18–35 are on Gau; median village size 125.

(PDF)

Click here for additional data file.

Scabies prevalence by village at baseline and 12 months.

CI, confidence interval; ICC, intracluster correlation; IVM-1, one-dose ivermectin-based MDA; IVM-2, two-dose ivermectin-based MDA; MDA, mass drug administration; SAT, screen and treat with 1-dose permethrin to index cases of scabies and their household contacts. aVillages 1–17 are on Rotuma; Villages 18–35 are on Gau. bOne-sided 97.5% CI. cAdjusted for clustering by village and stratified by island. dAdjusted for clustering by village. The ICC coefficient for scabies at baseline was 0.120, and 12 months was 0.207.

(PDF)

Click here for additional data file.

Impetigo prevalence by village at baseline and 12 months.

CI, confidence interval; ICC, intracluster correlation; IVM-1, one-dose ivermectin-based MDA; IVM-2, two-dose ivermectin-based MDA; MDA, mass drug administration; SAT, screen and treat with 1-dose permethrin to index cases of scabies and their household contacts. aVillages 1–17 are on Rotuma; Villages 18–35 are on Gau. bOne-sided 97.5% CI. cAdjusted for clustering on village and stratified by island. dAdjusted for clustering on village. The ICC coefficient for impetigo at baseline was 0.07, and 12 months was 0.06.

(PDF)

Click here for additional data file.

Scabies prevalence at baseline and 12 months by treatment and demographic groups.

IQR: interquartile range; IVM-1, one-dose ivermectin-based MDA; IVM-2, two-dose ivermectin-based MDA; MDA, mass drug administration; SAT, screen and treat with 1-dose permethrin to index cases of scabies and their household contacts. aParticipants allocated to treatment group of their current resident village in 2018.

(PDF)

Click here for additional data file.

Impetigo prevalence at baseline and 12 months by treatment and demographic groups.

IQR: interquartile range; IVM-1, one-dose ivermectin-based MDA; IVM-2, two-dose ivermectin-based MDA; MDA, mass drug administration; SAT, screen and treat with 1-dose permethrin to index cases of scabies and their household contacts. aParticipants allocated to treatment group of their current resident village in 2018.

(PDF)

Click here for additional data file.

Randomisation and treatment flowchart.

D, day; IVM, ivermectin; MDA, mass drug administration. aIneligible for treatment if not found to have scabies and no household contacts had scabies.

(PDF)

Click here for additional data file.

Anonymized individual level data at baseline and 12 months.

(XLSX)

Click here for additional data file.

Community-based safety of 2-drug (diethylcarbamazine and albendazole) versus 3-drug (ivermectin, diethylcarbamazine, and albendazole) therapy for lymphatic filariasis in Fiji—Protocol v6.0 6 August 2019.

(PDF)

Click here for additional data file.

Sample size calculation.

(PDF)

Click here for additional data file.

CONSORT 2010 checklist of information to include when reporting a cluster randomised trial.

(PDF)

Click here for additional data file.

16 Jun 2021

Dear Dr Hardy,

Thank you for submitting your manuscript entitled "Community control strategies for scabies: a cluster randomised non-inferiority trial" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by Jun 18 2021 11:59PM.

Login to Editorial Manager here: https://www.editorialmanager.com/pmedicine

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Beryne Odeny

Associate Editor

PLOS Medicine

13 Aug 2021

Dear Dr. Hardy,

Thank you very much for submitting your manuscript "Community control strategies for scabies: a cluster randomised non-inferiority trial" (PMEDICINE-D-21-02600R1) for consideration at PLOS Medicine.

Your paper was evaluated by an academic editor with relevant expertise and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to invite you to submit a revised version that addresses the reviewers' and editors' comments fully. You will appreciate that we cannot make a decision about publication until we have seen the revised manuscript and your response, and we expect to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We hope to receive your revised manuscript by Sep 03 2021 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

Please let me know if you have any questions, and we look forward to receiving your revised manuscript.

Sincerely,

Richard Turner PhD, for Beryne Odeny,

Senior editor, PLOS Medicine

rturner@plos.org

-----------------------------------------------------------

Requests from the editors:

You mention in the article metadata that all data are included in the ms and supplementary files - are you able to include anonymized patient-level date in excel files or similar?

PLOS Medicine style is to use "sex" rather than "gender", where appropriate.

Please quote aggregate demographic details for participants in the abstract; along with some key details of villages/clusters.

In the abstract and throughout the paper, please quote p values alongside 95% CI, where available.

Please combine the "Methods" and "Findings" subsections of your abstract.

The final sentence of the new combined subsection should begin "Study limitations include ..." or similar, and should quote 2-3 of the study's main limitations.

Please remove the information on funding from the abstract. In the event of publication, this information will appear in the article metadata, via entries in the submission form.

Please restructure the "Author summary" so that each of the three subsections consists of around 3 bulleted points, each consisting of no more than 1 or 2 short sentences.

Please remove the "Role of the funding source" section from the Methods.

Please avoid claims such as "the first", in the final paragraph for example, and where needed add "to our knowledge" or similar.

Throughout the text, please locate reference call-outs prior to punctuation and remove spaces from within the square brackets (e.g., "... over 26,000 [7,8].").

Please confirm that the map in fig. 1 can be published under a CC BY licence, in the event of publication.

Comments from the reviewers:

*** Reviewer #1:

Community control strategies for scabies: a cluster randomised non-inferiority trial

This is an important report on a cluster randomised trial for prevention and control of scabies. The authors do make a case for the scientific gap is whether a one-dose ivermectin-based mass drug administration (MDA) would not be inferior to a two-dose ivermectin-based MDA. So the authors designed an open-label cluster RCT with 3 arms:

- (IVM-2) Ivermectin-based treatment plus DEC and albendazole followed by a second dose of ivermectin 8 days later

- (IVM-1) Ivermectin-base treatment plus DEC and albendazole

- (SAT) Clinical screen for scabies and treatment (offered as well DEC and albendazole)

General comments:

1. The primary outcome in this trial is absolute reduction of prevalence from baseline to 12 months. OK to use the IVM-2 as the reference group.

a) The sample size calculation was done under the assumption of higher baseline prevalence and larger absolute reductions. This deserves note and more discussion. In fact the results section almost obscures this because it focuses more on the secondary outcome see below.

b) Please add more notes on how the simulation for sample size calculation was done.

c) Please add information on how cluster correction/adjustment was done (on table 2). The lines 213 to 218 do not explain this.

2. For the secondary outcome [scabies/impetigo prevalence at 12 months]. The authors state that they used "risk differences". However, the lines 222 and 223 say that they use a GLM regression model with binomial family and log-link. This model is also known as log-binomial in the literature and is typically used to obtain relative risks (or proportion ratios), a clear relative measure of association. I would suggest the authors change the terminology from "risk differences" to "prevalence ratio" (or "proportion ratio" etc...)

Please see more comments on the CONSORT checklist.

CONSORT checklist

1) Outcomes (Item 6a)

Completely defined pre-specified primary outcome measure including how and when it was assessed

R: Yes it is clearly defined. Lines 203 and 206. Absolute reduction in community prevalence of scabies between baseline and 12 months. This is in percentage.

2) Sample size (Item 7a)

How sample size was determined

R: Between lines 207 and 210 there is an explanation of how the sample size was computed. Expected effectiveness is collected from the literature review. A simulation procedure of 1000 confidence intervals with Bonferroni correction was used to determine the sample size of 24 clusters. However, I cannot find further details of this approach in the attached protocol. They assumed a power of 80% (β = 20%) and α error level of 5%. Another key assumption was that the scabies prevalence would be between 25 to 35% (their results show that overall baseline prevalence ranged between 11.7 to 15.2%, few communities/clusters reached above 25%).

3) Sequence generation (Item 8a)

Method used to generate random allocation sequence

Does the description make it clear if the "assigned intervention is determined by a chance process and cannot be predicted"?

R: Yes. Lines 171 to 173. An independent statistician generated the allocation using Stata.

4) Allocation concealment (Item 9)

Mechanism used to implement random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned

Is it clear how the care provider enrolling participants was made ignorant of the next assignment in the sequence (different from blinding)? Possible methods can rely on centralised or "third-party" assignment (i.e., use of a central telephone randomisation system, automated assignment system, sealed containers).

R: The authors state there was allocation concealment in line 173.

5) Blinding (Item 11a)

If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes)

Is it clear if (1) healthcare providers, (2) patients, and (3) outcome assessors are blinded to the intervention? General terms such as "double-blind" without further specifications should be avoided.

R: There was no blind. This is said in line 174.

6) Outcomes and estimation (Item 17a/b)

For the primary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence intervals)

Is the estimated effect size and its precision (such as standard deviation or 95% confidence intervals) for each treatment arm reported? When the primary outcome is binary, both the relative effect (risk ratio, relative risk) or odds ratio) and the absolute effect (risk difference) should be reported with confidence intervals.

R: For the primary outcome (absolute reduction of scabies or impetigo prevalence from baseline to 12 months follow up, reported on table 2) no measure of association is presented. The reporting text is a bit unclear on this but it is implicit (according to how the sample size was estimated) that the intention is to check the overlapping of the 95% confidence interval. Per arm baseline and 12 month prevalence are presented and differences corrected for clustering. However, is not described in the manuscript how this adjustment/correction per clustering was done for this particular analysis (that lead to table 2).

7) Harms (Items 19)

All important harms or unintended effects in each group

Is the number of affected persons in each group, the severity grade (if relevant) and the absolute risk (e.g. frequency of incidence) reported? Are the number of serious, life threatening events and deaths reported? If no adverse event occurred this should be clearly stated.

R: This was not reported and I do not think this is relevant for this cluster RCT.

8) Registration (Item 23)

Registration number and name of trial registry

Is the registry and the registration number reported? If the trial was not registered, it should be explained why.

R: The trial was registered prospectively lines 51 and 52.

Clinitrials.gov NCT03177993 and ANZCTR N12617000738325

9) Protocol (Item 24)

Where trial protocol can be accessed

Is it stated where the trial protocol can be assessed (e.g. published, supplementary file, repository, directly from author, confidential and therefore not available)?

R: The protocol is added as supplementary material.

10) Funding (Item 25)

Sources of funding and other support (such as supply of drugs) and role of funders

Are (1) the funding sources, and (2) the role of the funder(s) described?

R: There is a section declaring the funding sources (lines 66 to 73, only in the abstract). And there is a section for the role of funding source (lines 229 to 232).

*** Reviewer #2:

Scabies is an important problem and this will be an excellent addition to the literature on its control. The study design is simple and appropriate. It appears that the work was sound. The paper is concise and clear.

I have no major comments and only a few very minor ones for the authors' consideration.

Line 153: Having "residing in 35 villages" at the end of this sentence seems odd. Suggest add to the front of the sentence, which would then read, "The trial was conducted in 2017 and 2018 in 35 villages…"

Line 237, Table 1 and elsewhere: suggest replace "sex" with "gender", which is more likely to be what was recorded by field teams.

Line 257: I am not sure how to reconcile these two sentences, which at first reading seem to be inconsistent: "Treatment coverage in the IVM-2 group was 82.1% for at least one dose and 80.2% for two doses. Two doses of ivermectin were given to 1170 (87.5% enrolled) and two doses of permethrin to 128 (9.6%) participants." Are the authors using the resident population as the denominator in the first sentence and consenting participants in the second sentence?

Line 267: suggest add "aged" in front of "less" in the sentence, "Children less than 15 years…"

Line 295: "Of the 82 participants with impetigo at baseline, 62 (75.6%) had concurrent scabies, representing a population risk of impetigo attributable to scabies of 72.7% (95% CI 61.8-83.7, p<0.0001). At 12 months, 9 of 27 cases of impetigo (33.3%) had scabies, representing a population risk of impetigo attributable to scabies of 28.6% (95% CI 7.7-49.4, p=0.007)." Suggest just use two significant digits here, since in my view that's all that's justifiable given the data.

Line 320: "This approach would be labour-intensive and expensive, requiring a large workforce of highly skilled clinical examiners to screen all individuals within a population." I agree with this statement. It would be made more powerfully if the authors could add either here or in the methods at line 178 some more detail of how the examiners in the study were trained and assessed for competency.

Line 324: "approaching that of an MDA strategy": suggest simplify to "approaching that of MDA".

*** Reviewer #3:

Review comments

PMEDICINE-D-21-02600R1

Community control strategies for scabies: a cluster randomised non-inferiority trial

General comments

Scabies is a neglected tropical disease that is endemic in many parts of the world. The WHO Road Map for NTDs 2030 has set targets for the control/ eradication of scabies and this calls for renewed efforts and approaches to control. Optimisation of MDA approaches for scabies treatment is therefore an essential tool to aid the attainments of the targets set out in the road map. The authors are therefore to be commended for undertaking this important study.

The authors performed a cluster randomised, non-inferiority, open-label, three group unblinded study to compare the effectiveness of 3 control strategies on community prevalence of scabies on 2 Fijian islands 12 months after the intervention. The rationale for the study is clearly set out in the manuscript. The authors are to be commended for undertaking this important work which enables us answer some key questions on scabies control.

The manuscript is very well written.

The methodology is clear and results are very well presented. the findings and their public health implications have been well discussed

The manuscript has been reported in conformance with the CONSORT checklist. The main concern is regarding adverse events. No account is given regarding adverse events (if any). This is especially important as the trial was nested with co-administration with DEC and albendazole for LF. It is important to make some comment on the safety of this co-administered regimen

CONSORT checklist

1) Outcomes (Item 6a)

Completely defined pre-specified primary outcome measure including how and when it was assessed

Is it clear (1) what the primary outcome is (usually the one used in the sample size calculation), (2) how it was measured (if relevant; e.g. which score used), (3) at what time point, and (4) what the analysis metric was (e.g. change from baseline, final value)?

Well done

2) Sample size (Item 7a)

How sample size was determined

Is there a clear description of how the sample size was determined, including (1) the estimated outcomes in each group; (2) the α (type I) error level; (3) the statistical power (or the β (type II) error level); and (4) for continuous outcomes, the standard deviation of the measurements? Yes

3) Sequence generation (Item 8a)

Method used to generate random allocation sequence

Does the description make it clear if the "assigned intervention is determined by a chance process and cannot be predicted"? Yes

4) Allocation concealment (Item 9)

Mechanism used to implement random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned

Is it clear how the care provider enrolling participants was made ignorant of the next assignment in the sequence (different from blinding)? Possible methods can rely on centralised or "third-party" assignment (i.e., use of a central telephone randomisation system, automated assignment system, sealed containers).

5) Blinding (Item 11a)

If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes)

Is it clear if (1) healthcare providers, (2) patients, and (3) outcome assessors are blinded to the intervention? General terms such as "double-blind" without further specifications should be avoided. N/A

6) Outcomes and estimation (Item 17a/b)

For the primary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence intervals)

Is the estimated effect size and its precision (such as standard deviation or 95% confidence intervals) for each treatment arm reported? When the primary outcome is binary, both the relative effect (risk ratio, relative risk) or odds ratio) and the absolute effect (risk difference) should be reported with confidence intervals.

Done

7) Harms (Items 19)

All important harms or unintended effects in each group

Is the number of affected persons in each group, the severity grade (if relevant) and the absolute risk (e.g. frequency of incidence) reported? Are the number of serious, life threatening events and deaths reported? If no adverse event occurred this should be clearly stated.

Not included in current report. Authors should include some information on adverse events (if any) and how they were handled

8) Registration (Item 23)

Registration number and name of trial registry

Is the registry and the registration number reported? If the trial was not registered, it should be explained why.

Yes; trial was registered with Clinitrials.gov NCT03177993 and ANZCTR N12617000738325).

9) Protocol (Item 24)

Where trial protocol can be accessed

Is it stated where the trial protocol can be assessed (e.g. published, supplementary file, repository, directly from author, confidential and therefore not available)?

Yes; attached as a supplementary file

10) Funding (Item 25)

Sources of funding and other support (such as supply of drugs) and role of funders

Are (1) the funding sources, and (2) the role of the funder(s) described? Yes

*** Reviewer #4:

Scabies review

Accept

This is a well planned, executed, analysed and presented study.

However, I believe it would be worthwhile if the authors could make some points regarding the following issue:

1. Is there any evidence that the nurses who conducted the clinical examinations were able to accurately diagnose scabies? This can sometimes be difficult, even for dermatologists. Are the authors able to provide more information about their training?

Although not directly related to the study aims and findings, from the perspective of scabies control in general I think it would be helpful if the authors could (in the discussion)

1. Briefly mention that follow up incidence studies would be useful; for example in 2023 and 2028. This could yield information regarding the longevity of the effect. With this knowledge, an optimal frequency of mass treatments could be estimated.

2. Briefly comment on the very low incidence rates in adults greater than ~35 years of age. Does this age group need to be mass treated? If cost is an issue, then halving the number of doses administered may permit mass treatments to be done more often: for example, every 5 years instead of every decade. (And it is certainly significant that the authors have been able to show that they can reduce costs by half by simply avoiding the second dose).

*** Reviewer #5:

Statistical review

This paper reports a cluster randomised trial comparing different strategies for mass drug administration to reduce prevalence of scabies. The trial shows that the intervention arms were non-inferior to the control arm. The trial is generally reported well and the paper written clearly.

I have some comments, which I have provided below.

1. Abstract, Line 60 and results: I would recommend providing a p-value for non-inferiority in addition to the 95% CI.

2. Page 11 - how was stratification by island incorporated into the randomisation? Using stratified blocks? From this paragraph I would presume that villages agreed to participate prior to knowing the allocation and none dropped out after allocation - if this is not the case then please make this clear.

3. Page 13 - for the sample size calculation it appears the power was averaging over the different prevalence scenarios. I don't think enough detail on this is provided to allow reproduction of the sample size. Also, could the authors add what the assumed clustering coefficient (e.g. ICC) was? Lastly, Bonferroni correction was mentioned, but I did not see how this linked with using the 95% CI for non-inferiority (which implies no correction, unless the overall error rate is 5% one-sided).

4. Page 13-14: for the statistical analysis, two approaches are outlined - using the difference between follow-up and baseline prevalence, and then using a generalised linear approach.

For the former approach, could more details be provided on the model assumed. Presumably it is using summary data per cluster rather than individual patient data?

For the latter approach, is the baseline prevalence data used at all?

5. I would imagine it's normal for this type of study, but the differential consent rates per arm are noticeable in table 1. It would be useful if the authors could discuss implications of this on how robust the results are. I suspect they are robust as it would require a huge difference between non-consenting and consenting participants to change the conclusions.

6. Line 281 - many of the new cases were in participants newly in the study at 12 months - does this mean they were unlikely to have actually benefited from the interventions?

7. Line 297 - it's not clear to me what the significant p-value here means. Is this that it's significantly higher than 0? Can the estimated PAR and CI ever be negative?

8. There are several secondary outcome measures mentioned on the clinicaltrials.gov registration page that are not reported in this paper. I would recommend that these are mentioned in the outcomes section and either reported here or a statement that they are to be reported separately provided.

9. The protocol provided appears to be for the larger study rather than the scabies substudy specifically. If there is no specific protocol for the substudy, then pointing out the relevant sections of the protocol in the Supplementary text description may be useful.

James Wason

***

Any attachments provided with reviews can be seen via the following link:

[LINK]

31 Aug 2021

Submitted filename: PMEDICINE-D-21-02600_Response_to_Reviewers.docx

Click here for additional data file.

7 Oct 2021

Dear Dr. Hardy,

Thank you very much for re-submitting your manuscript "Community control strategies for scabies: a cluster randomised non-inferiority trial" (PMEDICINE-D-21-02600R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by two reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Oct 14 2021 11:59PM.

Sincerely,

Beryne Odeny,

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

1) Abstract:

a) Please structure your abstract using the PLOS Medicine headings (Background, Methods and Findings, Conclusions). The second subheading should be “Methods and Findings”

b) Please include p-values alongside 95% CIs

c) Please replace the subtitle “Interpretation” with “Conclusions”

Comments from Reviewers:

Reviewer #3: The authors have addressed all queries that were raised.

Reviewer #5: Thank you to the authors for addressing my previous comments well. I have no further issues to raise.

Any attachments provided with reviews can be seen via the following link:

[LINK]

14 Oct 2021

Dear Dr Hardy,

On behalf of my colleagues and the Academic Editor, Dr. Lorenz von Seidlein, I am pleased to inform you that we have agreed to publish your manuscript "Community control strategies for scabies: a cluster randomised non-inferiority trial" (PMEDICINE-D-21-02600R3) in PLOS Medicine.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process.

PRESS

We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with medicinepress@plos.org. If you have not yet opted out of the early version process, we ask that you notify us immediately of any press plans so that we may do so on your behalf.

We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper.

Sincerely,

Beryne Odeny

PLOS Medicine