Efficacy of Two Doses of Ivermectin Tablet in Treatment of Scabies in Comparison to Once Application of 5% Permethrin Lotion – A Randomized Controlled Trial

Abstract

Background:

Scabies may cause community outbreaks without early diagnosis and appropriate treatment. Oral ivermectin offsets some of the challenges associated with topical 5% permethrin application for treating scabies. We aimed to evaluate the efficacy of two doses of oral ivermectin (200 µg/kg) on day one and day seven compared to 5% (weight/volume [w/v]) once whole-body application of permethrin lotion in treating scabies.

Materials and Methods:

We recruited 100 participants with mild or moderate scabies and randomized them into ivermectin and permethrin arms using computer-generated sequences. Participants and their contacts in the ivermectin arm received two doses of ivermectin (200 µg/kg) on day one and day seven. Participants and their contacts in the permethrin arm received treatment with 5% (w/v) permethrin application over the whole body. The participants were followed up after 4–6 weeks of the intervention to determine the cure rate.

Results:

We got a similar cure rate among the scabies patients who received either ivermectin (90.70%) or permethrin (93.33%). The cure rate was 100% after one dose of whole-body application of permethrin or two appropriate doses of ivermectin among mild to moderate cases of scabies. The cost was lower in the ivermectin arm than in the permethrin arm.

Conclusion:

The cure rates of scabies with one local application of 5% permethrin lotion and two doses of oral ivermectin tablets are similar. Ivermectin has an added advantage that the cost is lower and its usage is convenient.

INTRODUCTION

Scabies is one of the contagious, neglected tropical diseases commonly affecting children and young adults of lower socioeconomic strata, specifically in lower–middle-income countries.[1] Scabies is caused by mites named Sarcoptes scabiei var. hominis, ectoparasites those usually live inside burrows in the human skin, specifically in the web space, genitalia and medial aspects of the palm, wrist, arm, forearm, and thigh. Scabies causes intense pruritus, specifically at night, along with erythematous papules. Scabies can cause community outbreaks and complications without appropriate and early management.[2,3] The global age-standardized Disability Adjusted Life Years per 100,000 people attributed to scabies was 62.53 (95% confidence interval [CI] 34.67–99.87) for both sexes, with 300 million scabies cases at any time.[4] Scabies can also cause mortality due to glomerulonephritis arising from impetigo or infected scabies.[2]

Different pharmacologic interventions such as 5% permethrin, 10% crotamiton, 5%–10% sulfur ointment, 1% lindane lotion, and oral ivermectin are approved to treat scabies.[5,6] Different studies found that permethrin better cures scabies by killing all stages of scabies mites. Click or tap here to enter text.[7,8] However, the acceptability of permethrin lotion may be on the lower side due to privacy issues, as it needs to be applied on the whole body. Specifically, when contact duration is prolonged, permethrin lotion can cause contact dermatitis.[9] The cost of ivermectin is also lower than permethrin in many lower–middle-income countries. The cost of the medicines has implications for treatment of any disease in lower–middle-income countries, especially in marginalized communities where scabies is more prevalent.[10] Oral use paired with directly observed administration can add extra leverage to ivermectin use in treating scabies. The World Health Organization also included ivermectin in the list of essential medicines for scabies.[1,11]

For treating scabies without any complication, 5% (w/v) permethrin lotion is prescribed for application once during bedtime, followed by bathing with soap water the next morning.[12] Oral ivermectin is prescribed at 200 µg/kg of body weight per day in two doses: one on day 1 and two after 7 days.[12] Ivermectin is not recommended in pregnant and lactating mothers, under-five children, and persons suffering from serious illnesses. In both drugs, the treatment of family contacts and cleaning of clothing and bedsheets are also required, along with antibiotics if a secondary infection is present.

Oral therapy can offset some of the challenges associated with topical therapy and can increase compliance, resulting in better control of scabies in communities. There is growing interest in oral ivermectin in the treatment of scabies. The safety of ivermectin has been well studied in large-scale disease eradication programs for other parasitic diseases. One of the nonrandomized controlled trials (RCTs) conducted in Fiji identified the potential role of ivermectin in treating scabies.[13] However, there is a lack of a well-designed RCT explaining whether treatment with ivermectin is noninferior to local permethrin application. We aimed to compare the cure rate between ivermectin and permethrin treatment groups among scabies patients.

MATERIALS AND METHODS

Study design

This open-labeled RCT was conducted in the Bhubaneswar rural block, situated on the outskirts of the capital city of Odisha, an eastern state of India. It has an estimated population of 1,47,000 distributed in 140 villages. Patients with scabies residing in the study area were recruited for the study. The patients were identified by active screening during door-to-door visits. Two expert physicians diagnosed patients with scabies based on the presence of more than one pruritic, inflammatory erythematous papule with a typical anatomic distribution involving the web spaces of fingers, hands, wrists, elbows, knees, trunk, groin, or ankles, and/or mites identified in the lesions using a hand lens. Expert opinion was obtained from expert dermatologists in case of any dilemma in diagnosis. Participants under 5 years of age, pregnant or lactating women, and those suffering from serious illnesses such as chronic liver or kidney disease, seizure disorder, or Parkinsonism were excluded from the study. Participants with a history of allergies to permethrin or ivermectin or who received any topical or systemic scabicide therapy in the month before entry into the trial were also excluded. Only one participant was recruited from one family. The nearest birthday method was used to select a single participant among multiple eligible participants in a single family. The rest of the participants were treated as contacts.

Sample size calculation

We estimated a final sample size of 50 in each arm with an expected cure rate of 93% and 73% by permethrin and ivermectin, respectively, and an expected noninferiority margin of 2%.[8] We considered an exclusion rate of 10% over initial calculated sample size of 34 in each arm. Further, we added a lost to follow-up rate of 20% to estimate a final sample size of 50 in each arm. The sample size was adequate for a noninferiority trial to achieve a power of 80% with an alpha error of 5%.

Randomization

One researcher generated simple randomization sequence using website (https://www.sealedenvelope.com).[14] Another researcher noted the randomization sequence and recruited participants consecutively using the earlier sequence.

Recruitment of participants

We approached 100 participants identified with scabies and recruited 92 participants who fulfilled the inclusion criteria after obtaining their consent. We randomized them into ivermectin and permethrin arms.

Ivermectin arm

Tablet ivermectin in a dose of 200 µg/kg body weight up to 24 mg was prescribed to be taken 30 min before food on day 1 and day 7 [Table 1]. Ivermectin was given in the form of 6 mg tablets.[15]

Table 1.

Dose of ivermectin for groups of different body weight

Body weight (kg)	Dose (mg/day)
15–30	6
31–60	12
61–90	18

Permethrin arm

Permethrin lotion (60 ml) in 5% strength (w/v) was given for local application from the neck to toes at bedtime for 8 h. The process of applying permethrin was explained to the patients.

A treatment similar to that of the participants was given for household contacts, and it was advised to wash the clothing and bedsheets of the participants (used by the patient in the last three days). Permethrin was given to the contacts of patients in the ivermectin arm with contraindications to ivermectin use. For infective scabies, amoxicillin and clavulanate tablets were given thrice daily at 30 mg/kg per dosage (with a maximum single dosage of 625 mg). Click or tap here to enter text.[12] Antihistamines in age-appropriate doses were provided to all participants for itching.

Outcome assessment

This study’s primary outcome was to measure the cure rate among scabies patients who received either two appropriate dosages of ivermectin or one proper application of permethrin lotion. Outcome assessment was done by a trained physician in consultation with expert dermatologists after 1 month of initiation of treatment. The outcome assessment for all participants was completed 4–6 weeks after the initiation of treatment. “Complete treatment” is defined as the application of permethrin in all body parts from the neck to toes or intake of ivermectin in two doses in 7-day intervals. “Partial treatment” is defined as the application of permethrin only in the itch sites or the application of permethrin only in some parts of the body or the intake of a single dose of ivermectin.[16] “Cure” is defined as a clinically significant reduction of papules and burrows and a significant clinical reduction of itching in patients. “Treatment failure” is defined as the persistence of itching and papules after 1 month of treatment initiation. A detailed consolidated standards of reporting trials (CONSORT) diagram was provided for the same [Figure 1]. The data related to adverse events related to both treatment arms was noted using a predesigned questionnaire consisting of signs and symptoms related to adverse effects. The adverse effects were assessed during the outcome assessment. Participants with any adverse events were followed up weekly until treatment was required.

Figure 1.

CONSORT diagram showing participant recruitment and their follow-up status

Data collection and data management

The basic demographic details and clinical signs and symptoms were noted in a case record form. The patients were followed up, data regarding clinical signs and symptoms were noted, and the outcome was assessed. All the data was collected in hard copies, then entered in Microsoft Excel software version 2019, and analyzed using International Business Machine Statistical Package for the Social Sciences Statistics Version 26 (SPSS Inc., Chicago, IL, USA).

Statistical analysis

We reported the continuous variables as mean and standard deviation (SD) and the categorical variables as proportion and CI. Continuous variables between two arms were compared using the Mann–Whitney U test (due to the non-normal distribution of the variables). The different proportions between the two arms were compared using the Chi-square test or Fisher’s exact test. The cure rate was calculated in the two arms using per-protocol analysis. A P value of < 0.05 was taken as significant. The cost of the treatment with permethrin and ivermectin was reported in US dollars.

Ethical statement

Ethical clearance was obtained from the Institutional Ethics Committee (IEC) with IEC reference number: T/IM-NF/CM and FM/21/149. Informed written consent was taken from one of the parents/legal guardians of participants below 18 years, and verbal and written assent was obtained from the participants aged 7–11 and 12–18 years, respectively. Participants aged less than 7 years were included after informed written consent was obtained from one of the parents/legal guardians of the participants. Participants aged more than 18 years were included in the study after written informed consent was obtained from them. IEC approved this consent-taking procedure. This trial was prospectively registered in the Clinical Trial Registry of India (CTRI) (CTRI/2022/03/040762).[17]

RESULTS

Baseline assessment

All the participants were aged between 5 and 35 years, with the mean age of participants being 11.97 years (SD 5.32 years). The mean age of the participants was similar in the two arms. Most participants were students, with the most common education status being primary level. The distribution of gender, occupation, and educational status was similar in the two arms [Table 2]. Two participants in each of the arms had infected scabies.

Table 2.

Baseline characteristics of ivermectin and permethrin groups (n=92)

Variable	Ivermectin (n=46) Mean (SD)/number (percentage)	Permethrin (n=46) Mean (SD)/number (percentage)	P
Age (in years)
Mean (SD)	11.67 (4.07)	11.85 (6.16)	0.323*
Gender
Male	24 (52.7)	28 (60.1)	0.400†
Female	22 (46.3)	18 (39.9)
Education status
Till class 5	20 (43.5)	26 (56.5)	0.050††
Class 5–class 8	22 (47.8)	10 (21.7)
Class 9–class 10	3 (6.5)	5 (10.9)
Class 11–class 12	0 (0)	1 (2.2)
Above class 12	1 (2.2)	4 (8.7)
Occupation
Student	43 (93.5)	41 (89.1)	0.434††
Manual laborer	2 (4.3)	05 (10.9)
Unemployed	1 (2.2)	0 (0)
Infected scabies
Yes	2 (4.4)	2 (4.4)	>0.999††
No	44 (95.6)	44 (95.6)

*Mann–Whitney U test. ^†Chi-square test. ^††Fischer’s exact test. SD=standard deviation

Outcome assessment

We completed an end-line assessment of 89 participants (96.7%). Three participants could not be contacted after three consecutive home visits in 2 weeks. Of the 89 participants, 19 (21.2%) either consumed one dose of ivermectin or applied permethrin over specific body parts. One participant in the ivermectin arm did not consume the tablet even after giving consent. The compliance in both treatment arms was similar (P > 0.999). We got a similar cure rate among the scabies patients who received either ivermectin (90.7%, CI: 77.9%–97.4%) or permethrin (93.3%, CI: 81.7%–98.6%). All participants were cured after complete treatment, and the cure rate among those who received partial treatment was similar in the two groups [Table 3].

Table 3.

Comparison between the two groups with respect to the outcome using per-protocol analysis (n=88)

Outcome	Ivermectin (n=43) Number (percentage)	Permethrin (n=45) Number (percentage)	P
Cured among those who took complete treatments	34 (100.0)	35 (100.0)	>0.999†
Treatment failure among those who took complete treatments	0	0
Complete treatment taken	34 (79.1)	35 (77.8)	0.883*
Partial treatment taken	9 (20.9)	10 (22.2)
Cured among those who took complete/partial treatments	39 (90.7)	42 (93.3)	0.710†
Treatment failure among those who took complete/partial treatments	4 (9.3)	3 (6.7)
Cured among those who took partial treatment	5 (55.6)	7 (70.0)	0.650†
Treatment failure among those who took partial treatment	4 (44.4)	3 (30.0)

*Fischer’s exact test. ^†Chi-square test

Safety assessment

We observed no serious adverse events, such as hospitalization or deaths, among participants in either group.

Cost description

We calculated the cost of treatment for ivermectin and permethrin. We took the cost for the participants and contacts. We estimated the cost using data from the websites that the national and state health authorities maintained.[18,19] The median number of 6 mg ivermectin tablets required for treating one participant and his/her contacts was 11. The median number of bottles of permethrin required was six for one participant and his/her contacts. The median total cost for one participant in the ivermectin arm was 0.1682$. The median cost of treating one participant with permethrin was 2.2756$. Permethrin’s cost was more than 10 times higher than the cost of ivermectin as per the national-level price.

DISCUSSION

We conducted this study to compare the cure rate after using single-dose permethrin lotion or two doses of oral ivermectin among scabies patients. Per-protocol analysis concluded no statistically significant difference between the cure rates of ivermectin and permethrin arms. Only two participants in the permethrin arm experienced mild adverse effects. Ivermectin was found to be cheaper than permethrin. The cure rate in the permethrin arm is similar to the rates reported in the studies conducted in India and other countries like Iran and Pakistan.[7,8,16,20,21] This finding can be attributed to the mechanism of permethrin, which usually acts against all stages of scabies ectoparasite. The cure rate of ivermectin is similar to the rates reported in the studies conducted by Sharma and Singal[16] and Ranjikesh et al.[8] However, the cure rate is higher than that reported in some of the studies.[10,20] This finding can be attributed to the fact that ivermectin was given as a single dose in those studies. Available studies suggested that the cure rate improved with time passed after treatment. The studies reported a better cure rate after 4 weeks than the outcome after 2 weeks. Previous studies were conducted in areas with facilities for sanitation and hygiene similar to our study. Improvements in Wash, Sanitation, and Hygiene are crucial for the long-term control of scabies as scabies is known as a water-washed disease.

The better safety profile with a similar cure rate outweighs the benefits of ivermectin over permethrin. Lower cost also plays a crucial role in treating scabies in India or similar countries belonging to lower–middle-income countries. Being an oral formulation, ivermectin has an advantage over permethrin, which requires adequate privacy for application. Privacy can be a significant barrier in communities with a higher burden of scabies.[22,23] As scabies is very common in lower–middle-income countries and ivermectin is available at a very low price with a similar cure rate, ivermectin can be used as an effective treatment in lower- and lower–middle-income countries. It can even be given as a directly observed therapy, such as the first dose of tablets can only be administered in the presence of a physician. Even the issue related to privacy in applying permethrin, especially in lower–middle-income countries, can be addressed by using ivermectin to treat scabies. Similarly, a validated tool for early detection of scabies by community health workers can be coupled with oral ivermectin therapy to control scabies disease in lower and lower-middle-income countries.[24]

This trial was conducted in rural marginalized communities where the number of scabies cases is usually higher. It has a significant implication for eliminating scabies as the oral formulation will help in the early treatment of scabies at the community level. We recruited the participants by active screening at the community level, which increases the study’s generalizability. We compared the cost of treatment between permethrin and ivermectin, which is the first of its kind.

Our results are limited to mild and moderate scabies; in our study, we did not have severe or Norwegian scabies, where the treatment regimen may differ. Secondly, we did not assess the outcome for all close contacts of study participants due to feasibility issues. Thirdly, it is not practically feasible to count all the skin lesions around the genitalia and breast region at the community level due to privacy issues. Fourthly, the 100% cure rate in both arms receiving full treatment may suggest a lack of resistance among mites to either ivermectin or permethrin in the study area.

CONCLUSION

Two doses of ivermectin (200 µg/kg) given on days 1 and 7 had a cure rate similar to a single 5% permethrin lotion whole-body application. The cost of treatment by oral ivermectin is low compared to permethrin lotion for scabies patients. Therefore, public health use of oral ivermectin may play a vital role in scabies control. However, further research is required to address environmental determinants to eliminate scabies.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.