Heukelbach et al. BMC Dermatology(2019) 19:14
https://doi.org/10.1186/s12895-019-0094-4

RESEARCH ARTICLE

Open AccessHigh efficacy of a dimeticone-based
pediculicide following a brief application:in vitro assays and randomized controlled
investigator-blinded clinical trial
Jorg Heukelbach1* , Doerte Wolf2, John Marshall Clark3, Hans Dautel4 and Kristina Roeschmann5

Abstract
Background: Increasing resistance of head lice against neurotoxic agents and safety concerns have led to thesearch for treatment alternatives. Dimeticones with a physical mode of action are safe, and bear a reduced risk forthe development of resistance.
Methods: We performed in vitro bioassays to assess pediculicidal and ovicidal activities of a new dimeticone-based
product, and a randomized controlled clinical trial to assess efficacy, following 10 min application. Of 153 individuals
screened, 100 participants with active head louse infestations were randomly assigned to treatment with either adimeticone-based test product, or a 0.5% permethrin-based reference product (50 participants per group).
Participants received two topical applications of either the test (10 min) or reference products (45 min) at days 0
and 7 or 8. Outcome measures included the efficacies of treatment and their safety, as well as global and local
tolerability at baseline, and days 1, 7, and 10.
Results: After 10 min exposure, all lice treated with the dimeticone test product were classified as non-viable in thein vitro assay. Ovicidal activity after treatment of eggs with the dimeticone test product was 96.8%. In the clinical
trial, 96 patients completed all study visits. In the full analysis set (FAS) population, on day 1 after one application,
98% of patients were cured in the test group, as compared to 84% cured in the reference group. All participants inboth groups were free of head lice on day 10, following two applications (100% cure rate). In total, 42 adverse
events (AEs) in 23 patients of both treatment groups were recorded, with the majority of AEs classified as mild.
Conclusions: We have shown a high level of pediculicidal and ovicidal activity, and clinical efficacy and safety, of abrief application of a new dimeticone-based product. The short application time and reduced risk for thedevelopment of resistance are key drivers for improved patients’ compliance.
Trial registration: EU Clinical Trials Register EudraCT 2016–004635-20. Registered 14 November 2016.
Keywords: Clinical trial, Head lice, Body lice, Dimeticone, Pediculicidal activity, Ovicidal activity* Correspondence: heukelbach@web.de
1
Department of Community Health, School of Medicine, Federal University of
Ceará, Rua Professor Costa Mendes 1608, 5. andar, Fortaleza, CE 60430-140,
BrazilFull list of author information is available at the end of the article© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Heukelbach et al. BMC Dermatology(2019) 19:14

Background
Infestation by head lice (Pediculus humanus capitis) is
one of the most common parasitic diseases in childhoodworldwide [1], and there is consensus that infestations
have increased during the last decade [2]. This increase
has been considered to be caused, in part, by the spreadof parasite populations that are no longer susceptible toseveral pediculicides with neurotoxic modes of action,such as permethrin and malathion, following their extensive use since the middle of the twentieth century [3–8].
Knockdown resistance (kdr) mutations in head lice havebeen identified to cause insensitivity to pyrethroid treatment [9, 10]. In Germany, kdr-like mutations were
found in 93% of head lice investigated, but the majority(92.8%) of children that carried these head lice weretreated successfully with permethrin-based products [11,12].
There is evidence that the occurrence of resistance toneurotoxic pediculicides is increasing. The frequency of
kdr-like mutations identified from head lice from allover the U.S. was found to be related to a decrease in
the efficacy of a permethrin-based pediculicide (Nix®)[13]. In fact, randomized controlled clinical trials (RCT)
conducted in the U.S. three decades ago showed curerates for pyrethroids of 96–100% [14, 15], whereas more
recent RCTs demonstrated cure rates of as low as 25%[16]. Obviously, local and geographical distinct resistance patterns are not yet fully understood.
The need for effective and non-toxic pediculicides has
driven investigations for new, effective compounds withgood safety profiles, and with a lower risk to induce insecticide resistance. Consequently, physically-acting pediculicides have become more and more popular, with thesilicone oil dimeticone as the main active ingredient[17]. Dimeticones are linear polydimethylsiloxanes(CH3SiO [SiO(CH3)2]nSI(CH3)2) of varying chain length.
The chain length substantially influences the molecularweight and physical properties of the substance, such as
spreading characteristics. Of the various dimeticonebased head louse products available on the market, convincing data on the efficacy and mode of action exist for
4% dimeticone products (Hedrin®/EtoPril®) and a 92%
dimeticone product (NYDA®) [18–23].
There is a tendency to shorten the application
time in order to increase treatment compliance. Application times as short as 10 min have been described to be effective for products based on mineraloil [24] and neem seed extract [25]. Given the highsocio-economic and psycho-social burden of headlouse infestations, effective, reliable, safe and rapid
treatment options are needed. Contrary to body lice
(Pediculus humanus humanus), head lice are usually
not considered to function as effective vectors for
infectious diseases. However, recent studies provided

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evidence that head lice may serve as vectors for important bacterial pathogens [26].
We performed laboratory and clinical studies to investigate the efficacy and safety of a new rapid-acting
dimeticone-based product of the NYDA® family, following a brief application of 10 min.

Methods
Test and reference products

The pediculicidal test product (PB790) used for both thein vitro studies and the clinical trial, is a dimeticonebased medical device from the NYDA® product family.
All components of the NYDA® formulations have a long
history of use in cosmetics and pharmaceutics and are
regarded as safe. The dimeticones represent the active
component by blocking the respiratory spiracles, thereby
inducing death of both lice and eggs by suffocation [23].
The test product was provided by G. Pohl-Boskamp
GmbH & Co. KG (Hohenlockstedt, Germany).
A formulation containing 1% permethrin (Nix®, CVS
Pharmacy, USA) was used as internal control for the assessment of permethrin resistance of the louse strain in
the in vitro bioassay. The active ingredient of the reference product used in the clinical trial is 0.5% permethrin(cis−/trans-relation 25:75) in alcoholic solution (InfectoPedicul®; InfectoPharm Arzneimittel und Consilium
GmbH, Germany). Permethrin is a broad-spectrum synthetic pyrethroid and has been widely used for the treatment of head louse infestations in children.
InfectoPedicul® and NYDA® are recommended by theFederal Office of Consumer Protection and Food Safety
in Germany (Bundesamt für Verbraucherschutz undLebensmittelsicherheit, 20.10.2015) as disinfestation
agents for the treatment of head louse infestation andare thus recommended pursuant to Section 18 of theGerman Infection Protection Act (IfSG).
Assessment of pediculicidal activity in vitro

Adult body lice (Pediculus humanus humanus) fed on
rabbits were kept at 30.0 ± 1.0 °C and 73.8 ± 3.8% relative
humidity and used within 24 h after the last feeding. The
procedures were applied as described by Oliveira et al.
and Sonnberg et al. [27, 28]. In brief, 40–50 ml of thetest product were placed into porcelain bowls, and prewarmed. For every test run, 30 male and female lice
were transferred into a plastic sieve. The sieve wasplaced into the porcelain bowl, and lice were completely
immersed in the product for 10 min. Upon immersion,lice were carefully separated from each other using aplastic spatula. As a negative control, identical procedures were followed with demineralized water.
Exposure was stopped by washing the test product off
with a 1:4 solution of shampoo (pH Eucerin® Dermo
capillaire, Beiersdorf AG, Hamburg) in tap water. The

Heukelbach et al. BMC Dermatology(2019) 19:14

sieve was then dabbed on tissue paper, rinsed with lukewarm tap water for 1 minute and finally again dabbed
on a tissue paper. Afterwards, the lice were individuallytransferred into labelled glass vials containing some gerbil (Meriones unguiculatus) hairs as a walking substrate.
The vials were left open to observe the lice with a binocular microscope. The time points of observation were:10, 20, and 30 min, 1, 2, 3, 8 and 24 h after treatment.
During monitoring, the viability of each louse was categorized as follows:
L: Alive and walking
M: Moribund, reflexes and small movements observed,
not walking
G: Without reflexes, only gut movements are observed
D: Dead, no movements are observed
Based on published criteria for the assessment of mortality and in compliance to the CRO’s standard protocol,
lice in categories M, G and D were defined as non-viable[27, 29, 30]. Tests were repeated three times to obtain atotal of 90 lice in each group.

Assessment of ovicidal activity in vitro

To evidence ovicidal activity of the test product, we performed laboratory tests. Two in vitro hair tuft bioassays
were performed. First, lice were immersed in the test
and control products, respectively. To simulate moreclosely the exposure conditions as they exist for in vivo
application of the test product, a spray protocol was developed in a second bioassay.
Eggs from permethrin-resistant head lice (Pediculus
humanus capitis, BR-HL strain), originally collectedfrom infested children in Bristol/UK and maintained on
an in vitro rearing system at the University of Massachusetts at Amherst/USA were used in the hair tuft bioassays, similar to the method developed by Strycharz et al.
(2012) [31].
For the immersion bioassays, eggs attached to humanhair tufts (at least 30 eggs/hair tuft of different developmental stages) were treated with the dimeticone test
product or control following an immersing-swirling
method for 10 min. A tuft with attached eggs was saturated with the test product by immersing it into 0.5 ml
for 30 s with swirling on a small glass slide to ensure saturation and complete egg coverage. As an internal control for permethrin resistance, tufts with attached eggs
were saturated for 30 s with 0.5 ml of the 1% permethrin
product as above. For a negative control, a dry tuft with
attached eggs was saturated with 0.5 ml distilled deionized water (ddH2O) as above. After treatments, the tufts
were transferred to a clean Petri dish and placed in an
incubator (31 °C, 70–80% relative humidity) for 10 min.

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Besides immersion, the protocol of the spray bioassays
followed the procedures described above, including a 10
min exposure time. Hair tufts with attached eggs weresaturated with the dimeticone test product or with
ddH2O by spraying the formulation until complete egg
coverage was achieved by visual observation. The preoptimized spraying technique using 12 pumps was
employed to establish consistent applications. Due to thetexture of the internal permethrin control product, theimmersion protocol was used for these groups.
At the end of the exposure time, the tufts from bothbioassays were shampoo-washed by applying 0.5 ml baby
shampoo (Johnson and Johnson, New Brunswick, USA).
The shampoo-treated hair tufts were sequentiallywashed in three separate water baths, each placed on amagnetic stirrer for 40 s per wash and air dried on filter
paper for 5 min at room temperature. Dried tufts withtreated eggs were placed into covered sterile glass Petridishes and moved to an incubator at 31 °C, 70–80% relative humidity. Egg viability was recorded daily by examining individual eggs for proper site, shape, and color.
The number of lice that hatched from eggs was recorded
and used to determine the relative ovicidal activity of thetreatments. Underdeveloped eggs and stillborn lice wererecorded as dead. All treatments were performed threetimes.
Clinical trial
Study design/regulatory background

This monocentric, randomized, controlled investigatorblinded trial with a 1:1 allocation ratio was approved by
the Ethical Review Board of the Landesärztekammer
Thüringen/Germany and by the German Federal Institute for Drugs and Medical Devices (BfArM) by the department for medical devices for the test product, andthe department for medicinal products for the reference
product, respectively. The design of this study and all assessments performed followed international agreements
regarding clinical trials with pediculicides [32]. The primary objective of the RCT was to show that the curerate, corrected for re-infestation, of the dimeticone treatment is superior to 70% (literature-based lowest acceptance rate). The main secondary objectives were to showthat the cure rate of the test product was superior or
non-inferior to the reference product, and to assess
safety and tolerability of the pediculicidal products
tested.
The study protocol followed the ethical principles of
the Declaration of Helsinki, ICH-GCP guidelines (International Conference on Harmonization of Technical Requirements for registration of Pharmaceutical for
Human Use – Good Clinical Practice), requirements of
the German Drug Law including the GCP regulation,and the German Medical Device Law. The trial was

Heukelbach et al. BMC Dermatology(2019) 19:14

registered at the EU Clinical Trials Register(EudraCT2016–004635-20). The study adheres to CONSORT guidelines for reporting clinical trials.
Eligibility criteria

Patients of both sexes with active head louse infestations
were eligible. Children were included, if they were 2
years of age or older. The reference product was administered according to the most current SPC that wasavailable in Germany before start of the study. For children aged 2 months to 3 years, a maximum dose of 25
ml must not be exceeded, which was strictly followed forchildren < 3 years. Active infestation was defined as thepresence of at least 5 live lice, confirmed by diagnostic
combing using combs with a tooth gap of 0.2 mm andtips with blunt parallel-sided teeth.
Patients or their guardians had to be capable of understanding written informed consent form and to give
written informed consent after being informed about
benefits and potential risks of the trial, as well as details
on the insurance covering the subjects participating inthe study. Patients had to agree not to use any otheranti-lice treatment for the duration of the study. Female
patients of childbearing potential had to be tested negative for pregnancy and had to agree to use a reliable
method of birth control or remain abstinent during thestudy.
Patients were excluded if they had used any head lice
treatment within the last 30 days prior to the screening
visit; used systemic or topical drugs or medications, including systemic antibiotics, which in the opinion of theinvestigative personnel may interfere with the study results; in the case of allergies or hypersensitivities against
any of the active ingredients or the constituents of the
products used, skin allergies, multiple drug allergies ormultiple allergies to cosmetic products, severe acutescalp disorders, hair longer than mid-back, high probability or known not to follow instructions, or previous
participation in this study or in any other investigational
trial within the preceding 30 days. Pregnant and breastfeeding women were also excluded.
We did not include patients unable to understand thewritten and verbal instructions given by the study
personnel, in particular regarding the risks and inconveniences. Personnel directly affiliated with this study and/or their immediate families and G. Pohl-Boskamp employees or employees of third-party organizations involved in the study were also excluded.
Setting

Recruitment, treatment and diagnostic assessment of patients took place from 18th April, 2017 (first patient in)
to 16th March, 2018 (last patient out) at a clinical trial
center in Erfurt, Germany, specialized in conducting

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trials with children and experienced in diagnosis andtreatment of head louse infestations. Patients/guardians/
caretakers were informed about this study via advertisements, flyers, letters to primary schools and preschools,
and internet on-screen displays. All texts used for recruitment had been approved by the responsible ethics
committee. Patients/ guardians/caretakers had to contact
the study center to arrange an appointment, and after
initial assessment of infestation and informed consent
procedure, patients were included and allocated to treatment groups.

Intervention

Two topical applications, as recommended for treatmentof head louse infestations, were performed [32, 33]. The
first treatment was applied on day 0 (V1), the second on
day 7 or 8 (V3).
Treatments required individual amounts of the investigational products to completely cover hair and scalp of
the patient. Both products were applied as recommended by the manufacturers. The test product was
evenly sprayed until the hair was completely wetted withthe solution and then massaged into the dry (notwashed) hair over its full length, with special diligenceon the base of the hair near the scalp and the ear region.
Curly, long and thick hair was treated in strands. After
10 min without covering, the hair was combed carefully
with the nit-comb to remove suffocated lice and eggs.
Afterwards the product was washed out with a commercially available shampoo and the hair was rinsed
thoroughly.
For application of the reference product, the hair waswashed with a commercially-available shampoo andtowel-dried. Afterwards, the product was evenly dispensed onto the hair over its full length, again, with special diligence on the base of the hair near the scalp andthe ear region. Curly, long and thick hair was treated instrands. After 45 min without covering the hair, theproduct was washed out with warm water without shampoo. Afterwards, the hair was again carefully toweldried. Before the hair was completely dry, combing witha nit-comb was performed according to the manufacturer’s instruction for use, to eliminate the eggs. The
participants dried their hair by themselves or with thehelp from their guardians, using a hair dryer.
Metal combs were used, with a gap of 0.2 mm and tips
with blunt parallel-sided teeth. The same comb types
were used for both groups.
According to the instructions for the reference product, participants were instructed not to wash their hairwith shampoo within the next 3 days, to possibly increase the ovicidal efficacy of permethrin. To keep both
treatments as similar as possible, the instruction of not

Heukelbach et al. BMC Dermatology(2019) 19:14

washing the hair within 3 days after application was also
given for the test group.
Informed consent, outcome measures and assessments

The primary outcome was defined as the cure rate at theend of day 10 (V4), corrected for re-infestation. Assessments for head louse infestations were performed ondays 1 (V2), 7 or 8 (V3) and 10 (V4), by blinded study
staff. Definition of re-infestation was based on current
literature: no adult lice or third stage nymphs following
first treatment at day 1 (V2), and no more than two
adult lice or third stage nymphs found by combing following second treatment on day 10 (V4) [34].
Secondary outcome measures included: global tolerability and local tolerability, rated by the patients andthe blinded investigator via 4-point VRS (Tables 4 and5); skin irritation and eye irritation, assessed by theblinded investigator using a 4-point VRS. The estheticaleffect of the products was evaluated (look of hair; feelingof hair; sensation on scalp; categories: “strongly agree”,“agree”, “disagree”, “strongly disagree”) by structured
questionnaires. Date, number and type of adverse eventswere documented.
A total of four assessments were performed (V1-V4).
At day 0, during the screening visit, patients were registered and enrolled. After informed consent procedureand signing of the informed consent form (ICF), confirmation of the diagnosis, and assessment for exclusion
and inclusion criteria, participants were randomized to
one of the two intervention groups. Baseline data (gender, age, hair length, hair type, medical history, concomitant medication) were assessed before treatment. Within
1 hour before first application and 1 hour after application of the respective product, the following assessments
were done: assessment of skin irritation, assessment ofeye irritation and assessment of adverse events (AE).
Additionally, 1 hour after application on V1 and V3 andalso during V2 and V4, assessment of global tolerability
and local tolerability were performed. These assessments
were repeated on days 7 (V3, before and after treatment)
and on 10 (V4, final assessments). Application of thequestionnaire on esthetical effects was done only after
treatment on day 0 (V1) and day 7 (V3).
At all visits after treatment (V2-V4), AEs were recorded for start and end dates and times, seriousness,
expectedness, severity, causal relationship to investigational product, and causal relationship to study procedure and evaluated for events per subject and study
group. All deteriorations were documented as AEs.
Upon recommendations of the Robert Koch Institute[33] and in line with current state-of-the-art clinical trials [24], patients were allowed to use a nit-comb between study visits. At every visit, patients or theirguardians (in the case of minors) were asked if they used

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the nit-comb provided and answers were documented in
the electronic case report form (eCRF).
All assessments of primary and secondary outcome
measures were performed by investigators blinded to thetreatment applied.
Sample size

According to previous preclinical studies with the dimeticone test product and to preclinical and clinical studies
with products from the NYDA® family, a 90% cure rate
was expected for the test product. A pre-defined limit of
70% was determined from reported cure rates forpermethrin-containing products (range from 34.8 to
98.0%, mean 66.6%, approximated to a 70.0% cure rate)
and was defined to be the minimal acceptable cure rate
[35–38]. A sample size of 42 was required for a one
group χ2-test comparing cure rate of 90% with a fixed
limit of 70% (two-sided test; alpha-level of 0.05; power =90%; software nQuery advisor 7.0; power = 80%: sample
size = 34). Assuming a 10% drop out rate and 5% reinfestation rate, 49 cases would be required in eachgroup, which was rounded up to 50.
Randomization

Participants were randomized to one of the two headlouse treatments by a computer-generated code using
randomly mixed blocks of 10, with a final and random 1:
1 allocation. Randomization, enrollment of participants,
and assignment of specific participants to one of the twointerventions were performed by an investigator not involved with assessment of outcome measures.
Blinding

The study was observer-blinded. As both products differ
substantially from each other in terms of packaging,smell, application method and exposure time, doubleblinding was not possible.
All staff members involved in assessments of primaryand secondary outcome measures (investigators andstudy staff performing the assessments of hair and scalp,
eyes, as well the efficacy and safety evaluations) wereblinded to treatment assignment. The assessors were not
involved in handling, storage, and use of the products,
and did not have access to the eCRF entries regarding
application of investigational products, such as usedamount or start and stop time of exposure.
Statistical analyses
Pediculicidal activity in vitro

At each point of time of observation, the relative frequencies of non-viable lice (categories M + G + D) were
calculated for each test run, and the arithmetic mean ±standard deviation (SD)was calculated. Relative frequencies of lice treated with the test product and the waterHeukelbach et al. BMC Dermatology(2019) 19:14

control were compared using Fisher’s exact test using
the Statistica® v.7.1 software (StatSoft, Tulsa, USA). For
determination of pediculicidal activity, endpoint mortality of lice (mortality determined 24 h after treatment)
was compared between test and control.
Ovicidal activity in vitro

The mean percent ovicidal activity (± SD) was determined and statistically analyzed using Shapiro-Wilk Testfor determination of normal distribution, 2-factorial
ANOVA and test for homogeneity of variance (Levenes).
Number of replicates was 3 (immersion protocol) and 4(spray protocol), respectively.
Clinical trial

Statistical analysis of data obtained from the RCT
followed the predefined statistical and analytical plan
(SAP). Descriptive statistics (continuous variables:
mean ± SD; ordinal variables: median, min, max, Q1, Q3;
categorical variables: counts and relative frequencies)
was performed by visit and treatment.
For the primary objective, the following null hypothesis was tested: H0prim: pT = 70%. If pT > 70% and if thenull hypothesis was rejected by a two-sided, one sample
χ2 test at 0.05 level, superiority would be concluded.
The primary objective was analyzed in the full analysis
set (FAS). The secondary objectives were analyzed in
FAS and per-protocol population (PP).
Due to no observed differences for the cure rates after
correction for re-infestation (100% efficacy for both
treatments), non-inferiority testing was performed in the
PP population, with a predefined non-inferiority marginof 7.5%. The following null-hypothesis was tested at an
α-level of 0.025. H0,NI: pT-pR < δ, whereby δ = − 7.5%.
The lower, one sided 97.5% confidence interval of difference pT-pR was used for the test. With a confidence
limit of ≥ − 7.5, hypothesis H0,NI was rejected and noninferiority was concluded. The differences of cure rates
pT-pR as well the cure rates pT and pR are presented
with two-sided 95% confidence interval. NCSS 12.0.2
software was used to calculate the 95% confidence interval for the difference of zero (Miettinen-Nurminen
Score).
Cure rates (pT and pR) and difference between curerates (pDiff = pT - pR) with their two-sided 95% CI including results of two-sided, two sample Fisher’s exact
test were calculated. Effect of hair characteristics on efficacy of the products was evaluated via Kruskal-WallisTest.
The use of a nit-comb during clinical trials is controversial, as combing may increase efficacy [32]. To estimate the effect of combing, in a post hoc analysis, theassociation between the occurrence of treatment failures
and patients’ implementation of combing was evaluated.

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For this purpose, treatment failures and combing were
evaluated for independence of categorical variables by
chi-squared test and by Fisher’s exact test (for small expected frequencies).

Results
Pediculicidal activity in vitro

Figure 1 shows the pediculicidal activity of the test product. Ten minutes after treatment, all lice were classified
as non-viable (categories M, G or D). After 10 min, only
two lice (2.2%) and after 120 min one louse (1.1%) wereclassified in the category M (moribund, reflexes andsmall movements observed); at all other observation
points, all lice were classified as G or D (i.e. no or only
gut movements). No lice recovered from the nonviability status during the observation period of 24 h(Fig. 1).
All control lice were viable 3 hours after treatment.
After 8 hours, mortality was only 1.1%. After 24 h, mortality was 7.8% (SD ± 2.4%). The difference in endpoint
mortality between treated and control lice was highly
significant at all observation points (p < 0.001).
Ovicidal activity in vitro

A total of 98 eggs were tested for ovicidal activity of thetest product according to the immersion protocol, and159 eggs according to the spraying protocol. The use ofdifferent treatment protocols did not result in significant
differences: mean ovicidal activity after treatment of eggs
with the test product was 93.0% (SD ± 4.2%) after
immersion, and 96.8% (SD ± 3.7%) after spraying.
Ovicidal activity for the internal permethrin control
was 63.1% (SD ± 25.2%) and 56.2% (± 33.2%), respectively. Incubation of the eggs with ddH2O as negative
control did not result in any considerable ovicidal effect(6.8%; SD ± 3.7% after immersion and 4.2%; SD ± 8.3%
after spraying).
Clinical trial
Participants and baseline demographic data

The flow of participants through the trial is presented inFig. 2. Out of 153 subjects assessed, 103 were eligible
and screened for head louse infestations. Of these, 100
were enrolled and randomized into one of the two treatment groups. One patient of the test group withdrew
consent after day 1 (V2) for unknown reasons and was
excluded from the trial.
In total, 96 patients completed all study visits. One patient of the test group dropped out after a serious adverse event (SAE). Due to hospitalization, the patient
missed the second treatment at day 7 (V3), but returned
to complete the final visit at day 10 (V4). Two patientsof the reference group were excluded from PP analysis

Heukelbach et al. BMC Dermatology(2019) 19:14

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Fig. 1 Pediculicidal activity of the test product during monitoring from 10 min to 24 h after treatment, 90 adult body lice per group; Lice fulfillingthe categories “M” (moribund), “G” (only gut movements) and “D” (dead) were classified as non-viable

Fig. 2 Flow of participants through the trial

Heukelbach et al. BMC Dermatology(2019) 19:14

after day 1 (V2) because they used additional head louse
treatments.
Baseline characteristics are presented in Table 1. Most
participants were children and female. Adults (18 years
and older) accounted for about 20% of participants. In
general, both treatment groups were comparable. The
proportion of children aged 2 to 6 years was higher inthe test group, as compared to the control group. In
total, 33 patients had thin hair, distributed similarly tothe treatment groups (Table 1).
The majority of participants were initially assessed tohave a mild or moderate grade of head lice infestation.
In general, infestation grades were comparable for both
treatment arms. At baseline, patients had a mean

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number of 1.7 adult lice (SD ± 2.0; range: 0–13) and 9.34
nymphs of all grades. Mean, median and maximum
numbers of adult lice and nymphal stages at baseline are
depicted by group in Table 2. Maximum number ofadult lice and nymphs per patient was 49 in the test
group and 41 in the reference group.

Primary outcome

In the FAS population, all participants in both groups
were cured from head lice infestations on day 10 (100%cure rate, Table 3). In the reference group, one participant was assessed to have a re-infestation. Both treatment products achieved the primary objective of

Table 1 Baseline demographic and clinical characteristics for both study groups
Age (years)

Age (groups)

Dimeticone group (n = 50)

Permethrin group (n = 50)

Mean (SD)14.08 (13.7)

15.2 (11.7)

Median (Q1-Q3)

9.5 (6.0–13.7)

10.5 (8.1–13.7)

2 to < 6 years (n, %)13 (26.0)

3 (6.0)

6 to < 11 years (n, (%)

19 (38.0)

24 (48.0)

11 to < 18 years (n, %)8 (16.0)

12 (24.0)≥ 18 years (n, %)10 (20.0)

11 (22.0)

Sex

Male (n, %)6 (12.0)

8 (16.0)

Female (n, %)44 (88.0)

42 (84.0)

Childbearing Potentiala

Yes (n, %)21 (47.7)

24 (57.1)

Ethnicity/skin color

Hair length

Hair color

Hair thickness

Hair type

Severityab

Women onlyb
including adult lice and nymphs

No (n, %)23 (52.3)

18 (42.9)

Caucasian (n, %)47 (94.0)

49 (98.0)

Other (n, %)3 (6.0)1 (2.0)

Short (n, %)8 (16.0)

8 (16.0)

Shoulder long (n, %)24 (48.0)

22 (44.0)

Mid back (n, %)18 (36.0)

20 (40.0)

Long (n, %)0 (0)0 (0.0)Black (n, %)5 (10.0)

2 (4.0)Blonde (n, %)19 (38.0)

20 (40.0)

Brown (n, %)24 (48.0)

22 (44.0)

Red (n, %)1 (2.0)5 (10.0)

Grey (n, %)1 (2.0)1 (2.0)Thin (n, %)18 (36.0)

15 (30.0)

Normal (n, %)22 (44.0)

25 (50.0)

Thick (n, %)10 (20.0)

10 (20.0)

Straight (n, %)33 (66.0)30 (60.0)

Wavy (n, %)17 (34.0)

15 (30.0)

Curly (n, %)0 (0.0)5 (10.0)

Mild 5–9 lice (n, %)26 (52.0)

20 (40.0)

Moderate 10–24 lice (n, %)23 (46.0)

28 (56.0)

Severe > 24 lice (n, %)1 (2.0)2 (4.0)

Heukelbach et al. BMC Dermatology(2019) 19:14

Page 9 of 14

Table 2 Grade of infestation at baseline (V1)
Dimeticone group
Mean (median; maximum; Q1-Q3)

Permethrin group
Mean (median; maximum; Q1-Q3)

Adult lice

1.6 (1.0; 13; 0–2)

1.9 (2.0; 7; 1–3)

Nymphal instars 1

3.6 (3.0; 21; 2–5)

4.0 (3.0; 13; 2–4)

Nymphal instars 2

3.6 (3.0; 15; 2–5)

3.6 (3.0; 14; 2–4)

Nymphal instars 3

1.7 (2.0; 8; 0–3)

2.2 (2.0; 7; 1–3)

superiority to the pre-defined cure rate of > 70% (p-value< 0.001).
Non-inferiority of the test product could be concluded
for both PP (Miettinen-Nurminen Score: 95% CI = [−7.41; 7.41]; p = 0.025) and FAS populations (MiettinenNurminen Score: 95% CI = [− 7.27; 7.41]; p = 0.024).
These confidence limits are greater than the pre-defined
margin of − 7.5, and therefore, the null hypothesis was
rejected, and non-inferiority was concluded.
At day 1 (V2) efficacy of the test product (98.0%) was
significantly higher (95% CI = 89.35–99.95%), as compared to the control group (84.0%; 95% CI = 74.75–
95.27%; p = 0.031). For mild and moderate infestation
rates, the test product showed a higher efficacy, as compared to the control group (98% versus 87.5%), albeit
not statistically significant (p = 0.059).
In the dimeticone group, within a post hoc analysis,
one adult louse and 1 second instar (N2) nymph were
found at day 7, but no live lice or nymphs at day 1 (V2).
However, the N2 nymph detected most likely resulted
from eggs that survived treatment and therefore a reinfestation is not assumed.
Hair characteristics of participants, such as hair length,
hair color, or hair type had no effect on the efficacy ofthe products tested when baseline infestations were of
mild or moderate severity (for all parameters p > 0.5;
Kruskal-Wallis-Test). Due to the low number of severebaseline infestations, the possible effect of hair characteristics on efficacy could not be evaluated.
We found that 39 patients of the 100 patients includedin the trial reported at least at one of the visits no additional combing. A total of five patients reported no
combing at all throughout the course of the study. All
these five patients were cured from head lice. Evaluation
for independence of the variables for each of the visits
revealed no statistically significant association between
cure rates at V2 (p = 0.67) and V3 (p = 0.69), and the implementation of combing by the participants or their
Table 3 Cure rates at day 1, day 7, and day 10 (FAS analysis)
Dimeticone group

Permethrin groupDay 1 (V2)

49/50 (98.0%)42/50 (84.0%)

Day 7 (V3)

40/48 (83.3%)

35/48 (72.9%)

Day 10 (V4)

49/49 (100%)

48/48 (100%)

guardians. Twenty seven patients reported no combing
at V4, but the effect could not be evaluated statistically,
as no treatment failures occurred.
Adverse events

After adjustment for pre-treatment signs and symptoms(PTSS), a total of 26 adverse events (AEs) occurred in 11
patients in the dimeticone group, and 16 AEs in 12 patients in the permethrin group. One patient treated withthe test product presented a serious AE (atypical pneumonia), which was also initially considered a serious adverse device effect which led to the drop-out of thepatient for V3. A detailed evaluation revealed that the
SAE was not product-related.
Most AEs classified as related to treatment included
skin and subcutaneous disorders. Erythema occurred in
3 participants of the test and 7 of the reference group.
Pruritus was reported by 4 participants of the test groupand 3 of the reference group. Skin burning was stated by
2 participants treated with the test product, and 3
treated with the reference product. Six patients of thetest group and one patient of the reference group reported paresthesia after treatment.
The AEs were mild in 30 of 42 documented cases; thisrefers to 20 AEs in the test group and to 10 AEs in thereference group. Moderate severity was noted for 10 AEs(test group 4 AEs; reference [6] AEs). All other eventswere classified as unrelated or unlikely to be related withthe products.
Two patients received specific medication for treatment of AEs (atypical pneumonia in the test group; conjunctivitis in the reference group). All other AEs
resolved spontaneously without any specific treatment.
Secondary outcomes
Global tolerability

Global tolerability was mostly assessed as “very good” byparticipants or their guardians, followed by “good” inboth treatment arms (Table 4).
Only a few patients (3.1%) stated “moderate” global
tolerability. Global tolerability as assessed by the investigators was “very good” in nearly all patients, only in a
few patients (4.0%) “good” or “moderate” (2.0%) global
tolerability was documented. In total, both treatments
showed a comparable global tolerability, which was “veryHeukelbach et al. BMC Dermatology(2019) 19:14

Page 10 of 14

Table 4 Global tolerability assessed by patients/their guardiansand blinded investigator via 4-point VRS
Patient

Investigator

Dimeticone

Permethrin

Dimeticone

Permethrin

Very good 41/49 (85.4%) 41/48 (85.4%) 48/49 (98.0%) 44/48 (91.7%)
Good

6/49 (12.2%)

6/48 (12.5%)–

4/48 (8.3%)

Moderate

2/49 (4.1%)

1/48 (2.1%)

1/49 (2.0%)

–

Poor

–

–

–

–

good” or “good”, none of the products was assessed to
be of poor tolerability.
Local tolerability

Pruritus, burning sensation and paresthesia after treatment are presented in Table 5. Burning sensation andparesthesia occurred in a comparable number in both
treatment groups. Pruritus was more common in thereference group, which is reflected by the more pronounced improvement of pruritus at visit 1 after treatment in the test group (73.5% improvement), as
compared to the reference group (62.0% improvement).
Skin irritation

There was a good skin tolerability in both groups. Erythema occurred more often in the reference group (12%versus 16% after first treatment and 2.1% versus 8.3%
after second treatment). No secondary infections werereported at any point in time during the trial.
Esthetical effects

The majority of patients/their guardians was satisfied
with the esthetical effects of the treatments. In the test
group, 90% of patients agreed with the statement “hairlooks good”, as compared to 96% in the reference group.
The item “hair feels well-groomed” was agreed less
Table 5 Local tolerability assessed after treatment in both study
groups at any visit (total events)
Dimeticone group

Permethrin group

Mild

37

52

Moderate

4

6

Severe

0

1

Mild

3

2

Moderate02

Severe

0

0

Mild

12

7

Moderate00

Severe00Pruritus

Burning

Paresthesia

commonly by patients that received the test product(88% versus 96%). The item “scalp feels pleasant” wasslightly more agreed by patients treated with the test
product than by patients treated with the reference
product (66.7% versus 64.6%).

Discussion
Our in vitro bioassays and the clinical trial have shownthat the dimeticone-based pediculicide is a safe and efficacious treatment against head louse infestations. After
brief exposure time, the product produced a 100% curerate. This result is particularly important in the current
situation of increasing head lice resistance to thepermethrin-based OTC formulations available. We consider our study population in the randomized trial as
representative of the general population with head louse
infestations in Germany that seek care at clinical centers,
because the only exclusion criterion that led to noninclusion was the absence of active infestation.
Technological constraints in the treatment of headlice, such as product concerns, treatment techniques,
and resistance to products, are important head lice management issues, as perceived by parents [39]. An excellent safety profile and short application time may
increase patients’ and parents’ compliance. In this context, the dimeticone product fills a critical gap: it is a
rapid, highly efficacious and safe treatment, based oncomprehensive evidence. Data available include description of the precise mode of action, appropriately designed clinical trials, pediculicidal and ovicidal bioassay
data, and evidence a high efficacy even in the case ofhigh parasite load and in the presence of resistant strains[23, 31, 40, 41].
The in vitro bioassays have shown 100% pediculicidal
activity after an application time of only 10 min. Thesefindings corroborate previous in vitro studies with adimeticone-based product and an application time of 20
min [31] and support data showing that the product kills
head lice within minutes. The criteria for determinationof mortality followed standard protocols of the laboratory. Even after applying more stringent criteria for thesurvival of lice, the results were similar.
An explanation of the extremely rapid onset of the lethal effect has been provided previously by Richling and
Böckeler (2007) [23]: the high concentration dimeticone
product penetrates into the respiratory system of headlice in less than 1 minute and vital signs disappear after
dimeticone completely fills the oxygen-supplying tracheae of the louse’s head. Similarly, ovicidal activity wasalmost 100%, following the brief exposure time of 10
min. Increasing the exposure time to 20 or 30 min only
marginally increased the efficacy (data not shown).
Simulation of practical application by testing the activity
using a spray protocol instead of immersion of eggs did

Heukelbach et al. BMC Dermatology(2019) 19:14

not substantially change the ovicidal activity of the test
product. These results confirm data from previous
in vitro bioassays in which exposure times slightly longer
than 10 min were used [31]. The consistently high ovicidal efficacy of the dimeticone test product can be explained by the extremely low viscosity of one dimeticone
acting as a vehicle for the other dimeticone with aslightly higher viscosity, facilitating the rapid entry of
both into the aeropyles of eggs, similar to the entry into
the spiracles of lice. The current findings of our randomized trial validate the in vitro data.
In comparison to other pediculicides with a physicalmode of action, the test product had a substantially improved efficacy only after one treatment, with 98% of patients assessed to be free from lice 24 h post treatment.
In previous studies using comparable study protocols, amineral oil-based pediculicide had a cure rate of 90%
after one treatment [24], and a 4% dimeticone-based
product was assessed to achieve a cure rate of 69.8%
after a single 15 min application [42].
Interestingly the permethrin-based reference product also showed high efficacy in our trial, where 84%of patients were assessed to be free from lice at day
1, following a single treatment. This observed efficacy for the reference product was higher than expected.
Geographicallydistinct
patternsofpermethrin resistance are not fully understood sofar, but obviously, local German lice populations do
not display high levels of resistance, as observed forhead lice in other countries such as the U.S. Treatment of head louse infestations with products basedon a physical mode of action, like dimeticones,
which is the treatment of choice in Germany, has
likely decreased the selection pressure on head louse
populations from the permethrin-based pediculicides,
thereby reducing the level of resistance in local populations. Also, the permethrin-based product used inGermany is not the same as the permethrin-based
product used in the U.S.
The majority of patients (97.0%) was assessed tohave mild to moderate grades of infestation at baseline, which is in line with current literature and clinical trials performed in Europe. Sex distribution andgrade of infestation at baseline were comparable inboth treatment groups. After random allocation to
one of the two treatment groups, the proportion ofchildren in the age group 2 to 6 years was higher inthe test product group when compared to the reference product. Evaluation of the hair structure of thepatients, however, revealed that there was no relevant
difference in the allocation of patients with the haircharacteristic “thin” to either of the treatment groups.
Furthermore, all hair characteristics documented had
no influence on the efficacy of the products tested.

Page 11 of 14

As one key element of successful eradication of headlouse infestations is the correct administration of the
product, treatment at the study center by well-trained
personnel diminished the risk of application errors, ascompared to administration at home by the parents. The
strict adherence to the instructions for use might, inpart, explain the unexpected high cure rates observed
for the permethrin reference product. Furthermore, application time for the reference product within this study
was 45 min, which is at the top end of the recommended
application time range of 30 to 45 min. The fact that efficacy in the permethrin group was better than expectedfrom reports on similar preparations might be attributed,
in part, to absence of local resistance.
At day 7 (V3), treatment with the test product resulted
in a cure rate of 83.3%. Nymphs hatching from treated
and apparently dead eggs may not be able to develop to
adults. Even if they become fully matured, they may not
be fertile or display reduced longevity, as shown informer studies. Strycharz et al. (2002) showed thatnymphs hatching from dimeticone-treated eggs showed
reduced longevity. After 10 min exposure of eggs to adimeticone-based product, 16% of eggs hatched, butfrom these only 7% of nymphs reached adulthood and,furthermore, were observed to have a reduced longevity
in comparison to controls. Thus, apoptotic processes
may have been initiated early on in the louse’s development because of the stress incurred during embryonicdevelopment after treatment with a dimeticone-based
product. Consequently, reduced adult longevity would
result in the production of substantially fewer eggs during the shorter adult lifespan [31].
Pruritus showed a more pronounced decrease after
treatment within the group of patients receiving dimeticone, possibly reflecting the higher cure rates observed
for the test product at day 7. Both the test and the reference products were assessed to be safe and welltolerated, with the majority of AEs being classified as
mild. One patient treated with the test product presented a serious AE (atypical pneumonia). Although initially evaluated as “possibly related” by the principal
investigator, a causality between the SAE and the treatment with the test product was later considered as unlikely, as the SAE occurred 5–6 days after treatment, andindependent from an initial mild erythema and allergic
reaction that resolved without medical treatment shortly
after occurrence.
In general, there are several safety concerns of thegroup of pediculicides with a neurotoxic mode of action,such as transcutaneous resorption of the active ingredient [43], development of hypersensitivity against pyrethroids, severe neurological complications after
accidental ingestion, and increased risk for the development of childhood leukemia [44]. According to the Co-

Heukelbach et al. BMC Dermatology(2019) 19:14

ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), warnings had to be
implemented in the respective summary of permethrin
products characteristics in order to maintain a positiverisk-benefit profile [45]. The information on the risk for
hypersensitive reactions had to be included and for therisk of systemic intoxication in children 2–23 months ofage the need for a close medical supervision had to bestated. In this context, dimeticone-based products havethe advantage that they do not bear these risks and thatthey are effective, also in the presence of pyrethroid
resistance.

Study limitations

In general, in vitro test conditions only partially reflectin vivo conditions. To better mimic the in vivo situation,for ovicidal testing we applied the products using a spraymethod, in addition to the traditional immersion procedure. However, the differences between the methods,
did not influence the high ovicidal efficacy observed
throughout the experiments.
For technical reasons, eggs in different developmental
stages were used in the experiments on ovicidal activity.
It would have been preferable to perform the tests withbatches of eggs with defined developmental characteristics, such as developed eye spots and embryonic movements. A previous study showed that the ovicidal
activity of dimeticone was not influenced by the development stage of the embryo. However, with other dimeticone products and treatment options based on aneurotoxic mode of action hatchability depended on developmental stages [41].
The use of a nit comb within clinical trials testingproducts to control head louse infestation is controversial, as efficacy of the products tested may be affected.
This is definitely the case for therapeutic wet combing,but is less of concern with diagnostic dry combing. In apost hoc analysis, we did not find any statistically significant association between the cure rates and the implementation of combing, and all patients that did not use
a nit comb throughout the course of the study were
cured.
To have treatment protocols as similar as possible forboth groups of patients, the restriction not to wash thehair within 3 days after application of the treatment was
followed for all patients, even though this restriction resulted from the instruction for use only for the reference
product and was to the disadvantage of the test product.
The minor differences observed in the evaluation of theesthetical effects may have therefore resulted from dimeticone residues in the patient’s hair, which would havebeen washed off, if the test product instructions had
been followed.

Page 12 of 14

Conclusions
We have shown a high level of safety and efficacy following brief application of a new dimeticone-based product,as evidenced by in vitro bioassays and a randomized
controlled trial. The short application time and the highefficacy, also in the case of resistance, are key drivers for
improved patients’ compliance.
Abbreviations
AE: Adverse Event; BfArM: German federal Institute for Drugs and medical
Devices; CRO: Contract Research Organization; eCRF: Electronic case Report
Form; FAS: Full Analysis Set; GCP: Good Clinical Practice; ICF: Informed
Consent Form; ICH: International Conference on Harmonization; IfSG: German
Infection Protection Act; Kdr: Knockdown Resistance; min: Minute;ml: Milliliter; mm: Millimeter; PP: Per Protocol; PTSS: Pre Treatment Signs andSymptoms; RCT: Randomized Controlled Clinical Trial; SAE: Serious Adverse
Event; SAP: Statistical and Analytical Plan; SD: Standard Deviation; U.S.: UnitedStates of America; V: Visit; VRS: Verbal Rating Scale
Acknowledgements
The authors would like to thank all patients that contributed to this trial, theinvestigators and the study personnel at the study center for including
patients in compliance with the study protocol. The authors also would liketo thank the independent contract research organisation (CRO) responsible
for conducting and reporting the study (CardioSec GmbH, Erfurt, Germany).
JH and KR had full access to all the data in the study and take responsibility
for the integrity of the data and the accuracy of the data analysis. Planned
statistical analysis was performed by Dr. Thomas Keller, ACOMED statistik,
who is a self-employed statistician.
Authors’ contributions
DW, JC, HD and KR were responsible for study concept and design. DW, JC
and HD conducted the study and the statistical analysis. JH, DW, JC and HD
were responsible for interpretation of data. JH and KR drafted themanuscript. All authors critically revised the manuscript for intellectual
content, read and approved the final manuscript.
Funding
Pohl-Boskamp GmbH & Co. KG as the sponsor of the in vitro studies and the
RCT was involved in the study planning as well as in the decision to publish,
but was not involved in data collection, data analysis and data interpretation.
Availability of data and materials
The final clinical study report (CSR) contains full names and addresses of thestudy personnel involved, as well as commercially confident information.
Therefore, a blackened version of the CSR will be made available only upon
reasonable request (Dr. Kristina Röschmann, Director Clinical Research, G.
Pohl-Boskamp GmbH & Co. KG Germany, k.roeschmann@pohl-boskamp.de).
Ethics approval and consent to participate
The clinical trial was approved by the Ethical Review Board of theLandesärztekammer Thüringen/Germany and by the German Federal
Institute for Drugs and Medical Devices (BfArM) by the department for
medical devices for the test product, and the department for medicinal
products for the reference product, respectively. All participants were
undertaken an informed consent procedure and signed the informed
consent form (ICF). As children that participated in this study were unable toprovide legally binding consent, the legal representative/s of all minor
participants had to give informed written consent on his/her behalf prior toenrolment in the trial, and after having been informed about all details
concerning the trial (patient information and informed consent from).
Furthermore, age appropriate consent forms were used for children aged 7–
11 year, and adolescents aged 12–17 years. All minors included in this trial
provided written or verbal assent, according to age, witnessed by the parent
or guardian.
Consent for publication
Not applicable.

Heukelbach et al. BMC Dermatology(2019) 19:14

Competing interests
KR is an employee of Pohl-Boskamp and was involved in drafting the manuscript, revising it critically for important intellectual content, ensuring thatquestions related to accuracy and integrity of the work are resolved. PohlBoskamp engaged the CRO CardioSec Clinical Research GmbH to design andperform the clinical trial. Principle investigator was DW, who is managing director of CardioSec Clinical Research. Pohl-Boskamp provided salaries to JC
and HD on a work-for-hire basis and remunerated the CRO CardioSec ClinicalResearch GmbH for their services in performing the study. DW is a company
member of CardioSec Clinical Research GmbH without any financial or personal interest in the test product. JH has been an independent scientific consultant to Pohl-Boskamp GmbH & Co. KG.
Author details
1
Department of Community Health, School of Medicine, Federal University of
Ceará, Rua Professor Costa Mendes 1608, 5. andar, Fortaleza, CE 60430-140,
Brazil. 2CardioSec Clinical Research GmbH, Dalbergsweg 21, 99084 Erfurt,
Germany. 3Department of Veterinary & Animal Sciences, MassachusettsPesticide Analysis Lab, University of Massachusetts Amherst, Amherst, MA
01003, USA. 4IS Insect Services GmbH, Motzener Straße 6, 12277 Berlin,
Germany. 5G. Pohl-Boskamp GmbH & Co. KG, Kieler Straße 11, 25551
Hohenlockstedt, Germany.
Received: 25 April 2019 Accepted: 20 September 2019

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