1 Supplemental Table I. Databases and search strategies Database Step Query Items found MEDLINE via PubMed #1 scabi* 4555 #2 sulfur 76488 #3 sulphur 76488 #4 "benzyl benzoate" 493 #5 lindane 5422 #6 "benzene hexachloride" 695 #7 hexachlorocyclohexane 6123 #8 malathion 3482 #9 malation 11 #10 crotamiton 147 #11 permethrin 3273 #12 ivermectin 6985 #13 pyrethr* 9580 #14 aloe* 3046 #15 "Plants, Medicinal"[Mesh] 56204 #16 #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 161400 #17 #1 AND #16 1080 #18 #1 AND #16 Filters: Humans 806 Scopus #1 ALL ( scabi* ) 18593 #2 ALL ( sulfur ) 838627 #3 ALL ( sulphur ) 838627 #4 ALL ( "benzyl benzoate" ) 2833 #5 ALL ( lindane ) 22366 #6 ALL ( "benzene hexachloride" ) 2196 #7 ALL ( hexachlorocyclohexane ) 12811 #8 ALL ( malathion ) 21789 #9 ALL ( malation ) 208 #10 ALL ( crotamiton ) 962 #11 ALL ( permethrin ) 18777 #12 ALL ( ivermectin ) 22790 #13 ALL ( pyrethr* ) 42890 #14 ALL ( aloe* ) 33768 #15 ALL ( plant* ) 4543180 #16 ALL ( herb* ) 1521822 #17 ALL ( sulfur OR sulphur OR "benzyl benzoate" OR lindane OR "benzene hexachloride" OR hexachlorocyclohexane OR malathion OR malatio n OR crotamiton OR permethrin OR ivermectin OR pyrethr* OR a loe* OR plant* OR herb* ) 6189842 #18 ( ALL ( scabi* ) ) AND ( ALL ( sulfur OR sulphur OR "benzyl benzoate" OR lindane OR "benzene hexachloride" OR hexachlorocyclohexane OR malathion OR malatio n OR crotamiton OR permethrin OR ivermectin OR pyrethr* OR a loe* OR plant* OR herb* ) ) 8297 #19 ALL ( "clinical trial" ) 2151728 #20 ALL ( randomi* ) 2993656 #21 ( ( ALL ( scabi* ) ) AND ( ALL ( sulfur OR sulphur OR "benzyl benzoate" OR lindane OR "benzene hexachloride" OR hexachlorocyclohexane OR malathion OR malatio n OR crotamiton OR permethrin OR ivermectin OR pyrethr* OR a loe* OR plant* OR herb* ) ) ) AND ( ( ALL ( "clinical trial" ) ) OR ( ALL ( randomi* ) ) ) 1192 Cochrane Central #1 scabies (in ‘all text’) 169 #2 #1 Limit: Trials 150
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1
Supplemental Table I. Databases and search strategies
Database Step Query Items found
MEDLINE via PubMed
#1 scabi* 4555 #2 sulfur 76488 #3 sulphur 76488 #4 "benzyl benzoate" 493 #5 lindane 5422 #6 "benzene hexachloride" 695 #7 hexachlorocyclohexane 6123 #8 malathion 3482 #9 malation 11 #10 crotamiton 147 #11 permethrin 3273 #12 ivermectin 6985 #13 pyrethr* 9580 #14 aloe* 3046 #15 "Plants, Medicinal"[Mesh] 56204 #16 #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11
OR #12 OR #13 OR #14 OR #15 161400
#17 #1 AND #16 1080 #18 #1 AND #16 Filters: Humans 806
Scopus #1 ALL ( scabi* ) 18593 #2 ALL ( sulfur ) 838627 #3 ALL ( sulphur ) 838627 #4 ALL ( "benzyl benzoate" ) 2833 #5 ALL ( lindane ) 22366 #6 ALL ( "benzene hexachloride" ) 2196 #7 ALL ( hexachlorocyclohexane ) 12811 #8 ALL ( malathion ) 21789 #9 ALL ( malation ) 208 #10 ALL ( crotamiton ) 962 #11 ALL ( permethrin ) 18777 #12 ALL ( ivermectin ) 22790 #13 ALL ( pyrethr* ) 42890 #14 ALL ( aloe* ) 33768 #15 ALL ( plant* ) 4543180 #16 ALL ( herb* ) 1521822 #17 ALL ( sulfur OR sulphur OR "benzyl
benzoate" OR lindane OR "benzene hexachloride" OR hexachlorocyclohexane OR malathion OR malation OR crotamiton OR permethrin OR ivermectin OR pyrethr* OR aloe* OR plant* OR herb* )
6189842
#18 ( ALL ( scabi* ) ) AND ( ALL ( sulfur OR sulphur OR "benzyl benzoate" OR lindane OR "benzene hexachloride" OR hexachlorocyclohexane OR malathion OR malation OR crotamiton OR permethrin OR ivermectin OR pyrethr* OR aloe* OR plant* OR herb* ) )
8297
#19 ALL ( "clinical trial" ) 2151728 #20 ALL ( randomi* ) 2993656 #21 ( ( ALL ( scabi* ) ) AND ( ALL ( sulfur OR sulphur OR "benzyl
benzoate" OR lindane OR "benzene hexachloride" OR hexachlorocyclohexane OR malathion OR malation OR crotamiton OR permethrin OR ivermectin OR pyrethr* OR aloe* OR plant* OR herb* ) ) ) AND ( ( ALL ( "clinical trial" ) ) OR ( ALL ( randomi* ) ) )
#1 scabies (in abstract, keywords; only from 2014 onwards) 0 #2 scabies (in title) 5
WHO-ICTRP
#1 scabies 216
3
Supplemental Table II. Studies excluded on full text
Citation Reason for exclusion
Alebiosu CO, Ogunledun A , Ogunleye DS. A report of clinical trial conducted on Toto ointment and soap products. J Natl Med Assoc 2003;95:95-105.
Non-RCT
Alrawashdeh B , Alazab K. Comparison between 25% benzyl benzoate, 5% permethrin and 10% crotamiton in the treatment of scabies in Gaza. Rawal Medical Journal 2013;38:125-6.
Non-RCT
Amer M, El-Bayoumi M , Rizk MK. Treatment of scabies: preliminary report. Int J Dermatol 1981;20:289-90.
Non-RCT
Bockarie MJ, Alexander ND, Kazura JW, Bockarie F, Griffin L , Alpers MP. Treatment with ivermectin reduces the high prevalence of scabies in a village in Papua New Guinea. Acta Trop 2000;75:127-30.
Non-RCT
Burkhart CN , Burkhart CG. Before using ivermectin therapy for scabies. Pediatr Dermatol 1999;16:478-9; discussion 80.
Narrative review
Elgart ML. Cost-benefit analysis of ivermectin, permethrin and benzyl benzoate in the management of infantile and childhood scabies. Expert Opin Pharmacother 2003;4:1521-4.
Narrative review
Goldust M , Rezaee E. Comparative trial of oral ivermectin versus sulfur 8% ointment for the treatment of scabies. J Cutan Med Surg 2013;17:299-300.
Comment/letter
Goldust M, Babae NS, Rezaee E , Raghifar R. Comparative trial of permethrin 5% versus lindane 1% for the treatment of scabies. Journal of Dermatological Treatment.
Duplicate study
Gulzar K, Mujtaba G , Hameed S. Comparison between effectiveness of topical 1% lindane cream and oral ivermectin in the management of scabies. Medical forum monthly.
Non-RCT
Haas N, Frank K, Jacobi U, Katzung W, Sterry W , Lademann J. [Inside-out application of ivermectin in scabies -- a hypothesis]. J Dtsch Dermatol Ges 2003;1:933-7.
Non-comparative
Hansen R, Remmers E , Menter M. A controlled comparative trial of permethrin 5 per cent cream and 1 per cent lindane lotion for the treatment of scabies. Clinical research
Duplicate study
Isaacs D , Britton P. Scabies control with ivermectin. Journal of Paediatrics and Child Health 2016;52:579.
Comment/letter
Kullavanijaya P, Pakunwanich W, Sudsuk N, Jongsatian S. [Treatment of scabies with sugar apple leaf extract in coconut oil]. Journal of the Department of Medical Services. 1992: 31-4.
Non-RCT
Mohebbipour A, Saleh P, Goldust M, Amirnia M, Zadeh YJ, Mohamad RM et al. Comparison of oral ivermectin vs. lindane lotion 1% for the treatment of scabies. Clin Exp Dermatol 2013;38:719-23.
Duplicate study
Mounsey KE, Bernigaud C, Chosidow O , McCarthy JS. Prospects for Moxidectin as a New Oral Treatment for Human Scabies. PLoS Neglected Tropical Diseases 2016;10.
Narrative review
NCT00262418. Comparison of the Efficacy and Safety of Ivermectin to Permethrin 2005.
Registered trial without author contact information
Oladimeji FA, Orafidiya LO, Ogunniyi TAB, Adewunmi TA , Onayemi O. A comparative study of the scabicidal activities of formulations of essential oil of Lippia multiflora Moldenke and benzyl benzoate emulsion BP. International Journal of Aromatherapy 2005;15:87-93.
Non-RCT
Oladimeji FA, Orafidiya OO, Ogunniyi TA , Adewunmi TA. Pediculocidal and scabicidal properties of Lippia multiflora essential oil. J Ethnopharmacol 2000;72:305-11.
Non-RCT
Riska O. [Treatment of scabies in Senegal]. Tidsskr Nor Laegeforen 2009;129:1490.
Comment/letter
Saeedi M, Hajheydari Z, Akbari J, Morteza-Semnani K , Emadian A. Preparation of malathion 0.5% lotion and studying its effect on healing scabies compared with permethrin cream 5%. Journal of Mazandaran University of Medical Sciences 2015;25:128-31.
RCT without outcomes of interest (exclusively compared efficacy using mean lesion
4
count; safety not assessed)
Sule HM , Thacher TD. Comparison of ivermectin and benzyl benzoate lotion for scabies in Nigerian patients. Am J Trop Med Hyg 2007;76:392-5.
Non-RCT
Wong LC, Amega B, Barker R, Connors C, Dulla ME, Ninnal A et al. Factors supporting sustainability of a community-based scabies control program. Australas J Dermatol 2002;43:274-7.
Non-comparative
RCT, randomized controlled trial.
5
Supplemental Table III. Characteristics of included trials
Country Treatments n Setting Age group(s)
% Male patients
% Severe cases
Use of microscopy in diagnosis and cure assessment
Abdel-Raheem (2016)19
Egypt OralIverm vs Permethrin vs BenzylB vs Sulfur
200 Hospital out-patient Both 42.0 NR Yes
Aggarwal (2014)66 India OralIverm vs Permethrin 100 Hospital out-patient Both 54.5 NR No
Ahmad (2016)21 Egypt TopIverm vs OralIverm 62 Hospital out-patient Both 41.9 56.5 Yes
Alipour (2015)22 Iran OralIverm vs Sulfur 420 Hospital out-patient Both NR NR Yes
Amer (1992)48 Egypt Permethrin vs Crotamiton vs Lindane 150 Hospital in-patient Both NR NR Yes
Amerio (2003)40 Italy SynPyrethr vs Permethrin 40 Hospital out-patient Adults 22.5 NR Yes
Ayaz (2011)58 Pakistan Herb (ScaNeem ointment) vs BenzylB 120 Hospital out-patient Both 81.7 NR Yes
Bachewar (2009)59 India OralIverm vs Permethrin vs BenzylB 80 Hospital out-patient Both 61.2 NR No
Biele (2006)37 Italy SynPyrethr vs BenzylB 240 Prison Adults 100.0 NR Yes
Bokhari (2000)62 Pakistan Permethrin vs Lindane 78 Hospital out-patient Both NR NR Yes
Brooks (2002)41 Vanautu OralIverm vs BenzylB 80 Hospital out-patient Children NR NR No
Castillo (2013)56 Philippines Herb (Tinospora cordifolia lotion) vs Permethrin
60 Youth reception centers
Both NR 1.7 No
Chhaiya (2012)32 India TopIverm vs OralIverm vs Permethrin 300 Hospital out-patient Both 55.6 16.2 Yes
Chouela (1999)45 Argentina OralIverm vs Lindane 42 Hospital out-patient Adults 35.8 NR Yes
Daneshpajooh (1999)63
Iran OralIverm vs Lindane 58 Hospital out-patient Both 63.8 NR Yes
Das (2006)70 India OralIverm vs Permethrin vs Lindane vs Paraffin
200 Hospital out-patient Both 70.0 NR Yes
Glaziou (1993)46 French Polynesia
OralIverm vs BenzylB 44 NR Both 52.3 NR No
Goldust (2014)28 Iran OralIverm vs Crotamiton 320 Hospital out-patient Both 62.5 57.8 Yes
Goldust (2014)23 Iran OralIverm vs Malathion 340 Hospital out-patient Both 61.8 57.4 Yes
Goldust (2014)24 Iran TopIverm vs Crotamiton 340 Hospital out-patient Both 55.9 52.9 Yes
6
Goldust (2013)25 Iran TopIverm vs Permethrin 380 Hospital out-patient Both 57.9 55.3 Yes
Goldust (2013)26 Iran OralIverm vs Lindane 440 Hospital out-patient Both 54.5 60.2 Yes
Goldust (2013)27 Iran Permethrin vs BenzylB (Tenutex®) 440 Hospital out-patient Both 65.9 54.5 Yes
Goldust (2012)33 Iran OralIverm vs Permethrin 242 Hospital out-patient Both 54.5 56.2 Yes
Gulati (1978)61 India BenzylB vs Sulfur 158 General community Both 47.5 NR No
Kanwar (2016)68 India OralIverm vs Permethrin vs Lindane 306 Hospital out-patient Both 58.5 NR No
Khan (2007)60 Pakistan OralIverm vs Permethrin 30 Hospital out-patient Both 63.3 NR No
Ly (2009)35 Senegal OralIverm vs BenzylB 181 Clinic Both 64.1 NR Yes
Macotela-Ruiz (1993)47
Mexico OralIverm vs Placebo 55 Hospital out-patient Both 32.7 NR No
Madan (2001)42 India OralIverm vs Lindane 150 Hospital out- and in-patient
Both 66.0 NR Yes
Manjhi (2014)65 India OralIverm vs Permethrin vs Lindane vs BenzylB
240 Hospital out-patient Both NR NR No
Meenakshi (2014)67
India OralIverm vs Permethrin vs Lindane 210 Hospital out-patient Both 67.1 21.2 No
Mila-Kierzenkowska (2017)53
Poland Permethrin vs Crotamiton vs Sulfur 54 NR Adults 40.7 NR No
Mohebbipour (2012)29
Iran OralIverm vs Lindane 248 Hospital out-patient Both 53.2 NR Yes
Mushtaq (2010)64 Pakistan OralIverm vs Permethrin 86 Hospital out-patient Both 48.8 43.0 Yes
Nnoruka (2001)43 Nigeria OralIverm vs BenzylB 59 Hospital out-patient Both NR NR Yes
Oyelami (2009)36 Nigeria Herb (crude Aloe vera gel) vs BenzylB 28 Prison and hospital out-patient
Both 73.3 NR Yes
Pourhasan (2013)30 Iran Permethrin vs Crotamiton 400 Hospital out-patient Both NR NR Yes
Rahman (2015)54 India Herb (Jarb wahikka paste) vs BenzylB 60 Hospital out-patient Adults 56.7 NR No
Ranjkesh (2013)31 Iran OralIverm vs Permethrin 60 Hospital out-patient Both 70.0 58.3 Yes
Razaee (2015)20 Iran Permethrin vs Lindane 120 Hospital out-patient Both 56.7 66.7 Yes
Razaee (2015)55 Iran TopIverm vs BenzylB (Tenutex®) 360 Clinic Both 55.6 58.3 Yes
Saqib (2012)57 Pakistan OralIverm vs Permethrin 120 Hospital out-patient Adults NR NR Yes
7
Schultz (1990)50 Mexico, USA
Permethrin vs Lindane 404 Clinic Both 63.6 51.0 Yes
Supplemental Table VI. Definition of severe case at baseline and outcomes
Definition of severe case at baseline
Term used for cure outcome
Definition of cure outcome Definition of persistent itching outcome
Abdel-Raheem (2016)19
Severity NR Cure Negative parasitological examination, absence of new lesions
Presence of itch
Aggarwal (2014)66 > 50 lesions Efficacy Clearance of lesions, itching and absence of mites on microscopy
Outcome NR
Ahmad (2016)21 > 50 lesions Effective Marked to excellent improvement in pruritus, no lesions, absence of mites/products on microscopy
Presence of itch
Alipour (2015)22 Severity NR Cure Absence of new lesions and healing of all old lesions, regardless of postscabietic nodules
Outcome NR
Amer (1992)48 Severity NR Cure No new lesions and all original active lesions healed Outcome NR
Amerio (2003)40 Severity NR No lesion Cleared from lesions Presence of itch
Ayaz (2011)58 Severity NR Not described Improved on examination of skin (no further description) Not improved
Bachewar (2009)59 Severity NR Cure Did not have any new lesions Outcome NR
Biele (2006)37 Severity NR Clinical cure No or mild itching, no dermatological evidence of scabies, absence of positive signs of infestation in skin scrapings
Moderate to severe itch
Bokhari (2000)62 Severity NR Successfully treated
(No description) Outcome NR
Brooks (2002)41 Severity NR Not described No skin lesions Nocturnal itch
Castillo (2013)56 > 10 body sites affected
Clinical cure Complete disappearance of signs and symptoms Outcome NR
Chhaiya (2012)32 > 50 lesions Clinical cure Clinical cure of scabietic lesions (no further description) Presence of itch
Chouela (1999)45 Severity NR Clinical cure, heal
Absence of both pruritus and clinical lesions or reduction of signs and symptoms to a mild degree
Outcome NR
Daneshpajooh (1999)63
Severity NR Recovery Elimination of skin lesions, absence of any symptoms of scabies, negative microscopy
Itching and scratching
Das (2006)70 Severity NR Outcome NR (Efficacy reported as % improvement of lesions) Outcome NR
Glaziou (1993)46 Severity NR Recovery Complete disappearance of initial skin lesions and pruritus Outcome NR
Goldust (2014)28 > 100 lesions Cure Absence of new lesions, healing of all old lesions, regardless of postscabietic nodules
Outcome NR
Goldust (2014)23 > 100 lesions Cure Absence of new lesions, healing of all old lesions, regardless of postscabietic nodules
Outcome NR
14
Goldust (2014)24 > 100 lesions Cure Absence of new lesions, healing of all old lesions, regardless of postscabietic nodules
Outcome NR
Goldust (2013)25 > 100 lesions Cure Absence of new lesions, healing of all old lesions, regardless of postscabietic nodules
Outcome NR
Goldust (2013)26 > 100 lesions Cure Absence of new lesions, healing of all old lesions, regardless of postscabietic nodules
Outcome NR
Goldust (2013)27 > 100 lesions Cure Absence of new lesions, healing of all old lesions, regardless of postscabietic nodules
Outcome NR
Goldust (2012)33 > 100 lesions Cure, effective Absence of new lesions and all old lesions healed Outcome NR
Gulati (1978)61 Severity NR No lesions Clearance of scabies lesions Outcome NR
Kanwar (2016)68 Severity NR Not described Severity of lesions (based on number of lesions) improved Severity of itching (based on visual analog scale) not improved
Khan (2007)60 Severity NR Efficacy, cure Relief of symptoms and disappearance of lesions Outcome NR
Ly (2009)35 Severity NR Effectiveness Complete disappearance of visible lesions and itching Outcome NR
Macotela-Ruiz (1993)47
Severity NR Clinical cure Absence of itching and no dermatologically active lesions Outcome NR
Madan (2001)42 Severity NR Complete improvement scale
No signs or symptoms of scabies Presence of itch
Manjhi (2014)65 Severity NR Not described Improvement seen with severity of lesions as parameter (no further description)
Not improved
Meenakshi (2014)67 > 50 lesions Clinical cure Reduction both in clinical grading score (up to grade 0 or 1) and itching grading score (up to grade 0, 1, or 2)
Outcome NR
Mila-Kierzenkowska (2017)53
Severity NR Cure Absence of new lesions, clinical improvement in skin lesions and improvement in pruritus
Outcome NR
Mohebbipour (2012)29
Severity NR Cure Absence of new lesions, healing of all old lesions, regardless of postscabietic nodules
Outcome NR
Mushtaq (2010)64 > 50 lesions Efficacy, cure Disappearance of itching, clearance of skin lesions, absence of mites on microscopy
Nocturnal itch
Nnoruka (2001)43 Severity NR Recovery, heal Complete disappearance of initial skin lesions and pruritus Reported in 4-point scale, but with inconsistent n (data not included in meta-analyses)
Oyelami (2009)36 Severity NR Not described Skin lesions cleared Presence of itch
Pourhasan (2013)30 Severity NR Cure Absence of new lesions, healing of all old lesions, regardless of postscabietic nodules
Outcome NR
Rahman (2015)54 Severity NR No lesions No lesions on clinical grading Reported mean, SD of itch visual analog scale (data not included in meta-analyses)
15
Ranjkesh (2013)31 > 100 lesions Cure Absence of new lesions, healing of all old lesions, regardless of postscabietic nodules
Outcome NR
Razaee (2015)20 > 100 lesions Cure, effective Absence of new lesions, all old lesions healed Outcome NR
Razaee (2015)55 > 100 lesions Cure Absence of new lesions, healing of all old lesions, regardless of postscabietic nodules
Outcome NR
Saqib (2012)57 Severity NR Cure Absence of itching and skin lesions, negative microscopy Outcome NR
Schultz (1990)50 > 50 lesions Cure All original primary lesions were healed Presence of itch
Shaheen (2017)52 Severe itching Cure No history of itching and pruritus, evaluation of sites of lesion by physician
Outcome NR
Sharma (2011)34 > 50 lesions Clinical cure Reduction in both the number of lesions and grade of pruritus by more than or equal to 50%, and negative microscopy
At least 50% improvement in pruritus
Singalavanija (2003)39
> 100 lesions Parasitic cure No new lesions and healing of all old lesions, absence of parasites by skin scraping
Outcome NR
Taplin (1990)49 > 100 lesions Cure No new lesions, all original lesions healed Presence of itch
Taplin (1986)51 > 100 lesions Cure Absence of new lesions, all old lesions healed Outcome NR
Usha (2000)44 NR Improved Improvement in pruritus, clinical improvement in skin lesions with no new lesions, absence of mites or their products on microscopy
Outcome NR
Wankhade (2016)69 > 50 lesions Cure No new clinical lesions and improvement in pruritus Outcome NR
Zargari (2006)38 Severity NR Effective Signs of improvement of itching and no new lesions Outcome NR
NR, not reported.
16
Supplemental Table VII. Findings of re-infestation outcome
Term used for re-infestation
Time of assessment
Treatment Total patients
Patients re-infested
Re-infestation rate (%)
Quote
Ahmad (2016)21
Recurrence 4 weeks Topical ivermectin
32 0 0.0 With further follow up, lesions completely disappeared in all patients after 2 weeks of treatment with no recurrences at 4-weeks end point Oral ivermectin 30 0 0.0
Castillo (2013)56
Reinfestation 4 weeks Tinospora cordifolia
34 1 2.9 Another patient was considered reinfested because marked improvement (50%) was seen on seventh day but only a mild improvement at 14th day (17%) and 21st day (17%) was observed while on 28th day, no improvement was noted and there was reappearance of new papules in the wrist, legs and interdigits and persistent papules on genitals from 14-28th days were noted.
Permethrin 32 0 0.0
Glaziou (1993)46
Relapse 30 days Oral ivermectin 23 0 0.0 Among the patients healed before day 30 (whatever the group), no relapse was observed until day 30. Benzyl
89 7 7.9 On revisit six months after the entire family had been treated, it was found I that scabies had recurred in 21 (13.3 percent) of the 158 cases. The recurrence was only in 7 (7.9 percent) of the 89 patients treated with benzyl benzoate as compared to 14 (20.4 percent) of the 69 patients treated with sulphur ointment.
Sulfur 69 14 20.3
Mila-Kierzenkowska (2017)53
Reinfestation 1 month Permethrin 18 0 0.0 None of the patients experienced worsening of infestation during the study, but at two patients treated with sulfur ointment re-infestation occurred at one-month follow-up.
Crotamiton 18 0 0.0
Sulfur 18 2 11.1
Nnoruka (2001)43
Relapse 30 days Oral ivermectin 29 0 0.0 Amongst the patients healed before day 30 (whatever group), no relapse was observed. Benzyl
benzoate 29 0 0.0
Saqib (2012)57 Relapse, reinfested
2 weeks Oral ivermectin 60 4 6.7 A total of 8 patients in our study became reinfested with S. scabiei two weeks after treatment, n=4 in each group. Permethrin 60 4 6.7
Taplin (1986)51 Reinfestation 4 weeks Permethrin 27 1 3.7 Four weeks was considered the definitive point for evaluating the efficacy of treatments. At this time only two patients treated with permethrin had active lesions, and we were able to recover mites from both of them. One
Lindane 25 0 0.0
17
had previously been scored as completely cured at 2 weeks. We considered this patient to have become reinfested after successful treatment.
Usha (2000)44 Recurrence 8 weeks Oral ivermectin 50 0 0.0 All the patients were completely cured at the end of 8 weeks. There was no recurrence of scabies at the end of 2 months of follow-up in either group.
Permethrin 45 0 0.0
18
Supplemental Table VIII. Data for pooling
Treatment Total patients
Patients with cure at 1-2 weeks (week of assess-ment)
Patients with cure at 3-6 weeks (week of assess-ment)
Patients with persistent itching
Patients with adverse events
Abdel-Raheem (2016)19
Oral ivermectin 55 42 (2) 13 7
Permethrin 54 44 (2) 10 4
Benzyl benzoate 53 40 (2) 19 13
Sulfur 54 26 (2) 30 50
Aggarwal (2014)66
Oral ivermectin 50 27 (2) 33 (4)
Permethrin 50 39 (2) 43 (4)
Ahmad (2016)21 Topical ivermectin 32 32 (2) 32 (4) 0
* Data in both benzyl benzoate arms were merged into 1 arm in meta-analyses. ** Data in both oral ivermectin arms were merged into 1 arm in meta-analyses.
21
Supplemental Table IX. Cutaneous adverse events as reported in the studies
* Data in both benzyl benzoate arms were merged into 1 arm in meta-analyses. ** Data in both oral ivermectin arms were merged into 1 arm in meta-analyses.
27
Supplemental Table X. Systemic adverse events as reported in the studies
Treatment Foul smell
Nausea/ vomiting
Abdominal pain
Diarrhea Blurred vision
Fever Headache Insomnia Hypo-tension
Minor adverse drug reactions
Abdel-Raheem (2016)19
Oral ivermectin
- 2 - - - - - - - -
Permethrin - 0 - - - - - - - -
Benzyl benzoate
- 0 - - - - - - - -
Sulfur - 0 - - - - - - - -
Aggarwal (2014)66
Oral ivermectin
Outcome NR
Permethrin Outcome NR
Ahmad (2016)21 Topical ivermectin
Outcome NR
Oral ivermectin
Outcome NR
Alipour (2015)22
Oral ivermectin
Outcome NR
Sulfur Outcome NR
Amer (1992)48 Permethrin - - - - - - - - - -
Crotamiton - - - - - - - - - -
Lindane - - - - - - - - - -
Amerio (2003)40
Synergizedd pyrethrins
- - - - - - - - - -
Permethrin - - - - - - - - - -
Ayaz (2011)58 ScaNeem - - - - - - - - - -
Benzyl benzoate
- - - - - - - - - -
Bachewar (2009)59
Oral ivermectin
Outcome NR
28
Permethrin Outcome NR
Benzyl benzoate
Outcome NR
Biele (2006)37 Synergizedd pyrethrins
- - - - - - - - - -
Benzyl benzoate
- - - - - - - - - -
Bokhari (2000)62
Permethrin - - - - - - - - - -
Lindane - - - - - - - - - -
Brooks (2002)41 Oral ivermectin
- - - - - - - - - -
Benzyl benzoate
- - - - - - - - - -
Castillo (2013)56
Tinospora cordifolia
- - - - - - - - - -
Permethrin - - - - - - - - - -
Chhaiya (2012)32
Topical ivermectin
- - - - - - 0 - - -
Oral ivermectin
- - - - - - 1 - - -
Permethrin - - - - - - 0 - - -
Chouela (1999)45
Oral ivermectin
- 1 1 - - - 1 - 1 -
Lindane - 0 0 - - - 6 - 0 -
Daneshpajooh (1999)63
Oral ivermectin
- - - - - 1 - - - -
Lindane - - - - - 0 - - - -
Das (2006)70 Oral ivermectin
- - - - - - - - - -
Permethrin - - - - - - - - - -
Lindane - - - - - - - - - -
White soft paraffin
- - - - - - - - - -
Glaziou (1993)46
Oral ivermectin
- - - - - - - - - -
29
Benzyl benzoate
- - - - - - - - - -
Goldust (2014)28
Oral ivermectin
- - - - - - - - - -
Crotamiton - - - - - - - - - -
Goldust (2014)23
Oral ivermectin
- - - - - - - - - -
Malathion - - - - - - - - - -
Goldust (2014)24
Topical ivermectin
- - - - - - - - - -
Crotamiton - - - - - - - - - -
Goldust (2013)25
Topical ivermectin
- - - - - - - - - -
Permethrin - - - - - - - - - -
Goldust (2013)26
Oral ivermectin
- - - - - - - - - -
Lindane - - - - - - - - - -
Goldust (2013)27
Permethrin - - - - - - - - - -
Benzyl benzoate (Tenutex®)
- - - - - - - - - -
Goldust (2012)33
Oral ivermectin
- - - - - - - - - -
Permethrin - - - - - - - - - -
Gulati (1978)61 Benzyl benzoate
Outcome NR
Sulfur Outcome NR
Kanwar (2016)68
Oral ivermectin
Outcome NR
Permethrin Outcome NR
Lindane Outcome NR
Khan (2007)60 Oral ivermectin
- - - - - - - - - -
30
Permethrin - - - - - - - - - -
Ly (2009)35 Oral ivermectin
- - 5 2 - - - - - -
Benzyl benzoate*
- - 0 0 - - - - - -
Macotela-Ruiz (1993)47
Oral ivermectin
Outcome NR
Placebo Outcome NR
Madan (2001)42 Oral ivermectin
Outcome NR
Lindane Outcome NR
Manjhi (2014)65 Oral ivermectin
Outcome NR
Permethrin Outcome NR
Lindane Outcome NR
Benzyl benzoate
Outcome NR
Meenakshi (2014)67
Oral ivermectin
- - - - - - - - - -
Permethrin - - - - - - - - - -
Lindane - - - - - - - - - -
Mila-Kierzenkowska (2017)53
Permethrin Outcome NR
Crotamiton Outcome NR
Sulfur Outcome NR
Mohebbipour (2012)29
Oral ivermectin
- - - - - - - - - -
Lindane - - - - - - - - - -
Mushtaq (2010)64
Oral ivermectin
- - - - - - 1 - - -
31
Permethrin - - - - - - 0 - - -
Nnoruka (2001)43
Oral ivermectin
- - - - - - - - - -
Benzyl benzoate
- - - - - - - - - -
Oyelami (2009)36
Crude Aloe vera gel
- - - - - - - - - -
Benzyl benzoate
- - - - - - - - - -
Pourhasan (2013)30
Permethrin - - - - - - - - - -
Crotamiton - - - - - - - - - -
Rahman (2015)54
Jarb wahikka
- - - - - - - - - -
Benzyl benzoate
- - - - - - - - - -
Ranjkesh (2013)31
Oral ivermectin
- - - - - - - - - -
Permethrin - - - - - - - - - -
Razaee (2015)20 Permethrin - - - - - - - - - -
Lindane - - - - - - - - - -
Razaee (2015)55 Topical ivermectin
- - - - - - - - - -
Benzyl benzoate (Tenutex®)
- - - - - - - - - -
Saqib (2012)57 Oral ivermectin
Outcome NR
Permethrin Outcome NR
Schultz (1990)50 Permethrin - - - - - - - - - -
Lindane - - - - - - - - - -
Shaheen (2017)52
Oral ivermectin
Outcome NR
Permethrin Outcome NR
32
Sharma (2011)34
Oral ivermectin**
- - - - - - - - - -
Permethrin - - - - - - - - - -
Singalavanija (2003)39
Lindane 3 - - - - - - - - -
Sulfur 10 - - - - - - - - -
Taplin (1990)49 Permethrin Outcome NR
Crotamiton Outcome NR
Taplin (1986)51 Permethrin - - - - - - - - - -
Lindane - - - - - - - - - -
Usha (2000)44 Oral ivermectin
Outcome NR
Permethrin Outcome NR
Wankhade (2016)69
Permethrin+oral ivermectin combination
- - - - - - - - - 3
Oral ivermectin
- - - - - - - - - 1
Permethrin - - - - - - - - - 2
Zargari (2006)38 Permethrin - - - - - - - - - -
Lindane - - - - - - - - - -
NR, not reported.
* Data in both benzyl benzoate arms were merged into 1 arm in meta-analyses. ** Data in both oral ivermectin arms were merged into 1 arm in meta-analyses.
33
Supplemental Table XI. Results of risk of bias assessment
Random sequence generation
Allocation concealment
Blinding of participants and personnel
Blinding of outcome assessment
Incomplete outcome data Selective reporting
Cure Persistent itching
AEs Cure Persistent itching
AEs Cure Persistent itching
AEs
Abdel-Raheem (2016)19
L U H H H U H H H H H H
Aggarwal (2014)66 H H H N N U N N H N N H
Ahmad (2016)21 L U H H H U H H L L U H
Alipour (2015)22 U U H N H L N H H N H L
Amer (1992)48 U U H N H U N H L N L L
Amerio (2003)40 L L H H H L H H L L L L
Ayaz (2011)58 U U H H H H H H H H H L
Bachewar (2009)59 L U H U U H U U H U U H
Biele (2006)37 L U H H H L H H L L L H
Bokhari (2000)62 U U H N H U N H H N H L
Brooks (2002)41 L L H H H L H H H H H L
Castillo (2013)56 L U H H H U H H H H H H
Daneshpajooh (1999)63 U U H H H U H H L L L L
Das (2006)70 U U H H H U H H U U U U
Chhaiya (2012)32 L U H H H H H H H H H L
Chouela (1999)45 L U L L L L L L H H H H
Glaziou (1993)46 U U H N H U N H L N L L
Goldust (2014)28 U U H N H L N H H N H L
Goldust (2014)23 U U H N H L N H H N H L
Goldust (2014)24 U U H N H L N H H N H L
Goldust (2013)25 U U H N H L N H H N H L
Goldust (2013)26 U U H N H L N H H N H L
Goldust (2013)27 U U H N H L N H H N H L
Goldust (2012)33 U H H N H L N H H N H L
34
Gulati (1978)61 U U H N N U N N L N N H
Kanwar (2016)68 U U H H N U H N L L N H
Khan (2007)60 U U H N H H N H L N L L
Ly (2009)35 L U H N H H N H H N H L
Macotela-Ruiz (1993)47 U U U N N U N N U N N H
Madan (2001)42 U U H H N U H N H H N H
Manjhi (2014)65 U U H U N U U N U U N H
Meenakshi (2014)67 L U H N H H N H H N H L
Mila-Kierzenkowska (2017)53
U U H U H L U H L U L U
Mohebbipour (2012)29 U U H N H L N H H N H L
Mushtaq (2010)64 L U H U U U U U H H H L
Nnoruka (2001)43 L U H H H U H H L L L L
Oyelami (2009)36 U U H H H U H H H H H L
Pourhasan (2013)30 U U H N H L N H H N H L
Rahman (2015)54 L H H H H H H H L L L L
Ranjkesh (2013)31 U U H N H L N H H N H L
Razaee (2015)20 U U H N H L N H H N H L
Razaee (2015)55 U U H N H L N H H N H L
Saqib (2012)57 U U H U N U U N L U N H
Schultz (1990)50 U U H H H U H H H H H L
Shaheen (2017)52 L U H N N L N N L N N H
Sharma (2011)34 L L L L L U L L H H H H
Singalavanija (2003)39 L U H H H U H H H H H L
Taplin (1990)49 U U L L N L L N L H N H
Taplin (1986)51 U U H N H L N H H N H L
Usha (2000)44 U U H U N U U N L U N H
Wankhade (2016)69 U U H N H H N H L N L L
Zargari (2006)38 U L L N L U N L H N H L
Number (%) of studies
35
Low risk 17 (32.7)
4 (7.7)
4 (7.7)
3 (11.5)
3 (7.1)
21 (40.4)
3 (11.5)
3 (7.1)
17 (32.7)
7 (26.9)
10 (23.8)
33 (63.5)
High risk 1 (1.9)
3 (5.8)
47 (90.4)
17 (65.4)
37 (88.1)
8 (15.4)
17 (65.4)
37 (88.1)
32 (61.5)
13 (50.0)
29 (69.1)
17 (32.7)
Unclear risk 34 (65.4)
45 (86.5)
1 (1.9)
6 (23.1)
2 (4.8)
23 (44.2)
6 (23.1)
2 (4.8)
3 (5.8)
6 (23.1)
3 (7.1)
2 (3.9)
AEs, adverse events; H, high risk; L, low risk; N, outcome not assessed in study; U, unclear risk.
The majority of RCTs had unclear risk of bias in random sequence generation (65.4%) and allocation concealment (86.5%), due to their lack of description for the processes. For blinding of participants and personnel, the risk was high for most RCTs (90.4%) because they were investigator-blind or open-label, or did not use double dummy technique when drugs in different formulations were studied. For blinding of outcome assessment, fewer studies were at high risk in cure outcome (15.4%) than in persistent itching (65.4%) and AEs (88.1%) because cure was mainly assessed by blind investigators but itching and AEs by unblinded patients. Risk of bias for incomplete outcome data was high in 50.0-69.1% of the studies due to high dropout. For selective reporting, 32.7% of studies were at high risk because AEs were not reported.
36
Supplemental Table XII. Results of direct meta-analysis for cure at 1-2 weeks
Results are risk ratios (95% confidence intervals) from network meta-analysis between each pair of treatments. Comparisons are read from left to right. Bold font indicates statistical significance.
46
Supplemental Fig 1. Network map of direct comparisons for each outcome: cure at 1-2 weeks (A), cure at 3-6 weeks (B), persistent itching (C), and adverse events (D). Sizes of nodes and edges correspond to numbers of trials and included patients, respectively. BenzylB, benzyl benzoate; Herb, herbal medicine; OralIverm, oral ivermectin; Paraffin, white soft paraffin; Perm+OralIverm, permethrin+oral ivermectin combination; SynPyrethr, synergized pyrethrins; TopIverm, topical ivermectin.
47
Supplemental Fig 2. Comparison-adjusted funnel plot of studies included in network meta-analysis for cure at 1-2 weeks
48
Supplemental Fig 3. Comparison-adjusted funnel plot of studies included in network meta-analysis for cure at 3-6 weeks
49
Supplemental Fig 4. Comparison-adjusted funnel plot of studies included in network meta-analysis for persistent itching outcome
50
Supplemental Fig 5. Comparison-adjusted funnel plot of studies included in network meta-analysis for adverse events outcome