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1 Supplementary webappendix This webappendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Moser W, Coulibaly JT, Ali SM, et al. Efficacy and safety of tribendimidine, tribendimidine plus ivermectin, tribendimidine plus oxantel pamoate, and albendazole plus oxantel pamoate against hookworm and concomitant soil-transmitted helminth infections in Tanzania and Côte d Ivoire: a randomised, controlled, single-blinded, non-inferiority trial. Lancet Infect Dis 2017; published online August 29.

2 Appendix Table of contents Table S Table S Table S Table S Table S Table S Table S Figure S

3 Efficacy and safety of tribendimidine, tribendimidine-ivermectin, tribendimidine-oxantel pamoate and albendazole-oxantel pamoate against hookworm and concomitant soiltransmitted helminth infections in Tanzania and Côte d Ivoire: a randomised, controlled, single blinded, non-inferiority trial Wendelin Moser, Jean T Coulibaly, Said M. Ali, Shaali M. Ame, Amour K. Amour, Richard B. Yapi, Marco Albonico, Maxim Puchkov, Jörg Huwyler, Jan Hattendorf, Jennifer Keiser Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, and University of Basel, Basel, Switzerland (W Moser MSc, J T Coulibaly PhD, Prof J Keiser); Laboratory Division, Public Health Laboratory-Ivo de Carneri, Chake Chake, Tanzania (S M Ali MSc, S M Ame MSc, A K Amour); Centre Suisse de Recherches Scientifiques, Abidjan, Côte d Ivoire (R B Yapi PhD, J T Coulibaly PhD); Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, and University of Basel, Basel, Switzerland (M Puchkov PhD, Prof J Huwyler PhD); Centre for Tropical Diseases, Sacro Cuore Hospital, Negrar Verona, and University of Turin, Turin, Italy (Prof M Albonico PhD); Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, and University of Basel, Basel, Switzerland (J Hattendorf PhD) Correspondence to: Prof Jennifer Keiser, Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, P.O. Box, CH-4002 Basel, Switzerland jennifer.keiser@unibas.ch 2

4 Table S1 Detailed inclusion and exclusion criteria for participants (age 15-18) in Tanzania and Côte d Ivoire. Inclusion criteria Written informed consent signed by parents and/or legal guardian; and assent by children. Able and willing to be examined by a study physician at the beginning of the study. Able and willing to provide two stool samples at the beginning (baseline) and approximately three weeks after treatment (follow-up). Exclusion criteria No written informed consent by parents and/or legal guardian and assent for children. Presence of major systemic illnesses (e.g. diabetes, anemia) as assessed by a medical doctor, upon initial clinical assessment. History of acute or severe chronic disease. Positive for hookworm eggs in the stool. Recent use of anthelminthic drug (within past 4 weeks). Absence of major systemic illnesses (e.g. Attending other clinical trials during the study. diabetes, anemia) as assessed by a medical doctor, upon initial clinical assessment. No known or reported history of chronical illness as cancer, diabetes, chronic heart, liver or renal disease. No recent anthelminthic treatment (within past 4 weeks). No known allergy to study medications (e.g. albendazole, mebendazole). Negative diagnostic result for hookworm eggs in the stool. 3

5 Table S2 Baseline characteristics for the participants of the four treatment arms tribendimidine; tribendimidineivermectin; tribendimidine-oxantel pamoate and albendazole-oxantel pamoate for Tanzania (TZ), Côte d Ivoire ( and the total. Tribendimidine Tribendimidine- Tribendimidine- Albendazole- Ivermectin Oxantel pamoate Oxantel pamoate TZ No CI Tot TZ Age years Ŧ 15 6(0 7) 15 6(0 8) 15 7(0 9) 15 6(0 9) CI 16 1(1 1) 16 3(1 1) 16 4(1 1) 16 2(1 1) Tot 15 8(0 9) 15 9(1 0) 15 9(1 0) 15 8(1 0) TZ Sex no boys CI Tot Schools/Health districts TZ Wingwi Mizingani Wesha Tumbe CI Azaguié Rubino TZ Weight kg Ŧ 47 2(6 9) 47 8(8 5) 46 8(7 9) 46 5(7 9 CI 49 0(9 0) 50 9(8 8) 50 7(8 8) 52 2(7 9 Tot 47 9(7 8) 48 9(8 7) 48 2(8 3) 48 5(8 4 TZ Height cm Ŧ 156 6(8 2) 155 5(9 7) 156 0(14 7) 156 3(10 5) CI 159 5(9 1) 161 5(8 6) 162 5(10 2) 162 2(7 2) Tot 157 7(8 7) 157 6(9 8) 158 3(13 6) 158 5(9 8) Tanzania Côte d Ivoire Hookworm Tribendimidine Tribendimidine- Tribendimidine- Albendazole- Ivermectin Oxantel pamoate Oxantel pamoate Participants infected Geometric mean no of eggs/g Arithmetic mean no of eggs/g Infection intensity no (%) + light 99 (98 0) 99 (97 0) 99 (97 0) 99 (96 0) moderate 2 (2 0) 2 (2 0) 3 (3 0) 2 (2 0) Heavy - 1 (1 0) - 2 (2 0) Participants infected no (%) Geometric mean no of eggs/g Arithmetic mean no of eggs/g Infection intensity no (%) + light 54 (93 1) 54 (94 7) 54 (98 2) 55 (94 8) moderate 4 (6 9) 2 (3 5) 1 (1 8) 1 (1 7) Heavy - 1 (1 8) - 2 (3 5) 4

6 Total Participants infected no (%) Geometric mean no of eggs/g Arithmetic mean no of eggs/g Infection intensity no (%) + light 153 (96 2) 153 (96 2) 153 (97 5) 154 (95 7) moderate 6 (3 8) 4 (2 5) 4 (2 6) 3 (1 9) Heavy - 2 (1 3) - 4 (2 5) Tanzania Côte d Ivoire Total Trichuris trichiura Tribendimidine Tribendimidine- Tribendimidine- Albendazole- Ivermectin Oxantel pamoate Oxantel pamoate Participants infected no (%) 99 (98 0) 102 (100 0) 98 (96 1) 103 (100 0) Geometric mean no of eggs/g Arithmetic mean no of eggs/g Infection intensity no (%) light 54 (54 6) 60 (58 8) 58 (59 2) 53 (51 5) moderate 43 (43 4) 41 (40 2) 38 (38 8) 50 (48 5) Heavy 2 (2 0) 1 (1 0) 2 (2 0) - Participants infected no (%) 3 (5 2) 4 (7 0) 3 (5 5) - Geometric mean no of eggs/g Arithmetic mean no of eggs/g Infection intensity no (%) light 2 (66 7) 4 (100 0) 3 (100 0) - moderate 1 (33 3) Heavy Participants infected no (%) 102 (64 2) 106 (66 7) 101 (64 3) 103 (64 0) Geometric mean no of eggs/g Arithmetic mean no of eggs/g Infection intensity no (%) light 56 (54 9) 64 (60 4) 61 (60 4) 53 (51 5) moderate 44 (43 1) 41 (38 7) 38 (37 6) 50 (48 5) Heavy 2 (2 0) 1 (1 0) 2 (2 0) - 5

7 Ascaris lumbricoides Tribendimidine Tribendimidine- Tribendimidine- Albendazole- Ivermectin Oxantel pamoate Oxantel pamoate Participants infected no (%) 71 (70 3) 74 (72 6) 73 (71 6) 78 (75 7) Geometric mean no of eggs/g Arithmetic mean no of eggs/g Infection intensity no (%) light 35 (49 3) 30 (40 5) 34 (46 6) 34 (43 6) moderate 33 (46 5) 38 (51 4) 37 (50 7) 40 (51 3) Heavy 3 (4 2) 6 (8 1) 2 (2 7) 4 (5 1) Participants infected no (%) 3 (5 2) 3 (5 3) 2 (3 6) 1 (1 7) Geometric mean no of eggs/g Arithmetic mean no of eggs/g Infection intensity no (%) light 2 (66 7) 2 (66 7) 2 (100 0) 1 (100 0) moderate 1 (33 3) 1 (33 3) - - Heavy Participants infected no (%) 74 (46 5) 77 (48 4) 75 (47 8) 79 (49 1) Geometric mean no of eggs/g Arithmetic mean no of eggs/g Infection intensity no (%) light 37 (50 0) 32 (41 6) 36 (48 0) 35 (44 3) moderate 34 (46 0) 39 (50 7) 37 (49 3) 40 (50 6) Heavy 3 (4 1) 6 (7 8) 2 (2 7) 4 (5 1) Ŧ Values denote means (standard deviation) + Infection intensities for hookworm were categorized as light (1 to 1999 eggs per gram ), moderate (2000 to 3999 eggs per gram ), or heavy ( 4000 eggs per gram ). Infection intensities for T trichiura were categorized as light (1 to 999 eggs per gram ), moderate (1000 to 9999 eggs per gram ), or heavy ( 10,000 eggs per gram ). Infection intensities for A lumbricoides were categorized as light (1 to 4999 eggs per gram ), moderate (5000 to 49,999 eggs per gram ), or heavy ( 50,000 eggs per gram ). Tanzania Côte d Ivoire Total 6

8 Table S3 Cure rates and egg-reduction rates (geometric and arithmetic) for the four treatment arms tribendimidine, tribendimidine-ivermectin, tribendimidine-oxantel pamoate and albendazole-oxantel pamoate for Tanzania (TZ), Côte d Ivoire ( and the total. Tanzania Côte d Ivoire Total Hookworm Tribendimidine Tribendimidine - ivermectin Tribendimidine - Oxantel pamoate Albendazole - Oxantel pamoate Before treatment After treatment Cure rate - %(95% * 58 3 ( ) 81 0 ( ) 52 6 ( ) 53 5 ( ) Geometric mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% 97 7 ( ) 99 4 ( ) 96 6 ( ) 97 2 ( ) * Arithmetic mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% 79 0 ( ) 97 5 ( ) 85 1 ( ) 90 7 ( ) * Before treatment After treatment Cure rate - %(95% 45 5 ( ) 90 7 ( ) 50 9 ( ) 36 7 ( ) Geometric mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% 93 8 ( ) 99 6 ( ) 96 2 ( ) 92 0 ( ) Arithmetic mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% 74 9 ( ) 94 4 ( ) 75 6 ( ) 82 1 ( ) Before treatment After treatment Cure rate - %(95% 53 6 ( ) 84 4 ( ) 52 0 ( ) 48 0 ( ) Geometric mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% 96 7 ( ) 99 5 ( ) 96 5 ( ) 96 0 ( ) Arithmetic mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% 77 5 ( ) 96 3 ( ) 81 5 ( ) 87 2 ( ) 7

9 Tanzania Côte d Ivoire Total Trichuris trichiura Tribendimidine Tribendimidine - Tribendimidine - Oxantel pamoate Albendazole - Oxantel pamoate ivermectin Before treatment After treatment Cure rate - %(95% 6 4 ( ) 32 0 ( ) 65 2 ( ) 82 8 ( ) Geometric mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% 50 6 ( ) 96 4 ( ) 99 5 ( ) 99 8 ( ) Arithmetic mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% 15 0 ( ) 88 6 ( ) 94 1 ( ) 97 0 ( ) Before treatment After treatment Cure rate - %(95% 66 7 ( ) 75 0 ( ) Geometric mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% 99 1 ( ) 96 9 ( ) Arithmetic mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% 12 0 ( ) 88 5 ( ) Before treatment After treatment Cure rate - %(95% 8 2 ( ) 33 7 ( ) 66 3 ( ) 82 8 ( ) Geometric mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% 53 1 ( ) 96 4 ( ) 99 5 ( ) 99 8 ( ) Arithmetic mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% 15 0 ( ) 88 6 ( ) 94 1 ( ) 97 0 ( ) 8

10 Tanzania Côte d Ivoire Total Ascaris lumbricoides Tribendimidine Tribendimidine - Tribendimidine - Oxantel pamoate Albendazole - Oxantel pamoate ivermectin Before treatment After treatment Cure rate - %(95% 98 6 ( ) 98 6 ( ) 95 6 ( ) 93 5 ( ) Geometric mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% >99 99 (> ) >99 99 (> ) >99 99 ( ) >99 99 ( ) Arithmetic mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% >99 99 (> ) >99 99 (> ( ) 98 7 ( ) 100 0) Before treatment After treatment Cure rate - %(95% Geometric mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% Arithmetic mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% Before treatment After treatment Cure rate - %(95% 98 6 ( ) 98 7 ( ) 94 3 ( ) 93 6 ( ) Geometric mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% >99 99 (> >99 99 (> ( ( ) 100 0) 100 0) 100 0) Arithmetic mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% >99 99 (> >99 99 (> ( ) 98 7 ( ) 100 0) 100 0) *CI denotes the confidence interval 9

11 Table S4 Cure rates and egg-reduction rate of the four treatment arms with all missing data interpreted once as treatment success (cured, follow-up egg count=0) and once as treatment failure (not cured, follow-up egg counts equal to baseline). All missing data analysed as treatment success Variable Tribendimidine Tribendimidine - ivermectin *CI denotes the confidence interval Hookworm Tribendimidine - Oxantel pamoate Albendazole - Oxantel pamoate Before treatment Missing participants analysed as treatment success After treatment Cure rate - %(95% * 56 0 ( ) 84 9 ( ) 54 8 ( ) 52 2 ( ) Geometric mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% 96 9 ( ) 99 5 ( ) 96 9 ( ) 96 6 ( ) * All missing data analysed as treatment failure Variable Tribendimidine Tribendimidine - ivermectin Hookworm Tribendimidine - Oxantel pamoate Albendazole - Oxantel pamoate Before treatment Missing participants analysed as treatment failure After treatment Cure rate - %(95% * 50 9 ( ) 81 8 ( ) 49 0 ( ) 44 1 ( ) Geometric mean no of eggs/g Before treatment After treatment Egg-reduction rate - % (95% 96 0 ( ) 99 3 ( ) 95 7 ( ) 94 7 ( ) * 10

12 Table S5 Clinical symptoms and adverse events of the treatments arms tribendimidine, tribendimidineivermectin, tribendimidine-oxantel pamoate and albendazole-oxantel pamoate assessed at three time points (pre-treatment, 3 and 24 hours post treatment) in Tanzania. Treatment group Symptoms Headache Vertigo Abdominal cramps Fatigue Allergic reaction Nausea Vomiting Diarrhoea Fever Total number of symptoms Number of participants with any symptoms (%) Pre-treatment Tribendimidine (n=101) (7 9) Tribendimidineivermectin (n=102) (9 8) Tribendimidine-oxantel (6 9) pamoate (n=102) Albendazole-oxantel pamoate (n=103) (6 8) Total (n=408) (7 8) 3 hours post-treatment Tribendimidine (n=101) (7 9) Tribendimidineivermectin (12 8) (n=102) Tribendimidine-oxantel (13 7) pamoate (n=102) Albendazole-oxantel (11 7) pamoate (n=103) Total (n=408) (11 5) 24 hours post-treatment Tribendimidine (n=96) (24 0) Tribendimidineivermectin (26 0) (n=100) Tribendimidine-oxantel (27 3) pamoate (n=99) Albendazole-oxantel (14 4) pamoate (n=97) Total (n=392) (23 0) moderate adverse event 11

13 Table S6 Clinical symptoms and adverse events of the treatments arms tribendimidine, tribendimidineivermectin, tribendimidine-oxantel pamoate and albendazole-oxantel pamoate assessed at three time points (pre-treatment, 3 and 24 hours post treatment) in Côte d Ivoire. Treatment group Symptoms moderate adverse event Headache Vertigo Abdominal cramps Fatigue Allergic reaction Nausea Vomiting Diarrhoea Fever Total number of symptoms Number of participants with any symptoms (%) Pre-treatment Tribendimidine (n=58) (50 0) Tribendimidineivermectin (36 8) (n=57) Tribendimidine-oxantel (54 6) pamoate (n=55) Albendazole-oxantel pamoate (n=58) (32 8) Total (n=228) (43 4) 3 hours post-treatment Tribendimidine (n=58) (25 9) Tribendimidineivermectin (n=57) Tribendimidine-oxantel 8 pamoate (n=55) 1 Albendazole- oxantel pamoate (n=58) Total (n=228) (24 6) (30 9) (13 8) (23 7) 24 hours post-treatment Tribendimidine (n=57) (12 3) Tribendimidineivermectin (15 4) (n=52) Tribendimidine-oxantel pamoate (n=51) (11 8) Albendazole-oxantel pamoate (n=53) (0 0) Total (n=213) (9 9) 12

14 Table S7 Clinical symptoms and adverse events of the treatments arms tribendimidine, tribendimidineivermectin, tribendimidine-oxantel pamoate and albendazole-oxantel pamoate assessed at three time points (pre-treatment, 3 and 24 hours post treatment) in Tanzania and Côte d Ivoire. Treatment group Symptoms moderate adverse event Headache Vertigo Abdominal cramps Fatigue Allergic reaction Nausea Vomiting Diarrhoea Fever Total number of symptoms Number of participants with any symptoms Pre-treatment Tribendimidine (n=159) (23 3) Tribendimidine-ivermectin (19 5) (n=159) Tribendimidine-oxantel (23 6) pamoate (n=157) Albendazole-oxantel pamoate (n=161) (16 2) Total (n=636) (20 6) 3 hours post-treatment Tribendimidine (n=159) (14 5) Tribendimidine-ivermectin (17 0) (n=159) Tribendimidine-oxantel (19 8) pamoate (n=157) Albendazole-oxantel (12 4) pamoate (n=161) Total (n=636) (15 9) 24 hours post-treatment Tribendimidine (19 6) (n=153) 1 1 Tribendimidine-ivermectin (22 4) (n=152) Tribendimidine-oxantel (22 0) pamoate (n=150) Albendazole-oxantel (9 3) pamoate (n=150) Total (n=605) (18 3) 13

15 Figure S1 Predicted probability of being cured (A) and proportion of egg reduction (B) by baseline infection intensity stratified by treatment arm. Cure rate prediction were based on logistic regression estimates and the egg reduction via lowest scatterplot smoothing algorithm truncated at 1. Circles represent predicted values of participants cured after treatment, stars indicate participants remained infected after treatment. A B 14

Supplementary Appendix

Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Speich B, Ame SM, Ali SM, et al. Oxantel pamoate albendazole