The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: SKF-30310/002 Title: A multicentre, randomised, double-blind, parallel group study to assess the efficacy, safety and tolerability of a single 400 mg po dose of oxibendazole versus a single 500 mg po dose of mebendazole in the treatment of intestinal helminth infections in adults. Rationale: Contemporary efficacy data for the benzimidazoles, albendazole 400 mg and mebendazole 500 mg, given as a single dose for infections with Ascaris, hookworms and light infections of Trichuris, suggested that similar efficacy in humans could be achieved with a single 400 mg dose of oxibendazole. Phase: III Study Period: 12 February 2001 09 October 2001. Study Design: Multicentre, randomised, double-blind, comparative, parallel group study in adults with proven intestinal helminthiasis. Centres: Thirteen centres: one centre each in Benin, Ecuador, Guatemala, Ivory Coast, Mexico, Peru and Thailand, and two centres each in Nigeria, Philippines and Tanzania. Indication: Intestinal helminth infection. Treatment: Oxibendazole single 400 mg po dose or mebendazole single 500 mg po dose. Objectives: The primary objective was to compare the efficacy of a single 400 mg po dose of oxibendazole versus a single 500 mg po dose of mebendazole in the treatment of intestinal helminthiasis in adults. The secondary objective was to compare the safety and tolerability of oxibendazole single-dose versus mebendazole single-dose treatment in adults. Primary Outcome/Efficacy Variable: The primary efficacy variable was the cure rates of hookworm and Trichuris trichiura on Day 15 shown by the absence of eggs (larvae) in stool examinations using the Kato Katz test. Parasitological response was defined as:. Cure: parasitological cure. Failure: parasitological improvement, parasitological failure or parasitological outcome unavailable. Subjects with missing data for any individual day were not included in the analysis for that day. Parasitological outcome was defined as: Parasitological cure: zero or negative egg count at Day 15 and an egg count greater than zero at entry. Parasitological improvement: an egg count at the visit under consideration less than that observed at entry, but not zero. Parasitological failure: an egg count at the visit under consideration greater than or equal to the egg count at entry. Parasitological outcome unevaluable: egg count not done at the visit under consideration, but a stool sample taken. In addition, cure rates for overall helminth infection were determined for Day 15 either by using the investigator s assessment of overall response, or the calculated overall response based on egg count data from stool samples using the Kato Katz test or the scotch tape test (Graham s test) in the case of Enterobius infection. Overall cure: parasitological cure. Overall failure: parasitological improvement, parasitological failure or parasitological outcome indeterminate. Secondary Outcome/Efficacy Variable(s): Cure rate for helminths other than hookworm and Trichuris trichiura on Day 15. Cure rate of helminth infection (parasitological cure) for each infecting species on Days 8 and 22. Change in egg count from baseline for each infecting species on Days 8, 15 and 22. Overall cure rate on Days 8 and 22. Parasitological response on Days 8 and 22 was assessed using the same criteria as described above for the primary outcome. Statistical Methods: Cure rates on Day 15 for oxibendazole and mebendazole against hookworm and Trichuris trichiura, the overall cure rate (investigator assessment) and the calculated overall cure rate (from the stool egg count data) were compared (separately) using a Mantel-Haenszel test, adjusting for centre. The difference in cure rates was presented with 95% confidence intervals (CIs). The primary analysis population was the intent to treat (ITT) population. Cure rates on Days 8 and 22 of oxibendazole and mebendazole against hookworm and Trichuris trichiura were 1
compared as described for the primary endpoint, as were cure rates for the overall assessment (investigator s assessment and stool egg count data) at these timepoints. The results on Day 15 for the remaining species were presented as a difference in cure rates with 95%CIs with no statistical testing. The analysis of all secondary efficacy variables was performed using the ITT population. The change in egg count was calculated as the result at the baseline visit minus the result at the post-baseline of interest so that a negative value indicated failure (an increase in the number of stool eggs from baseline) and a positive value indicated improvement (a decrease in the number of stool eggs from baseline). For those subjects not cured, the absolute and percentage change from baseline to Day 15 in stool egg count were calculated for each subject and helminth. These were reported using summary statistics. The ITT population included all subjects who had taken study medication and who had an egg count greater than zero for at least one target helminth species in their baseline stool sample, a valid stool evaluation for at least one posttreatment visit and attended at least one follow-up visit. The safety population included all subjects who had received study medication. Study Population: Subjects of either sex aged 18 and 65 years (inclusive) with one of more of the following helminths demonstrated in stool samples during the week before enrolment: Enterobius vermicularis, Ascaris lumbricoides, hookworm (Necator americanus or Ancylostoma duodenalis), or Trichuris trichiura, were eligible for entry into the study. The presence of other helminths was not a cause for exclusion. All subjects provided written or witnessed oral informed consent prior to participation in the study. Pregnant or nursing women were excluded. Oxibendazole Mebendazole Number of Subjects: Planned, N 670 335 Randomised, N 640 319 Completed, n (%) 628 (98.1) 310 (97.2) Total Number Subjects Withdrawn, N (%) 12 (1.9) 9 (2.8) Withdrawn due to Adverse Events, n (%) 0 0 Withdrawn due to Lack of Efficacy, n (%) 0 0 Withdrawn for Other Reasons, n (%) 12 (1.9) 9 (2.8) Demographics Oxibendazole Mebendazole N (ITT) 629 316 Females: Males* 306:334 163:156 Median Age, years (range)* 34 (16 to 79) 33 (17 to 70) Black* 272 (42.5) 137 (42.9) Oriental* 180 (28.1) 89 (27.9) Other* 188 (29.4) 93 (29.2) *Data are for all randomised subjects (oxibendazole N = 640; mebendazole N = 319). Baseline Values: Target helminth species detected and stool egg counts (all subjects). Helminth Oxibendazole (N = 640) Mebendazole (N = 319) Hookworm n (%) 282 (44.1) 133 (41.7) Geometric mean 184.6 264.9 Range 24 to 8640 24 to 6312 Trichuris trichiura n (%) 223 (34.8) 120 (37.6) Geometric mean 257.3 182.4 Range 24 to 121800 24 to 9408 Ascaris lumbricoides n (%) 306 (47.8) 163 (51.1) Geometric mean 878.1 668.3 Range 24 to 300000 24 to 90400 Strongyloides stercoralis n (%) 6 (0.01) 8 (0.03) Geometric mean 72.7 61.6 Range 24 to 264 24 to 624 Primary Efficacy Results: Parasitological response on Day 15 (ITT population). Hookworm Oxibendazole (N = 276) Mebendazole (N = 130) Cure, n (%) 181 (65.6) 50 (38.5) Failure, n (%) 95 (34.4) 80 (61.5) Difference in cure rate (oxibendazole mebendazole), % 27.1 2
95%CI for difference, % 17.2, 37.2 P-value 0.001 Trichuris trichiura Oxibendazole (N = 219) Mebendazole (N = 119) Cure, n (%) 115 (52.5) 80 (67.2) Failure, n (%) 104 (47.5) 39 (32.8) Difference in cure rate (oxibendazole mebendazole), % 14.7 95%CI for difference, % 25.4, 4.0 P-value 0.013 Overall response Oxibendazole (N = 624) Mebendazole (N = 314) Cure, n (%) 393 (63.0) 182 (58.0) Failure, n (%) 231 (37.0) 132 (42.0) Difference in cure rate (oxibendazole mebendazole), % 5.0 95%CI for difference, % 1.6, 11.6 P-value 0.10 Calculated overall response Oxibendazole (N = 624) Mebendazole (N = 314) Cure, n (%) 394 (63.3) 189 (60.6) Failure, n (%) 228 (36.7) 123 (39.4) Difference in cure rate (oxibendazole mebendazole), % 2.8 95%CI for difference, % 3.8, 9.4 P-value 0.37 Secondary Outcome Variable(s): Parasitological response on Day 15 for other species (ITT population). Oxibendazole Mebendazole Ascaris lumbricoides N = 300 N = 161 Cure, n (%) 264 (88.0) 147 (91.3) Failure, n (%) 36 (12.0) 14 (8.7) Difference in cure rate (oxibendazole mebendazole), % 3.3 95%CI for difference, % 9.0, 2.4 Strongyloides stercoralis N = 8 N = 8 Cure, n (%) 6 (75.0) 7 (87.5) Failure, n (%) 2 (25.0) 1 (12.5) Difference in cure rate (oxibendazole mebendazole), % 12.5 95%CI for difference, % 50.2, 25.2 Parasitological outcome on Day 8 (ITT population). Helminth Outcome Oxibendazole Mebendazole Hookworm No. of subjects 276 131 Parasitological cure, n (%) 163 (59.1) 44 (33.6) Parasitological improvement, n (%) 94 (34.1) 70 (53.4) Parasitological failure, n (%) 19 (6.9) 17 (13.0) Trichuris trichiura No. of subjects 219 120 Parasitological cure, n (%) 127 (58.0) 78 (65.0) Parasitological improvement, n (%) 79 (36.1) 38 (31.7) Parasitological failure, n (%) 12 (5.5) 3 (2.5) Unevaluable, n (%) 1 (0.5) 1 (0.8) Ascaris lumbricoides No. of subjects 301 162 Parasitological cure, n (%) 210 (69.8) 103 (63.6) Parasitological improvement, n (%) 89 (29.6) 56 (34.6) Parasitological failure, n (%) 1 (0.3) 3 (1.9) Unevaluable, n (%) 1 (0.3) 0 Strongyloides stercoralis No. of subjects 8 8 Parasitological cure, n (%) 6 (75.0) 7 (87.5) Parasitological improvement, n (%) 1 (12.5) 0 Parasitological failure, n (%) 1 (12.5) 1 (12.5) 3
Parasitological outcome on Day 22 (ITT population). Helminth Outcome Oxibendazole Mebendazole Hookworm No. of subjects 280 130 Parasitological cure, n (%) 175 (62.5) 55 (42.3) Parasitological improvement, n (%) 77 (27.5) 56 (43.1) Parasitological failure, n (%) 28 (10.0) 19 (14.6) Trichuris trichiura No. of subjects 219 119 Parasitological cure, n (%) 117 (53.4) 85 (71.4) Parasitological improvement, n (%) 86 (39.3) 31 (26.1) Parasitological failure, n (%) 14 (6.4) 3 (2.5) Unevaluable, n (%) 2 (0.9) 0 Ascaris lumbricoides No. of subjects 299 158 Parasitological cure, n (%) 285 (95.3) 153 (96.8) Parasitological improvement, n (%) 11 (3.7) 5 (3.2) Parasitological failure, n (%) 1 (0.3) 0 Unevaluable, n (%) 2 (0.7) 0 Strongyloides stercoralis No. of subjects 8 8 Parasitological cure, n (%) 6 (75.0) 7 (87.5) Parasitological improvement, n (%) 1 (12.5) 1 (12.5) Parasitological failure, n (%) 1 (12.5) 0 Change from baseline in stool egg counts for subjects not cures at Days 8, 15 and 22 (ITT population). Helminth Timepoint Oxibendazole (N = 629) Mebendazole (N = 316) n* Median % decrease n* Median % decrease decrease decrease Hookworm Day 8 113 144 71.4 87 168 54.5 Day 15 95 144 74.4 79 240 62.6 Day 22 105 120 66.7 75 168 60.0 Trichuris trichiura Day 8 91 240 75.0 41 120 71.4 Day 15 102 180 57.8 39 216 69.2 Day 22 100 204 62.3 34 192 66.4 Ascaris lumbricoides Day 8 90 3768 84.1 59 3048 79.4 Day 15 34 4788 92.9 14 3876 94.0 Day 22 12 2916 93.5 5 7440 95.1 Strongyloides stercoralis Day 8 2 72 27.3 1 24 100 Day 15 2 108 40.9 1 48 200 Day 22 2 120 45.5 1 96 400 *Number of subjects not cured. NB: A negative result indicates an increase in egg count. Overall cure on Days 8 and 22 (ITT population). Timepoint Outcome Oxibendazole (N = 629) Mebendazole (N = 316) Day 8 No. of subjects 627 316 Parasitological cure, n (%) 359 (57.3) 142 (44.9) Parasitological improvement, (%) 234 (37.3) 151 (47.8) Parasitological failure, n (%) 30 (4.8) 22 (7.0) Parasitological outcome 4 (0.6) 1 (0.3) Indeterminate, n (%) Day 22 No. of subjects 628 311 Parasitological cure, n (%) 406 (64.6) 194 (62.4) Parasitological improvement, (%) 183 (29.1) 97 (31.2) Parasitological failure, n (%) 38 (6.1) 20 (6.4) Parasitological outcome Indeterminate, n (%) 1 (0.2) 0 4
Safety Results: Most Frequent Adverse Events On-Therapy Oxibendazole (N = 640) Mebendazole (N = 319) Subjects with any AE(s), n (%) 268 (41.9) 139 (43.6) Lactate dehydrogenase increased 73 (11.4) 31 (9.7) Creatine phosphokinase increased 51 (8.0) 23 (7.2) Lymphocytosis 46 (7.2) 28 (8.8) Aspartate aminotransferase increased 45 (7.0) 17 (5.3) Eosinophilia 28 (4.4) 20 (6.3) Granulocytopaenia 28 (4.4) 15 (4.7) Alanine aminotransferase increased 24 (3.8) 16 (5.0) Parasitic infection 24 (3.8) 9 (2.8) Bandaemia 23 (3.6) 13 (4.1) Hyperhaemoglobinaemia 20 (3.1) 4 (1.3) Serious Adverse Events On-Therapy Oxibendazole (N = 640) Mebendazole (N = 319) Subjects with non-fatal SAEs, n (%) 0 0 Subjects with fatal SAEs, n (%) 0 0 Conclusion: A single oral 400 mg dose of oxibendazole showed a significantly greater efficacy than single oral 500 mg dose of mebendazole in cure rate (65.6% vs. 38.5%, p=0.001) in hookworm infections. Mebendazole showed a significantly higher cure rate (67.2% versus 52.5%, p=0.013) than oxibendazole in the treatment of Trichuris infections. Baseline values for both hookworm and Trichuris may have impacted the day 15 results. The majority of adverse events were related to laboratory abnormalities, and occurred with similar frequency in both treatment groups. 5