Field Evaluation of the Efficacy and Safety of Emodepside plus Praziquantel Tablets (Profender ® Tablets for Dogs) against Naturally Acquired Nematode and Cestode Infections in Dogs

Field Evaluation of the Efficacy and Safety of Emodepside plus Praziquantel Tablets (Profender ® Tablets for Dogs) against Naturally Acquired Nematode and Cestode Infections in Dogs

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  S23  Abstract  A controlled, blinded and randomised multicentrefield study evaluated the efficacy and safety of anew anthelmintic tablet formulation containingemodepside plus praziquantel (Profender ® tabletsfor dogs) in the treatment of gastrointestinal nema -tode and cestode infections in dogs in France, Ger-many, Portugal and Slovakia. Dogs positive fornematodes and/or cestodes (demonstrated by fae-cal egg counts and/or the presence of proglottids)were treated with emodepside plus praziquanteltablets (n = 239) or the reference product contain-ing milbemycin oxime and praziquantel (Milbe-max ® [n = 115]) at the recommended dose rate. Twofaecal samples collected between 7 and 13 daysafter treatment were evaluated for proglottids,nematode and cestode eggs. No suspected adverse drug reactions were observedin the study. The following parasite species wereidentified: Trichuris vulpis , Toxocara canis , Tox -ascaris leonina , Uncinaria stenocephala ,  Ancy-lostoma caninum ,  Dipylidium caninum , Taeniidae and Mesocestoides spp. Geometric mean nematodeegg counts in dogs treated with emodepside plusprazi quantel tablets were reduced by 99.9 % com-pared with a reduction of 99.6 % for the referenceproduct. Statistical analysis demonstrated non-inferiority of investigational versus reference prod-uct (p = 0.0342). None of the dogs treated withemo depside plus praziquantel or reference productremained positive for cestodes after treatment.The study demonstrated that emodepside pluspraziquantel tablets are safe and highly efficaciousagainst a broad spectrum of nematodes and ces-todes under field conditions. Field Evaluation of the Efficacy and Safety of Emodepside plus Praziquantel Tablets(Profender  ® Tablets for Dogs) against Naturally Acquired Nematode and CestodeInfections in Dogs Parasitol Res (2009) 105:S23–S29 DOI 10.1007/s00436-009-1492-z ENDOPARASITESGertraut Altreuther  1 (  ), Isabelle Radeloff  2 , Christophe LeSueur  3 ,  Annette Schimmel 1 , Klemens J. Krieger  1 1 Bayer Animal Health GmbH, Leverkusen, Germany 2 Klifovet AG, Munich, Germany 3 Bayer Santé Division Santé Animale, Puteaux, France  E-mail:  Introduction Emodepside plus praziquantel tablets (Profender ® tablets for dogs) have been developed as a newbroad-spectrum anthelmintic treatment for dogs.The efficacy of this formulation against differentgastrointestinal helminths, i.e., mature and imma-ture nematodes ( Trichuris vulpis , Toxocara canis , Toxascaris leonina , Uncinaria stenocephala ,  Ancy-lostoma caninum ) and cestodes ( Echinococcus mul-tilocularis , Echinococcus granulosus , Taenia spp.,  Dipylidium caninum ), has been confirmed in aseries of laboratory dose confirmation studies(Altreuther et al. 2009; Schimmel et al. 2009a,b;Schroeder et al. 2009). This paper reports theresults of a controlled, blinded and randomisedmulticentre clinical field study that evaluated theefficacy and safety of emodepside plus praziquan-tel tablets at the recommended dose range in thetreatment of naturally acquired gastrointestinalnematode and cestode infections in dogs comparedto a currently licensed reference product. Materials and methods The study was conducted according to the VICHguidelines 9 (“Good Clinical Practice”, July 2000),7 (“Efficacy requirements for anthelmintics: gener-al requirements”, December 2000) and 19 (“Effica-cy of anthelmintics: specific recommendations forcanines”, July 2001), and the WAAVP guideline forevaluating the efficacy of anthelmintics for dogsand cats (Jacobs et al. 1994). Study animals and health evaluation  A total of 354 purebred (more than 70 differentbreeds) or crossbred dogs were enrolled in 33 vet-erinary clinics in France (13 vet clinics in 4 regions),Germany (14 vet clinics in 3 regions), Portugal (2 vet clinics in 1 region) and Slovakia (4 vet clin-ics in 1 region). The numbers of dogs that were usedin the evaluation of efficacy and safety are shownin Table 1. The age of the dogs ranged between 5 weeks and 19 years and their body weightbetween 2 and 75.5 kg. Informed consent was obtained from the animalowners before enrolment of the dogs. The dogs wererandomly allocated to the two treatment groups ina target ratio of 2:1 for emodepside plus praziquan-tel tablets and the reference product (see below). Two physical examinations were performed: thefirst was done before application of the treatmenton study day 0 and the second was done 7 to 13 dayspost treatment. After the treatment, the health of the dogs was observed by their owners. Faecal examination The dogs were screened for infection with nema-todes and/or cestodes by faecal egg count analysisand/or evidence of proglottids between day –7 andday 0 (sample A, period 0). Dogs that were positivefor nematodes and/or cestodes were enrolled in thestudy. Further faecal samples of two different defe-cations were collected from treated dogs 7 to 13days post treatment (samples B and C, period 1).Faecal egg counts were performed using a zinc sul-phate flotation method to detect nematode and/orcestode eggs. Results of the faecal egg counts wereexpressed as eggs per gramme of faeces (EPG). Treatment 239 dogs were treated with emodepside plus prazi -quantel tablets, while 115 dogs were treated witha reference product, a tablet containing milbemycinoxime plus praziquantel (Milbemax ® , NovartisTiergesundheit GmbH, Eschborn, Germany andNovartis Santé Animale S.A.S., Rueil Malmaison,France [Table 1]).Dogs were treated once orally with either emodep-side plus praziquantel tablets at a dosage of at least1 mg emodepside and 5 mg praziquantel per kgbody weight or with at least 0.5 mg milbemycinoxime and 5 mg praziquantel per kg body weightaccording to the manufacturers’ instructions. The ease of application of the investigational or ref-erence product was rated for each dog by the vet-erinarian as good, medium or bad.S24 ENDOPARASITES  Data analysis Efficacy of the treatment was assessed for bothnematodes and cestodes. Efficacy against nema-todes or nematode subspecies was assessed byanalysing the reduction in faecal egg countsbetween the first faecal sample (sample A) and thetwo faecal samples obtained post treatment (sam-ples B and C). If one or both faecal samples posttreatment were above zero, the higher value wasused for the calculation of efficacy.Efficacy (% reduction in faecal egg count) was cal-culated according to the following formula:To assess the relative efficacy of the two treatmentsagainst nematodes, a test of non-inferiority on post-baseline egg counts was carried out. With the cal-culations carried out on the log-transformed scale(ln [count + 1]), a non-inferiority margin of 0.38 wasused. The upper 95 % confidence limit of the leastsquare mean of the investigational product wasrequired to be ≤ 0.38 relative to the reference prod-uct to achieve non-inferiority. The efficacy against cestodes was assessed descrip-tively by the proportion of dogs positive for cestodes(demonstrated by faecal egg count and/or proglot-tids) in period 0 that were negative for cestode eggsand proglottids in period 1. % Reduction =(N1 – N2)N1 x 100 N1: geometric mean faecal egg count pre treatment(period 0)N2: geometric mean faecal egg count post treatment(period 1) S25 ENDOPARASITES GroupType of evaluationSafetyEfficacy nematodesEfficacy cestodes Emodepside plus praziquantel tablets23916238Milbemycin oxime plus praziquantel tablets1157214Total35423452 Group  TrichurisvulpisToxocaracanisToxascarisleoninaUncinaria stenocephala Ancy-lostomacaninumDipylidiumcaninumTaeniidae Meso-cestoides spp . Emodepside pluspraziquanteltablets89377572924116Milbemycin oximeplus praziquanteltablets51171no claim10743 Table 1 Numbers of dogs included in the evaluation of efficacy and safety Table 2 Number of dogs included in evaluation of efficacy per parasite species. Deviations to the numbers in Table 1 mayarise when a dog was infected with more than one parasite species, or when a dog in the control group wasinfected with U. stenocephala (efficacy against U. stenocephala not claimed for reference product)  S26 ENDOPARASITES GroupGeomean faecal egg count (EPG)ReductionPre treatmentPost treatment Emodepside plus praziquantel tablets4950.599.9 %Milbemycin oxime plus praziquantel tablets3681.699.6 % Table 3 Number and percentage of dogs infected with more than one helminth species at enrolment a not specified Parasite speciesNumber of dogs% of dogs enrolled T. vulpisT. leonina 10.3 T. vulpisTaeniidae a 10.3 T. vulpisT. canis 82.3 T. vulpisU. stenocephala 4713.3 T. vulpisA. caninum 123.4 T. vulpisD. caninum 10.3 T. canisT. leonina 10.3 T. canisU. stenocephala 10.3 T. canisA. caninum 30.8 T. canisCapillaria spp.20.6 T. canisD. caninum 20.6 T. canisMesocestoides spp. a 10.3 U. stenocephalaT. leonina 30.8 U. stenocephalaA. caninum 82.3 U. stenocephalaD. caninum 20.6 U. stenocephalaMesocestoides spp. a 20.6  A. caninumTaeniidae a 10.3 D. caninumTaeniidae a 30.8 T. vulpisT. leoninaU. stenocephala 20.6 T. vulpisT. canisA. caninum 20.6 T. vulpisU. stenocephalaA. caninum 41.1 T. canisU. stenocephalaTaeniidae a 10.3Total10830.5 Table 4 Efficacy of emodepside plus praziquantel tablets or the reference product against gastrointestinal nematodes  S27 ENDOPARASITES GroupNumber of dogs positive pre/post treatment (% reduction) D. caninum Taeniidae Mesocestoides spp. Emodepside plus praziquantel tablets24/0 (100 %)11/0 (100 %)6/0 (100 %)Milbemycin oxime plus praziquantel tablets7/0 (100 %)4/0 (100 %)3/0 (100 %) Results Efficacy evaluation Of the 354 dogs that were enrolled in the study andused in the safety assessment, 234 were used for theevaluation of the nematode efficacy and 52 were usedfor the cestode evaluation (Table 1). Eleven of the 354dogs enrolled (= 3.1 %) showed a concurrent nema-tode/cestode infection. 108 of the 354 dogs (30.5 %)were infected with more than one species (Table 3). The reduction of the geometric mean faecal eggcounts is shown for all nematodes combined and indi-vidual nematode species in Table 4, 5. In 162 dogspositive for nematodes, treatment with emodepsideplus praziquantel tablets resulted in a reduction of 99.9 %. For 72 dogs positive for nematodes that weretreated with the reference product, the reduction was99.6 %. The reduction for the individualnematodespecies were 99.9–100 % in dogs treated with emod-epside plus praziquantel tablets and 99.4–100 % indogs treated with the reference product. For the dogs with a nematode infection, the differ-ence in the least square means of faecal egg countsof both treatments was calculated as –0.53 with a95 % confidence interval of –1.02 to –0.04. Theupper bound of this confidence interval was belowthe specified upper boundary of 0.38 for achievingnon-inferiority, and hence, non-inferiority of thetreatment with emodepside plus praziquantel wasconfirmed (p = 0.0342).38 dogs positive for cestodes were negative aftertreatment with emodepside plus praziquanteltablets, thus reduction was 100 % (Table 6). For 14dogs treated with the reference product the reduc-tion was also 100 %. Table 6 Efficacy of emodepside plus praziquantel tablets or the reference product against cestodes Table 5 Efficacy of emodepside plus praziquantel tablets or the reference product against nematode subpopulations(Pre/post tx: geometric mean faecal egg count before/after treatment (EPG), Red.: reduction) a no geomeans calculated for T. leonina because of low case numbers b n = 1 (for case numbers refer to Tab. 2) Group T. vulpis T. canis T. leonina U. stenocephala A. caninum Pre txPost txRed.Pre txPost txRed.Red. a Pre txPost txRed.Pre txPost txRed. Emodepsideplus prazi-quanteltablets4620.599.9 %2420.299.9 %100 %3070100 %3700.2100 %Milbemycinoxime pluspraziquanteltablets3861.699.6 %2180.499.8 %(100 %) b no claim4772.799.4 %
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