Field study to investigate the effectiveness and safety of a novel orally administered combination drug product containing milbemycin oxime and lotilaner (Credelio® Plus) against natural flea and tick infestations on dogs presented as veterinary patients in Europe.

BACKGROUND: A pivotal randomised, blinded, positive-controlled, multicentre, European field study was conducted to evaluate the effectiveness and safety of a novel combination tablet of lotilaner and milbemycin oxime (Credelio® Plus) administered orally to client-owned dogs naturally infested with fleas and/or ticks. METHODS: In this field study, households with flea- or tick-infested dog(s) were enrolled on Day 0 into the study to provide data for either the tick or flea infestation cohorts. Households were randomised in a 2:1 ratio to receive either the combination investigational product (IP, Credelio Plus® tablets) or the control product (CP: Nexgard Spectra® tablets). Dogs were administered IP (flea cohort n = 135; tick cohort: n = 147) or CP (flea cohort: n = 67; tick cohort: n = 74) once every 4 weeks for a total of three times at a dose rate of 20.0-41.5 mg/kg bodyweight lotilaner and 0.75-1.53 mg/kg bodyweight milbemycin oxime (IP) or as recommended (CP). Percentage reduction was calculated by comparing individual dog flea and tick counts at each assessed post-treatment time point to their respective baseline (pre-treatment) infestation. Resolution of the clinical signs of flea allergy dermatitis (FAD) was assessed in flea-allergic dogs on the days that flea counts were performed. RESULTS: Flea effectiveness of Credelio Plus® after 3 consecutive monthly treatments was 100% against Ctenocephalides felis, C. canis and Pulex irritans. Tick effectiveness of Credelio Plus® over the same time frame was 99.3% for Ixodes ricinus and 100% against Rhipicephalus sanguineus (s.l.). Flea effectiveness of the CP after three consecutive monthly treatments was 100% against C. felis, C. canis and P. irritans. Tick effectiveness of the CP over the same time frame was 99.8% for I. ricinus and 100% against R. sanguineus. Credelio Plus® was well tolerated based on the safety assessments in all treated dogs in this field study. Within both treatment groups there was a reduction in total FAD scores from baseline. CONCLUSIONS: This pivotal European field study demonstrated the excellent effectiveness and safety of a combination of lotilaner and milbemycin oxime (Credelio Plus®) administered orally to dogs naturally infested with fleas and/or ticks.

Field study to investigate the effectiveness and safety of a novel orally administered combination drug product containing milbemycin oxime and lotilaner (Credelio® Plus) for the prevention of heartworm disease (Dirofilaria immitis) in client-owned dogs in the USA.

BACKGROUND: Dirofilaria immitis, a globally distributed filarial parasite of dogs, is known to cause serious or fatal cardiopulmonary disease. Client-owned dogs were enrolled in a clinical field study in the USA to evaluate the clinical effectiveness and field safety of an orally administered combination investigational product (IP) containing milbemycin oxime and lotilaner (Credelio® Plus) as compared to a control product (CP) for the prevention of heartworm disease when administered monthly for 11 consecutive months. METHODS: In this 11-month field study, 319 dogs ≥ 8 weeks old confirmed to be heartworm-negative were enrolled from eight geographically distinct US veterinary clinics, including sites in the southern USA and Mississippi River Valley. The dogs were treated with either the IP combination product at 0.75-1.53 mg/kg milbemycin oxime and 20-41.5 mg/kg lotilaner (n = 159) or the CP (Sentinel® Flavor Tabs®; milbemycin oxime/lufenuron) at the label-recommended dose rate (n = 158.) On day 330, effectiveness was evaluated in each dog using antigen and microfilarial (modified Knott's) testing to assess the establishment of any patent adult heartworm infections. RESULTS: All dogs treated with the IP combination product and the CP tested negative (100% prevention) for heartworm infection on day 330. The IP combination product tablets containing milbemycin oxime and lotilaner were well tolerated based on the safety assessments in all treated dogs. CONCLUSIONS: This multi-site clinical study using client-owned dogs demonstrated that monthly use of flavored, chewable tablets containing a combination of milbemycin oxime and lotilaner administered orally under end use conditions is safe for dogs. None of the enrolled dogs developed heartworm infections. Eleven consecutive monthly treatments of the IP provided 100% prevention of heartworm disease caused by D. immitis.

Effectiveness of a novel orally administered combination drug product containing milbemycin oxime and lotilaner (Credelio® Plus) for the treatment of larval and immature adult stages of Ancylostoma caninum in experimentally infected dogs.

BACKGROUND: The hookworm, Ancylostoma caninum, is a common and important zoonotic intestinal nematode parasite that infects dogs globally. Both the immature and adult stages of A. caninum ingest large volumes of blood during the feeding process and can cause severe anemia and death in young dogs, even before patent infections can be diagnosed using routine faecal examination methods. Thus, effective treatment of any pre-patent stages of immature hookworms can reduce or eliminate the risk of clinical disease in infected dogs and additionally reduce environmental contamination of eggs and infective larvae. Two randomized, blinded, GCP-compliant, pivotal laboratory dose confirmation studies were conducted to evaluate the effectiveness and safety of a new novel combination of lotilaner and milbemycin oxime tablets (Credelio Plus®) administered orally to dogs experimentally infected with immature (L4 and immature adult [L5]) stages of A. caninum. METHODS: Treatments using the intended global commercial tablet formulation of Credelio Plus were administered in a time frame relative to inoculation with infective larvae so that effectiveness could be assessed against each specific immature stage of A. caninum. In each study, dogs were randomized to one of six (study 1) or four (study 2) treatment groups. Each treatment group contained 8 (study 1) or 10 (study 2) dogs that had been experimentally inoculated with infective A. caninum larvae on day 0 and were dosed once on day 7 or day 11. Enrolled subjects were administered placebo tablets, Credelio Plus tablets, or lotilaner mono tablets to provide minimum dosages of 0.75 mg/kg of milbemycin oxime and 20 mg/kg of lotilaner. All dogs were necropsied 5 days after their respective treatment. All nematodes recovered from the gastrointestinal tract at necropsy were counted by species and stage. RESULTS: For both dose confirmation studies and based on geometric mean worm counts, efficacy of Credelio Plus was ≥ 97.3% against L4 larval stage of A. caninum and ≥ 98.7% against immature adult (L5) A. caninum. CONCLUSIONS: These studies demonstrated that the orally administered Credelio Plus combination tablet was highly efficacious in treating immature (L4 and immature adult [L5]) stages of A. caninum in experimentally infected dogs.

Effectiveness of Credelio® Plus, a novel chewable tablet containing milbemycin oxime and lotilaner for the treatment of larval and immature adult stages of Toxocara canis in experimentally infected dogs.

BACKGROUND: The ascarid, Toxocara canis, is a common and important zoonotic intestinal nematode parasite that infects dogs globally. An effective treatment that kills any pre-patent stages of immature T. canis could additionally reduce or eliminate the development of patent infections that can result in clinical disease in infected dogs and would further reduce environmental contamination of eggs. Two randomized, blinded, GCP-compliant, pivotal laboratory dose confirmation studies were conducted to assess the effectiveness and safety of a new novel combination of lotilaner and milbemycin oxime tablets (Credelio Plus) administered orally to dogs that were experimentally infected with immature (L4 or immature adult [L5]) stages of T. canis. METHODS: The commercial tablet formulation of Credelio Plus® was administered in a time frame relative to inoculation with infective eggs. This allowed for effectiveness to be assessed against each specific immature stage of T. canis. In each study, dogs were randomized and allocated to one of four treatment groups. Each treatment group contained ten dogs that had been experimentally inoculated on Day 0 with infective T. canis eggs and then were dosed once on Day 14 or Day 24 using either placebo tablets or Credelio Plus tablets (IP) to provide minimum dosages of 0.75 mg/kg of milbemycin oxime and 20 mg/kg of lotilaner. All dogs were necropsied 5 or 6 days after their respective treatment. At necropsy, all nematodes recovered from the gastrointestinal tract were counted by species and stage. RESULTS: In both dose confirmation studies using geometric mean worm counts, effectiveness of Credelio Plus was ≥ 98.6% and ≥ 96.8% against L4 larval stage T. canis and immature adult [L5] T. canis in both studies, respectively. CONCLUSIONS: These studies demonstrated that the Credelio Plus combination tablet administered orally to dogs was highly efficacious against experimental infections with L4 and immature adult [L5] stages of T. canis.

Field study to investigate the effectiveness and safety of a novel orally administered combination drug product containing milbemycin oxime and lotilaner (Credelio® Plus) against natural intestinal nematode infections in dogs presented as veterinary patients in Europe.

BACKGROUND: A randomised, blinded, positive controlled, multicentre, Good Clinical Practice-compliant, pivotal field study was conducted to evaluate the effectiveness and safety of a new combination of lotilaner + milbemycin oxime tablets (Credelio® Plus; Elanco Animal Health) administered orally to client-owned dogs naturally infected with intestinal nematodes. METHODS: Client-owned dogs presenting to veterinary clinics from households in France, Hungary and Germany were screened for intestinal nematodes. Dogs with an initial positive faecal egg count that was subsequently confirmed with a follow-up faecal examination to demonstrate the presence of naturally occurring mixed or mono-infections with Toxocara canis, Toxascaris leonina, Trichuris vulpis or Ancylostoma caninum were enrolled on Day 0 into the study. Households were randomised in an approximately 2:1 ratio to receive either an investigational product (IP; Credelio Plus tablets) or control product (CP; Nexgard Spectra® tablets) as treatment. Dogs were administered the IP (n = 278) or CP (n = 117) once on Day 0 at a dose rate of 0.75-1.56 mg/kg bodyweight milbemycin oxime and 20.0-41.5 mg/kg bodyweight lotilaner (IP) or as recommended (CP). Effectiveness of the IP and CP treatments was based on the post-treatment reduction in geometric mean faecal egg counts on Day 8 (range Day 7-10) after treatment as compared to their pre-treatment nematode faecal egg counts. RESULTS: Geometric mean (GM) faecal egg counts for T. canis, A caninum and T. vulpis were reduced by ≥ 97.2% in the Credelio Plus group and by ≥ 95.3% in the afoxolaner + milbemycin oxime group. There were insufficient data to calculate a percentage reduction in GM faecal egg counts between Day 0 and Day 8 for T. leonina due to low prevalence. Credelio Plus was well tolerated in this field study. Of the 355 total doses administered, 82.3% were accepted free choice in the IP group compared to 80.8% in the CP group. CONCLUSIONS: This study demonstrated effectiveness (≥ 97.2% reduction), safety and tablet acceptance of a combination of milbemycin oxime and lotilaner (Credelio Plus) administered orally to dogs with natural intestinal infections of T. canis, A. caninum and T. vulpis.

Effects of milbemycin oxime, combined with spinosad, when administered orally to microfilaremic dogs infected with adult heartworms (Dirofilaria immitis).

OBJECTIVE To evaluate the safety of PO administration of a milbemycin oxime (MBO) and spinosad product to heartworm (Dirofilaria immitis)-positive microfilaremic dogs. DESIGN Randomized, blinded, complete block trial. ANIMALS 32 purebred Beagles with a patent heartworm infection. PROCEDURES Dogs ranked by sex and microfilaria counts (range, 398 to 1,980 microfilaria/mL) were assigned to 4 groups of 8 to receive 3 treatments PO at 28-day intervals beginning on day 0: placebo (control group) or spinosad-MBO tablets containing MBO at the upper end of the label dose range (0.75 to 1 mg/kg [0.34 to 0.45 mg/lb]; 1× group) or 3 (3× group) or 5 (5× group) times that dose. Blood samples were collected at various points for adult heartworm antigen and Knott tests. Necropsies were performed on day 65, and recovered adult heartworms were counted. RESULTS 1 control dog died from heartworm-associated complications. Other adverse events included mild, transient emesis (1 dog in each of the 1× and 5× groups and 3 dogs in the 3× group). Similar adult heartworm counts (range, 13 to 41) were obtained for all 4 groups. Results of blood antigen and microfilaria tests were positive throughout the study, with 1 exception in each of the 3× and 5× groups. Mean microfilaria counts increased with time in the control group, whereas reductions from baseline in treated groups ranged from 61.5% to 96.4%. CONCLUSIONS AND CLINICAL RELEVANCE The evaluated MBO-spinosad formulation caused no severe adverse events when administered PO to microfilaremic dogs. Although microfilaria counts decreased following treatment, repeated monthly MBO treatments were incompletely microfilaricidal, suggesting MBO should not be used as a microfilaricide.

Efficacy of lotilaner (Credelio™), a novel oral isoxazoline against naturally occurring mange mite infestations in dogs caused by Demodex spp.

BACKGROUND: The oral systemic efficacy of lotilaner (Credelio™, Elanco) was evaluated against Demodex spp. in naturally infested dogs with generalized demodicosis. METHODS: In this study, 10 dogs with clinical signs of generalized demodicosis and positive for Demodex spp. mites based on skin scrapings were assigned to a single group orally treated with lotilaner (minimum dose of 20 mg/kg) on Days 0, 28 and 56. RESULTS: For lotilaner-treated dogs, pre-treatment mite counts based on skin scrapings performed at five different sites were reduced by > 99.9% (P < 0.0001) up to 56 days after the first and second monthly doses. No live mites were detected after Day 56 out to and including Day 84 post-treatment for 100% efficacy of each dog's Demodex mite infestation. Nine of 10 dogs were 100% mite-free from Day 28 (first evaluation) through Day 84 (end of study) and live mites were only found once on one dog (Day 56) following treatment with lotilaner. All dogs in the lotilaner-treated group showed marked improvement in the clinical signs of demodicosis and there were no drug associated adverse events. A marked improvement in hair re-growth was observed in all the dogs from 6 weeks following initiation of treatment. CONCLUSIONS: In this study lotilaner administered at a minimum oral dose of 20 mg/kg was highly effective in reducing and eliminating live mite counts in dogs with natural infestations of Demodex spp.

Effectiveness and residual speed of flea kill of a novel spot on formulation of spinetoram (Cheristin®) for cats.

BACKGROUND: A spot-on spinetoram formulation (Cheristin®) was developed to eliminate fleas from infested cats. This paper describes three spinetoram studies: two for registration (Studies 1 and 2), and one comparing residual speed of kill (SOK) with topically applied fipronil/(S)-methoprene (FSM) and imidacloprid (Study 3). METHODS: Cats were randomized to treatment based on flea counts from infestations placed within 2 weeks prior to treatment. In Studies 1 and 2, groups were untreated control and spinetoram; in Study 3, groups were untreated control, spinetoram, FSM and imidacloprid, all applied per label on Day 0. Cats were infested the day before treatment. In Studies 1 and 2, counts were completed 48 h post-treatment and after weekly challenges through 5 weeks. In Study 3, infestations were completed weekly through Day 28, with counts 1, 4, 8 and 12 h after treatment or post-infestation (PI). Efficacy was determined on geometric mean flea count reductions compared with controls, and in Study 3 mean flea counts in spinetoram-groups were compared with those in FSM and imidacloprid groups. RESULTS: In Studies 1 and 2, spinetoram effectiveness was 100% against existing infestations, and at least 96% through Day 37. In Study 3 mean counts were not significantly different from controls in any group until 8 h post-treatment when imidacloprid counts were significantly lower than spinetoram counts, which were in turn significantly lower than FSM counts (P < 0.05). At 1 h PI spinetoram-group counts were significantly lower (P < 0.05) than counts in: controls, all days; imidacloprid, Days 7, 14, and 28; FSM, Days 14 and 28. At 4 h PI, spinetoram mean counts were significantly lower (P < 0.05) relative to: controls, all days; imidacloprid, Days 7, 14 and 21; FSM, Days 7, 14, 21 and 28 (P < 0.05). On multiple occasions, at 8 and 12 h PI, mean counts were significantly lower (P < 0.05) for spinetoram than for imidacloprid and FSM; at no point were FSM or imidacloprid significantly more effective than spinetoram against new infestations. All treatments were well tolerated. CONCLUSIONS: Spinetoram was highly effective for at least 1 month post-treatment and provided more rapid month-long residual SOK than FSM or imidacloprid.

Initial evaluations of the effectiveness of spinetoram as a long-acting, oral systemic pulicide for controlling cat flea (Ctenocephalides felis) infestations on dogs.

Spinetoram is a semi-synthetic, spinosyn class natural product derived from fermentation by the actinomycete, Saccharopolyspora spinosa. Based on LD50 (50% lethal dose) values against adult cat fleas (Ctenocephalides felis) using an in vitro contact assay, spinetoram was approximately 4-fold more potent than spinosad. Subsequently, two parallel-arm, randomized block design laboratory studies were conducted to evaluate the effectiveness of orally administered spinetoram against experimental C. felis infestations on dogs, when administered as a single dose or multiple doses over a 6-12h interval. In the first study, 16 mixed-breed dogs were allocated to two treatment groups of eight dogs each, based on pre-treatment flea retention rates: negative (placebo) control; and a single dose of spinetoram at 30mg/kg. In the second study, 32 mixed- and pure-breed dogs were allocated to four treatments groups of eight dogs each, based on pre-treatment flea retention rates: negative (placebo) control; a single dose of 60mg/kg; three sequential 20mg/kg oral doses evenly administered over a 6h period; and three sequential 20mg/kg oral doses evenly administered over a 12h period. In both studies, treatments were administered to dogs in a fed state in order to enhance absorption of spinetoram. Therapeutic efficacy was assessed 24h after treatment and persistent efficacy was assessed 48h after each subsequent flea infestation. The duration of effectiveness was assessed at approximate weekly intervals beginning on Day 5 through Day 56 in the first study, or through Day 105 in the second study. In both studies, treatment efficacy was ≥99% (geometric means) through 44 d, with ≥99% efficacy continuing through 72 d for all three treatments in the second study. Efficacy remained ≥90% for at least 8 weeks with a single 30mg/kg dose; through 13 weeks with three sequential 20mg/kg doses; and through 15 weeks with a single 60mg/kg dose. For all time points and in both studies, spinetoram-treated groups had significantly fewer live fleas relative to their respective negative control group (p<0.05). The pharmacokinetic profile in dogs revealed that the mean plasma concentration of spinetoram required for effectiveness against fleas was maintained for at least 3 months regardless of whether the 60mg/kg total body dose was administered as a single bolus or in three sequential 20mg/kg doses administered over a 6-12h period of time. The results of preliminary in vitro and in vivo studies demonstrate that orally administered spinetoram was well tolerated, and provides long lasting effectiveness against C. felis infestations on dogs.

Speed of flea knockdown of spinosad compared to afoxolaner, and of spinosad through 28 days post-treatment in controlled laboratory studies.

BACKGROUND: The speed of flea knockdown by different products and their duration of effectiveness are factors which affect veterinarian prescribing decisions. To further validate the month-long pulicidal effectiveness of spinosad and determine its rate of flea knockdown to that of afoxolaner, three studies were conducted in two laboratories in the United States, utilizing flea infestations from colonies which are regularly refreshed through introduction of locally caught fleas. METHODS: All study assessors were blinded, dogs were ranked by pre-study flea counts and randomized accordingly, and treatments administered on Day 0. All studies included a negative control group; two also included an afoxolaner group. In one study, flea challenges for treated and control dogs (10 per group) were completed 21 and 28 days after treatment and counts were performed 24 h later. In each of two speed-of-knockdown (SOK) studies, 36 dogs were randomized, six dogs per group, to: untreated controls; administered oral afoxolaner (2.6-6.2 mg/kg); or oral spinosad (32.1-59.2 mg/kg). In the SOK studies, live fleas from Day -1 infestations were counted after being combed off at 1 and 3 h after treatment, and after reinfestations on Day 7. RESULTS: There were no treatment-related adverse events. Spinosad was 98.6% effective at 28 days post treatment. For SOK, geometric mean live flea counts for afoxolaner were not different from controls at any assessment. For spinosad, all mean counts were significantly lower than in controls (p ≤ 0.0128) except at 1 h post treatment in both studies. Spinosad was significantly more effective than afoxolaner in both studies at 3 h post treatment (p ≤ 0.0065) and post-Day 7 infestation (p ≤ 0.0054), and at 1 h post treatment (p = 0.0276) and post-Day 7 infestation in one study. CONCLUSIONS: These data validate spinosad's faster onset of flea knockdown than afoxolaner against infestations present at the time of treatment, and faster residual speed of flea knockdown for at least 7 days post treatment, and confirm spinosad's extended residual speed of kill for at least 28 days post treatment.

Field evaluation of the efficacy and safety of a combination of spinosad and milbemycin oxime in the treatment and prevention of naturally acquired flea infestations and treatment of intestinal nematode infections in dogs in Europe.

Two separate randomised, blinded, multicentre field trials were conducted to evaluate the efficacy and safety of a combination of spinosad and milbemycin oxime (MO) (Trifexis(®), Elanco Animal Health) in the treatment and prevention of naturally acquired flea infestations and intestinal nematode infections in European dogs. Treatments using Trifexis(®) and each control veterinary product (CVP) were administered once on Day 0 in both field studies. In the flea field trial, 11 veterinary clinics in France participated in the study. On Day 0, whole body flea comb counts were conducted on all dogs being evaluated for enrolment. Dogs with ≥7 fleas on Day 0 were enrolled, treated once on Day 0 with spinosad/MO or the CVP (Stronghold(®); selamectin) and then underwent post-treatment flea counts on Days 14 and 30. There were 150 spinosad/MO treated dogs and 71 CVP treated dogs included in the flea effectiveness population. Effectiveness against fleas (% reduction in geometric means; GM) was 98.97% and 97.37% for the spinosad/MO treated dogs, and 97.43% and 93.96% for the CVP dogs on Days 14 and 30, respectively, compared to the pre-treatment baseline flea counts. Of the spinosad/MO dogs, 89.3% and 80.0% had no live fleas on Days 14 and 30, compared to 77.5% and 70.4% of the CVP dogs, respectively. In the nematode field trial, data from 10 veterinary clinics in France and 19 in Ireland were pooled. Faecal samples from dogs at each clinic were analysed. A positive result at screening (parasite eggs from Toxocara canis, Toxascaris leonina, Trichuris vulpis or Ancylostoma caninum) allowed for enrolment. Dogs were randomised to spinosad/MO or the CVP (Milbemax(®); MO/praziquantel). On Day 8, a post-treatment faecal sample was taken and analysed. Of 2333 dogs screened for nematode eggs, 238 dogs were positive with one or more of these nematodes, and 229 were enrolled in the study. Of the 229 dogs, 151 were treated with a single dose of spinosad/MO, and 77 were treated with a single dose of CVP. Post-treatment effectiveness against all nematodes (% reduction GM) was achieved with reductions of 98.57% and 97.57% for the spinosad/MO treated dogs and CVP dogs, respectively, as compared to the pre-treatment baseline faecal egg counts. Trifexis(®) was shown to be safe and effective against natural infestations of fleas as well as mixed and single intestinal nematode infections in client owned dogs in Europe when administered as a single oral administration at the recommended dose.

Efficacy of milbemycin oxime in combination with spinosad in the treatment of larval and immature adult stages of Ancylostoma caninum and Toxocara canis in experimentally infected dogs.

Ancylostoma caninum and Toxocara canis are two important zoonotic parasites of dogs. The primary objective of these studies were to confirm the oral effectiveness of milbemycin oxime (MO) and spinosad in dogs experimentally infected with immature (L4 and immature adult) stages of T. canis or A. caninum. Both trials were conducted as randomized, blinded, placebo-controlled dose confirmation studies. Treatments using the intended European commercial tablet formulation of Trifexis were administered in a timeframe relative to inoculation so that effectiveness could be assessed against specific immature stages of A. caninum or T. canis. In each study on Day 0, each of 32, 3-4 month old dogs were inoculated with 250 infective eggs of T. canis or 300 infective L3 of the hookworm, A. caninum. All dogs were weighed before their scheduled treatment, randomized to 1 of the 4 treatment groups in each study (8 dogs/group). All dogs were fed just prior to dosing. For T. canis, dogs were treated orally with an MO/spinosad tablet on Day 14 or Day 24. For A. caninum, dogs were treated orally with an MO/spinosad tablet on Day 7 or Day 11. Corresponding control groups in each study received a placebo tablet. Dogs were necropsied 5 or 6 days after their respective treatments. The digestive tract was removed and processed to recover, count, and identify all stages. The GM worm count for the MO/spinosad tablet on Day 14 (L4 T. canis) was 0.0, with efficacy calculated as 100%; however, only 3 of 8 control dogs had adequate infections. The GM worm count for the MO/spinosad tablet on Day 24 (immature adult stage) was 0.30; efficacy calculated at 96.15%. This is based on 5 of the 8 control dogs with adequate infections. In the two A. caninum studies, GM worm counts for the MO/spinosad tablets on Day 7 (L4 efficacy) was 2.37 and 0.8 with efficacy calculated as 98.92% and 99.25%, respectively. The GM count for the group treated with the MO/spinosad combination on Day 11 (immature adult) was 6.19 and 1.4; efficacy calculated at 97.77% and 98.58%, respectively. A minimum MO oral dose of 0.75 mg/kg was highly effective for the treatment of immature stages of T. canis and A. caninum infections in dogs. The ability to kill immature stages of these two parasites before they become patent will benefit dogs, their owners and family members due to reduced exposure to these potentially zoonotic parasites.

Safety and efficacy of spinosad chewable tablets for treatment of flea infestations of cats.

OBJECTIVE: To compare safety and efficacy of spinosad and selamectin and determine effects of those products on flea allergy dermatitis (FAD) in cats. DESIGN: Randomized clinical trial. Animals-211 client-owned cats. PROCEDURES: Cats with ≥ 5 fleas evaluated at 8 veterinary clinics were allocated to receive spinosad (50 to 100 mg/kg [22.7 to 45.5 mg/lb], PO; n = 139) or selamectin (≥ 6 mg/kg [≥ 2.7 mg/lb], topically; 72) once per month. Flea comb counts and FAD scores were determined on day -1, between days 27 and 33, and between days 85 and 95 (evaluations 1, 2, and 3, respectively); day 0 was the first day of drug administration. RESULTS: The most common adverse event was vomiting (14.3% and 2.4% of spinosad- and selamectin-treated cats, respectively). Evaluation 2 and 3 geometric mean flea counts for spinosad-treated cats were significantly lower than those for selamectin-treated cats. Percentage reductions in flea counts for the spinosad and selamectin groups were 97.5% and 88.8% (evaluation 2) and 99.3% and 97.7% (evaluation 3), respectively. At evaluations 2 and 3, 70.6% and 92.6% of spinosad-treated cats and 29.4% and 64.7% of selamectin-treated cats were free of fleas, respectively. Weighted FAD scores for spinosad- and selamectin-treated cats decreased 94.2% and 80.0% during the study, respectively. Spinosad tablets were successfully administered during 98.1% of treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study indicated spinosad and selamectin both reduced flea counts and FAD scores for cats, although spinosad was more effective. Monthly oral administration of spinosad may be practical for treatment of flea infestations and FAD in cats.

Speed of kill efficacy and efficacy of flavored spinosad tablets administered orally to cats in a simulated home environment for the treatment and prevention of cat flea (Ctenocephalides felis) infestations.

The efficacy of spinosad against adult fleas (Ctenocephalides felis) on cats was evaluated in two separate controlled, blinded studies-one to determine flea knockdown and speed of flea kill (SOFK) on experimentally infested cats, another to assess the ability of spinosad to prevent flea infestations in a simulated home environment (SHE) study design. In each study, pre-treatment live flea counts were used as a blocking factor to randomize cats to treatment, and treated in the fed state, with flavored tablets containing either no active ingredient (control) or spinosad (50-100mg/kg in the SOFK study; 50-75 mg/kg body weight in the SHE study). In the SOFK study, 6 cats per group were infested with unfed adult fleas on Day -1. Groups 1-5 received control tablets; groups 6-10 received spinosad tablets. Flea counts were conducted at 0.5, 2, 4, 8 and 24h post-dosing. In the SHE study, 12 flea-free cats per group, treated on Days 0, 30 and 60, were maintained in solid-sided cages with solid carpeted floors. Each cat was infested on Days 1, 7 and 14 with 100 unfed adult fleas. Individual flea comb counts were performed on Days 3, 9, 16, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, 91 and 95. After each count, except Day 95, up to 300 live fleas were replaced on each cat. To augment flea challenge, the carpeted area in each cage was sprinkled weekly with larval flea growth media (dried blood, yeast). In the SOFK study, reductions in mean flea counts in the spinosad groups were observed at all post-treatment assessments, beginning at 0.5h post-infestation with significant differences (p<0.0001) from vehicle-treated cats from 2h post-treatment when efficacy was >90%, through the final flea counts 24h post-infestation when no fleas were found on spinosad treated cats. In the SHE study, GM post-treatment flea counts in the control group ranged between 38.9 and 107.0 (arithmetic means 58.8-118.1); no live fleas were combed from spinosad-treated cats (100% effectiveness) at any time point post-treatment. No adverse events that were attributable to the treatments were observed in either study. These studies demonstrated that spinosad administered orally to cats is safe and effective, providing >90% efficacy from 2h post-dosing and 100% knockdown at 24h, and preventing infestations over a 95 day study period from a flea-contaminated simulated home environment.

Assessment of owner-administered monthly treatments with oral spinosad or topical spot-on fipronil/(S)-methoprene in controlling fleas and associated pruritus in dogs.

Monitoring of the performance of flea control products under conditions of natural challenge is valuable in assessing continued effectiveness and determining the ongoing relevance of laboratory studies. A multi-clinic, investigator-blinded study was undertaken in client-owned dogs to investigate and compare the flea control provided by 3 consecutive monthly treatments of oral spinosad (SPN) or fipronil/(S)-methoprene topical (FSM) spot-on. The first household dog meeting enrollment criteria and with at least 10 fleas (whole-body flea count) served as the index dog in a household against which primary objectives were set. Stratification was based on pruritus scores at the enrollment visit and on single or multiple pet household. Index pets were randomized to treatment with either SPN or FSM, dispensed on day 0 for at-home administration by owners. All other household dogs and cats, maximum 4 pets per household, were dispensed the same treatment as the index dog (spinetoram was dispensed for cats in SPN households). Subsequent treatments were dispensed when index dogs were returned for whole-body flea counts and pruritus-scoring at visits on days 30 and 60, with final assessments on day 90 (±5 days on each occasion). Primary endpoints were the number of flea-free index dogs in each group one month after the final treatment, the reduction in owner-reported pruritus, and the reduction from baseline mean flea counts. One hundred twenty eight index dogs were enrolled (65 in the SPN arm; 63 in the FSM arm) at 10 clinics in FL (6), NC (2), LA (1), and TX (1). On day 0, geometric mean flea counts were 57.7 (range: 10-1469) and 44.8 (10-717) for the SPN and FSM groups, respectively. On Day 90, 55 of 58 (95%) and 21 of 55 (38%) index dogs completing the study were flea-free in SPN and FSM groups, respectively; mean SPN pruritus scores declined to 0.92 (6.67 on day 0), and to 3.83 (6.33 on day 0) for FSM; geometric mean flea counts (% control) were 0.08 (99.9%) and 5.19 (88.4%), for SPN and FSM groups, respectively. Between-treatment differences were highly statistically significant (p<0.0001). In conclusion, SPN provided reliable flea control in client-owned dogs, regardless of challenge level.

Dose confirmation and non-interference evaluations of the oral efficacy of a combination of milbemycin oxime and spinosad against the dose limiting parasites, adult cat flea (Ctenocephalides felis) and hookworm (Ancylostoma caninum), in dogs.

Two separate controlled and blinded studies were conducted to confirm the dose and non-interference of spinosad and milbemycin oxime (MO) administered orally in combination or alone to dogs for the treatment and control of experimentally induced flea infestations (Ctenocephalides felis) and adult hookworm infections (Ancylostoma caninum). For each study, dogs were allocated randomly based on pre-treatment adult flea and hookworm egg counts to one of four treatment groups of 10 animals each. In each study, spinosad and MO in combination, using the lower half (30-45 mg/kg spinosad; 0.5-0.75 mg/kg MO) of the US commercial dose band (30-60 mg/kg spinosad; 0.5-1.0mg/kg MO) of each active ingredient, or individually alone using the full dose range, were given orally to dogs on Day 0 using a tablet formulation. A placebo control was treated similarly. In one study, on Days -1, 5, 12, 19, 28 and 35 each dog was infested with approximately 100 unfed adult C. felis obtained from the investigator's established flea colony. All dogs were infested via the same method. Forty-eight hour post-infestation flea comb counts were conducted on Days 1, 7, 14, 21, 30 and 37 and were used to determine the knockdown and residual flea activity. In the second study, on Day -27 each of 48 dogs were experimentally inoculated with 100 third-stage infective larvae of the hookworm, A. caninum. Dogs were treated on Day 0 and necropsied on Day 7 or Day 8. All nematodes in the intestinal tract were collected on Day 7 or Day 8, identified and counted by species and stage. Post-treatment, the geometric mean live flea counts were significantly different (p-value<0.0001) between the spinosad/MO combination and the spinosad only treatment groups as compared to the vehicle control group. The flea counts in the MO only group and the control group were not statistically different. The spinosad and MO combination group and the spinosad only treatment group demonstrated significantly different knockdown (100%) and post-treatment residual flea efficacy at Day 30 was 100% for both groups as compared to the vehicle control. The presence of MO in combination with spinosad did not interfere with the flea efficacy of spinosad as compared to the spinosad only group. MO alone did not demonstrate any flea efficacy. Post-treatment, the geometric mean A. caninum worm counts were significantly different (p-value<0.0001) between the spinosad and MO combination group as compared to the vehicle control group. The worm counts in the MO only group and the combination group were not statistically different. The spinosad and MO combination group (99.8% reduction) and the MO only treatment group (99.5% reduction) both demonstrated significantly different hookworm efficacy as compared to the vehicle control group. The presence of spinosad in combination with MO did not interfere with the hookworm efficacy of MO as compared to the MO only group. Spinosad alone did not demonstrate any hookworm efficacy. In summary, flavored spinosad and MO combination tablets administered orally to dogs at the lower end (30-45 mg/kg spinosad; 0.5-0.75 mg/kg MO) of the US commercial tablet unit dose range (30-60 mg/kg spinosad; 0.5-1.0mg/kg MO) were both safe and highly efficacious delivering 100% knockdown and 30 days of residual adult flea control on experimentally infested dogs as well as >99% adult hookworm efficacy evaluated under laboratory conditions. Interference between either drugs was not demonstrated for both of these dose limiting parasites.

Confirmation of the efficacy of a combination tablet of spinosad and milbemycin oxime against naturally acquired infections of canine intestinal nematode parasites.

Four separate controlled and blinded studies were conducted to confirm the dose of spinosad and milbemycin oxime (MO) administered orally in combination to dogs for the treatment and control of naturally acquired infections of adult whipworm (Trichuris vulpis), hookworm (Ancylostoma caninum) and ascarids (Toxocara canis, Toxascaris leonina). Dogs were allocated randomly based on pre-treatment quantitative nematode egg counts of each species of interest to one of two treatment groups of 10 or 11 animals each. In each study, spinosad and MO in combination, was given orally to dogs using the lower half (30-45 mg/kg spinosad; 0.5-0.75 mg/kg MO) of the US commercial dose band (30-60 mg/kg spinosad; 0.5-1.0mg/kg MO) of each active ingredient on Day 0 using a tablet formulation. A corresponding vehicle control group was treated similarly in each individual study. Dogs were necropsied post-treatment on Day 7/8. All nematodes in the intestinal tract collected at necropsy were identified and counted by species and stage. The spinosad and MO combination group demonstrated significantly different adult intestinal nematode efficacy in each individual study as compared to the vehicle control group. Efficacy values for whipworm, hookworm, T. canis and T. leonina were 100%, 99.8%, 100%, 93.3%, respectively. Minor non-serious adverse events were observed in a small number of control and treated dogs that were attributed primarily to the natural nematode infections. In summary, flavored spinosad and MO combination tablets administered orally to dogs were both safe and highly efficacious delivering >93% up to 100% adult intestinal nematode control in naturally infected dogs.

Assessment of the effectiveness of a combination product of spinosad and milbemycin oxime on the prophylaxis of canine heartworm infection.

Three separate randomized, blinded, vehicle-controlled studies were conducted to determine the effectiveness of a single treatment and consecutive monthly treatments of a combination flavored tablet product containing spinosad and milbemycin oxime (MBO) in the prevention of the establishment of heartworm infections in dogs challenged with recent field isolates of the heartworm (HW), Dirofilaria immitis. For each study, dogs were allocated randomly based on pre-treatment body weights to treated or control groups of 10 animals each. Dogs were infected once with infective HW larvae, on Day-30, using either a Michigan isolate or a Georgia (MP3) isolate of D. immitis. Treatments of beef-flavored chewable tablets were administered in two studies one time either on Day 0 or Day 15, and in one study twice (Days 0 and 30, or Days 15 and 45) or 3 times (Days 0, 30 and 60). For the combination product groups, dosages were in the range of 30-45 mg/kg (13.6-20.5mg/lb) for spinosad and 0.5-0.75 mg/kg (0.2-0.34 mg/lb) for MBO. Necropsies for heartworm counts were completed following euthanasia on Day 120 or Day 123. A single treatment with the combination product of spinosad and MBO 30 or 45 days post-inoculation with infective HW larvae was completely effective (100%) in preventing establishment of the Michigan D. immitis isolate, but efficacy against the Georgia MP3 isolate was incomplete, with geometric mean reductions in HW counts relative to vehicle treated controls of 99% reduction of the 30 day infection and a 98.9% reduction of the 45 day old infection. Against this same MP3 isolate, 3 consecutive monthly treatments provided complete prevention (100%) against establishment of D. immitis infections. The combination product of spinosad and MBO provides effective control of canine heartworms. A single treatment at 30 days post infection showed high but incomplete effectiveness against a heartworm isolate that had been shown to be partially refractory to treatment with marketed monthly heartworm preventives. Three consecutive monthly treatments provided complete control, providing support to the recommendation that heartworm prophylaxis should be maintained year round for optimal effectiveness.

Effects of orally administered spinosad (Comfortis) in dogs on adult and immature stages of the cat flea (Ctenocephalides felis).

The efficacy of spinosad against adult fleas (Ctenocephalides felis) on dogs was evaluated in three controlled, blinded studies. One study was conducted to determine speed of kill on experimentally infested dogs. Two additional studies were designed to assess the efficacy of spinosad in preventing environmental contamination with flea eggs (USA study and EU study). An additional objective of the USA study was to assess the effects of skin and hair-coat debris from spinosad-treated dogs on eggs and larvae of C. felis. Dogs were randomly allocated to treatment with beef-flavored spinosad tablets, administered orally at a minimum dosage of 30mg/kg, or placebo. In the first study, speed of kill was determined by flea comb counts performed at 0.5, 1, 2, 4, 8, 12, 24 and 48h after spinosad treatment. Reductions in geometric mean flea counts for spinosad-treated dogs, compared to placebo were 53.7% at 0.5h, 64.2% at 1h, 85.8% at 2h and 100% at 4 through 48h post-treatment (p<0.05 at 1h and beyond). In the 2 flea egg production studies, dogs were treated (spinosad or placebo) once on day 0, infested with 600 fleas approximately 3h post-treatment and reinfested with approximately 600 fleas at intervals over 1 month. Flea eggs were collected starting at approximately 72h after each infestation. Eggs were examined for any effects of spinosad on egg viability. Efficacy of spinosad was also evaluated against environmental eggs and larvae exposed to canine hair-coat debris collected on days 3, 7, 14, 21, and 30. Spinosad was highly effective in reducing flea egg production (>99.8% across the entire study period) compared to control dogs in both egg collection studies. Insufficient numbers of eggs were recovered from spinosad-treated dogs to determine the viability of those eggs. There was no evidence of any effect on environmental flea stages, indicating that spinosad was not present in the skin debris of spinosad-treated dogs. The capability of spinosad to quickly kill adult fleas, and to greatly reduce egg production following challenge with high numbers of adult fleas is important in breaking the flea life cycle and preventing the introduction and establishment of new flea infestations in the household.

Preliminary study on the acaricidal efficacy of spinosad administered orally to dogs infested with the brown dog tick, Rhipicephalus sanguineus (Latreille, 1806) (Acari: Ixodidae).

Spinosad is a novel mode of action insecticide and acaricide derived from a family of natural compounds produced from fermentation of the actinomycete, Saccharopolyspora spinosa. Although spinosad has been shown to have rapid knockdown and 1 month of residual efficacy against fleas (Ctenocephalides spp.) following oral administration in dogs, potential activity against ticks infesting dogs has not been determined. To address this possibility, a proof-of-concept laboratory efficacy study was conducted using dogs orally treated with spinosad and experimentally infested with the brown dog tick, Rhipicephalus sanguineus (Latreille, 1806) (Acari: Ixodidae). In this randomized block (blocked by gender and pre-treatment tick counts), blinded, parallel-arm study, 12 dogs selected on health and ability to maintain pre-treatment tick populations were allocated equally among three groups: placebo-treated negative control, and spinosad in gelatin capsules at 50 and 100mg/kg administered per os. All treatments were administered once on Day 0. On days -6, -1, 7, 14, 21 and 28, each dog was infested with 50 unfed adult R. sanguineus, approximately 50% male and 50% female, obtained from the investigator's established tick colony. Tick comb counts were performed approximately 48 h post-infestation by study personnel who were blinded to treatments. Compared to geometric mean live tick counts in the control group, tick counts in the 50 and 100mg/kg spinosad doses were significantly (P<0.05) reduced by 94.8 and 97.2%, respectively, within 24h of treatment. Compared to geometric mean live tick counts in the control group at Days 9, 16, 23 and 30 after treatment, the 50mg/kg spinosad treatment group demonstrated 67.8, 49.1, 52.1 and 5.0% reductions, while the 100mg/kg spinosad treatment group demonstrated 88.6, 70.6, 61.9 and 71.3% reductions, respectively. This pilot efficacy study demonstrated that a single oral treatment with technical spinosad in gelatin capsules, at 50 and 100mg/kg, provides high efficacy against existing R. sanguineus infestations within 24h of dosing, and suggests that there is some post-treatment residual tick control in dogs for up to 1 month.