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A Prospective, Randomized, Masked, Placebo‐Controlled Multisite Clinical Study of Grapiprant, an EP4 Prostaglandin Receptor An

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A Prospective, Randomized, Masked, Placebo‐Controlled Multisite Clinical Study of Grapiprant, an EP4 Prostaglandin Receptor An J Vet Intern Med 2016;30:756–763 A Prospective, Randomized, Masked, Placebo-Controlled Multisite Clinical Study of Grapiprant, an EP4 Prostaglandin Receptor Antagonist (PRA), in Dogs with Osteoarthritis L. Rausch-Derra, M. Huebner, J. Wofford, and L. Rhodes Background: This study evaluated the effectiveness and safety of grapiprant for treatment of pain in dogs with osteoarthritis (OA). Hypothesis/Objectives: Grapiprant will relieve pain as measured by the owner’s and veterinarian’s evaluation of pain in dogs with OA. Another objective was evaluation of the safety of grapiprant. Animals: Two hundred and eighty-five client-owned dogs with OA were enrolled and treated with grapiprant or placebo with 262 cases (N = 131 in each group) evaluable for the effectiveness analysis. Methods: In this prospective, randomized, masked, placebo-controlled study dogs were treated daily with grapiprant (2 mg/kg) per OS or placebo. Owners completed an evaluation using the Canine Brief Pain Inventory (CBPI) on days 0, 7, 14, 21, and 28. Success was defined as improvement in the CBPI. Veterinary assessments were made on screening and days 14 and 28. Safety was evaluated by physical examination, evaluation of clinical pathology results, and owner observations. Results: Grapiprant treatment improved pain compared to placebo on day 28 (48.1 and 31.3% treatment successes respectively; P = .0315). The pain interference score (PIS) and pain severity score (PSS) improved in the grapiprant group compared to placebo (P = .0029 and 0.0022, respectively). Veterinary assessments were significantly better in the grapiprant- treated dogs (P = .0086). Grapiprant generally was well tolerated, but a higher percentage of treated dogs (17.02%) had occasional vomiting as compared to the placebo group (6.25%). Conclusions and Clinical Importance: Grapiprant is an effective treatment for alleviation of pain in dogs with OA, and represents a modality of treatment that may be better tolerated than current options. Key words: Anti-inflammatory; Osteoarthritis; Pain; Piprant. rapiprant (AT-001, CJ-023,423) is a potent and Gspecific antagonist of the prostaglandin E2 (PGE2) 1 EP4 receptor . It is a member of a newly defined class Abbreviations: of drugs, the piprant class, that block prostaglandin receptors. Grapiprant is an EP4 piprant, also known as Ca calcium an EP4 prostaglandin receptor antagonist (EP4 PRA).2 CBPI canine brief pain inventory It binds to human and rat EP4 receptors with high FDA Food and Drug Administration affinity.1 In several rat pain models of inflammatory GI gastrointestinal ITT intention to treat pain, grapiprant was shown to be effective in pain NSAID nonsteroidal anti-inflammatory drug reduction1 and in a rat model of adjuvant-induced OA osteoarthritis arthritis, grapiprant was shown to inhibit paw swelling, PGE prostaglandin E inflammatory biomarkers, and synovial inflammation.3 2 2 PGI2 prostaglandin I2 Many FDA-approved drugs are available to treat PIS pain interference score pain associated with osteoarthritis (OA) in dogs (e.g., PO per OS a b c d carprofen, firocoxib, meloxicam , and deracoxib ), all PPP per protocol population of which work by inhibiting cyclooxygenase enzymes. PRA prostaglandin receptor antagonist The adverse effect profile of the cyclooxygenase-inhibit- PSS pain severity score ing nonsteroidal anti-inflammatory drugs (NSAIDs) is SAE serious adverse event well established. The Food and Drug Administration SD standard deviation (FDA) has required language in the precaution section TOS total orthopedic score of the package inserts of these drugs warning that, as a class, they may be associated with renal, gastrointestinal From the Aratana Therapeutics, Leawood, KS (Rausch-Derra, (GI), and hepatic toxicity. Specifically, labels of these Wofford, Rhodes); and the ClinData Services, Ft. Collins, CO drugs warn of “the potential to produce GI ulceration (Huebner). b Corresponding author: L. Rausch-Derra, Aratana Therapeutics, and/or GI perforation.” Because grapiprant’s mecha- 11400 Tomahawk Creek Pkwy, Suite 340, Leawood, KS 66211; nism of action targets the EP4 receptor, it does not e-mail: [email protected]. inhibit the production of prostanoids, which are impor- Submitted December 22, 2015; Revised February 21, 2016; tant in a variety of physiological functions that main- Accepted March 16, 2016. tain normal homeostatic functions, including Copyright © 2016 The Authors. Journal of Veterinary Internal maintenance of GI integrity. Therefore, grapiprant may Medicine published by Wiley Periodicals, Inc. on behalf of the represent a treatment that could avoid the adverse American College of Veterinary Internal Medicine. This is an open access article under the terms of the Creative effects associated with inhibition of cyclooxygenase in Commons Attribution-NonCommercial License, which permits use, dogs. distribution and reproduction in any medium, provided the original Grapiprant binds to the canine EP4 receptor with work is properly cited and is not used for commercial purposes. high affinity and has been shown to be extremely well DOI: 10.1111/jvim.13948 Grapiprant for OA in Dogs 757 tolerated in a study in which it was given daily for autoimmune disorders that may have affected evaluations for the 9 months to laboratory Beagles at doses up to 15 times study, and concomitant disease at the site of the OA, such as infec- the therapeutic dose.4 Our study was conducted to eval- tions, parasitic or immunological arthritis, or neoplasia. Dogs that uate the effectiveness and safety of grapiprant given PO had had major surgery within 1 month, or cruciate ligament sur- q24h for 28 days in client-owned dogs with OA. Previ- gery within 3 months were excluded, as were dogs that had surg- eries that could confound the detection of OA pain and ous studies have shown that treatment of OA in dogs 5,6 inflammation. To ensure that no other medications that could elicits a large placebo effect, and thus appropriate confound results were being used during the study, the following power and use of a placebo were employed in the medications were restricted: cyclooxygenase-inhibiting NSAIDs (in- design of this study, which was conducted using a vali- cluding aspirin), polysulfated glycosaminoglycanf injections, or dated instrument to measure changes in pain, the laser treatment on the joints within 7 days before day 0; short-act- Canine Brief Pain Inventory (CBPI).7 Care was taken ing steroids, oclacitinibg , or other immunomodulatory drugs within that owners and veterinarians were masked to treat- 30 days before day 0; mid- to long-acting steroids within 60 days ment. In addition to effectiveness, we evaluated safety before day 0; nutraceuticals for joint pain or OA within 7 days < in this population of predominately older dogs using before day 0; or, a diet containing nutraceuticals for 30 days owner observations, physical examinations, and clinical before day 0. Dogs that were on a diet containing a nutraceutical for joints for ≥30 days before day 0 remained on that diet. pathology test results. Sample Size Calculation Materials and Methods An evaluable sample size of 138 dogs per treatment group was Study Design targeted to provide 90% power to detect a difference of 20% in Our study was a prospective, multicenter, masked, randomized, success rates between the grapiprant-treated group and the placebo placebo-controlled parallel study conducted at 16 veterinary group, assuming a 60% success rate in the grapiprant-treated hospitals located in Colorado, Florida, Georgia, Illinois, Maine, group and a 40% success rate in the placebo group. This assump- Michigan, Missouri, New York, Pennsylvania, and Texas. It was tion was based on results from a pilot field study using a dosage conducted according to Good Clinical Practice guidelines.e of 2 mg/kg (data on file). To account for a rate of attrition of approximately 10%, up to 300 subjects (150 per treatment group) could be enrolled. Animals Dogs of any age, breed, or sex were enrolled, but dogs that Screening were pregnant, lactating, or intended for breeding were excluded. To be enrolled, dogs had to weigh ≥3.6 kg. Owners signed an owner consent form that had been reviewed and approved by the Center for Veterinary Medicine at the FDA. This form was signed before any study activities, and then dogs Inclusion and Exclusion Criteria were screened to see if they met the inclusion and exclusion crite- ria, blood was drawn to evaluate standard serum biochemistry and Client-owned dogs that were candidates for enrollment were hematology variables, and urine was collected for urinalysis. The presented by the owner with clinical signs of OA, confirmed by CBPI was completed by the owner and veterinary assessment was radiographs of at least 1 appendicular joint taken within 60 days completed by the veterinarian. before enrollment. The veterinarian also confirmed OA by evaluat- During the study, owners completed the CBPI on day 0 (base- ing weight bearing on the affected limb, lameness at walking and line), day 14, and day 28 in the clinic, and at home after a tele- trotting, willingness to raise the contralateral limb, joint swelling, phone call on days 7 and 21. Veterinarians completed physical pain or resistance on palpation, forced movement and range of examinations and the veterinary assessment of the total orthopedic motion of the joint (veterinary assessment) and being in general score (TOS) on days 14 and 28. Blood and urine were collected good health or stabilized for chronic conditions and able to com- for clinical pathology
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