Response to letter regarding “Fuzapladib in a randomized controlled multicenter masked study in dogs with presumptive acute onset pancreatitis”

Thank you for allowing us to respond to the letter to the editor by Allenspach et al. We also thank Dr Allenspach and her co-authors for their comments and presenting us with the opportunity for additional dialog on this important topic. Study population and enrollment criteria: As stated by the letter writers, we were unable to demonstrate pancreatitis beyond a reasonable doubt in all patients, which is why our study was clearly described as a study in "dogs with presumptive acute onset pancreatitis." We also agree that we did not have many study subjects with severe pancreatitis (although there were some). However, we would respectfully suggest that this should have only led us to underestimate the effect of treatment rather than conclude that a treatment effect existed when there was none. Thus, the fact that we were able to show a significantly larger decrease in modified clinical activity index (MCAI) scores over the 3-day treatment period makes our findings even more relevant. We also would like to respond to a misconception of the letter writers. The goal of treatment with fuzapladib sodium is not to treat severe forms of acute pancreatitis in dogs, but instead to prevent severe forms of acute pancreatitis. Once massive extravasation of neutrophils into the lung has occurred and acute respiratory distress syndrome (ARDS) has been initiated, the impact of leukocyte function-associated antigen type-1 (LFA-1) antagonism resulting from fuzapladib sodium administration would be expected to be less than administration of fuzapladib sodium before ARDS initiation. Thus, inclusion of dogs with milder forms of pancreatitis is in fact not only justified, but also better represents the cases in which fuzapladib sodium should have the biggest benefit. Randomization and intention-to-treat (ITT) analysis: We agree with the letter writers that a larger study population would have helped even out baseline MCAI scores. However, as much as we would have liked a larger study population, there were limitations, such as the inability to convince additional study sites to participate. We were interested to read in the letter that dogs with pancreatitis often present with secondary bacterial infections. As far as we know, this statement is incorrect. Instead, secondary bacterial infections in dogs are exceedingly rare as has been demonstrated in the literature, which reports that even dogs with a pancreatic abscess frequently do not show evidence of bacterial infection.2-4 This is not surprising if one considers that secondary bacterial infections in people with pancreatitis usually do not occur until several weeks into the disease process, which is why initial antibiotic treatment is not recommended in humans with acute pancreatitis.5, 6 Thus, in our opinion, to demonstrate that fuzapladib sodium does not increase such infectious complications in dogs would have been impossible in a reasonably sized study protocol when such infection is already exceedingly rare. We believe the inclusion of dogs with serum Spec cPL concentrations <400 μg/L into a study of safety is justified as results speak to the overall safety of the drug. In fact, we believe that this information is valuable as it speaks to everyday practice where veterinarians may start treatment for pancreatitis based on their preliminary diagnosis, which ultimately may not be confirmed—safety of the medication in that group of patients would certainly constitute crucial information. Randomization and per protocol (PP) analysis: As already stated, we would have liked to include more dogs into the study and would also have liked to increase the number of enrolled dogs per site, but this simply was unrealistic. Use of the MCAI score was in fact prespecified, as described in our manuscript. The MCAI was selected over the canine acute pancreatitis clinical severity index (CAPSI) as the CAPSI does not allow severity scoring over the entire spectrum of pancreatitis cases in dogs. Canine acute pancreatitis clinical severity index is far better for scoring dogs within the subgroup of dogs with severe pancreatitis and not across the entire spectrum of severity because it is based on the development of systemic complications. As pointed out by the letter writers, our study included dogs with a wide spectrum of severities. It would have been more convenient to use a different end point after the study had been concluded (eg, the modified clinical activity index [MCAI] 5), but we refrained from doing so because it had not been pre-specified in the protocol.

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