Randomized blinded controlled trial of dipyrone as a treatment for pyrexia in horses

Peter R. Morresey Rood and Riddle Equine Hospital, 2150 Georgetown Rd, Lexington, KY 40511.

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Gary W. White Sallisaw Equine Clinic, 325 S Shiloh Rd, Sallisaw, OK 74955.

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H. Melinda Poole KindredBio, 1555 Old Bayshore Hwy, Ste 200, Burlingame, CA 94010.

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Tianhua Hu KindredBio, 1555 Old Bayshore Hwy, Ste 200, Burlingame, CA 94010.

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Ming Yin KindredBio, 1555 Old Bayshore Hwy, Ste 200, Burlingame, CA 94010.

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Emily A. Sundman KindredBio, 1555 Old Bayshore Hwy, Ste 200, Burlingame, CA 94010.

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Abstract

OBJECTIVE To evaluate the effectiveness and safety of dipyrone to control pyrexia in horses with naturally occurring disease under field conditions.

ANIMALS 138 horses with pyrexia and various infections evaluated at 14 veterinary sites in 12 states.

PROCEDURES In the first (effectiveness) phase of this 2-phase study, horses were randomly assigned 3:1 to receive 1 dose of dipyrone (30 mg/kg [13.6 mg/lb], IV) or an equivalent amount of placebo. Effectiveness was defined as a decrease in rectal temperature ≥ 1.1°C (2°F), compared with the pretreatment value, or a rectal temperature of ≤ 38.3°C (101.0°F) 6 hours after treatment administration. Horses deemed to have an appropriate reduction in rectal temperature (regardless of treatment group) by 6 hours were immediately entered into the safety phase of the study, in which dipyrone was administered IV at 30 mg/kg between 0 and 8 times up to every 8 hours on an as-needed basis, as determined by the clinical investigators. Horses were monitored throughout for adverse events.

RESULTS A significantly greater proportion of dipyrone-treated horses (76/99 [77%]) had an effective treatment response than did placebo-treated horses (6/31 [19%]). Posttreatment adverse events were mild and transient. No differences in types or prevalence of gastrointestinal adverse events were evident between treatment groups.

CONCLUSIONS AND CLINICAL RELEVANCE Dipyrone was effective in controlling pyrexia by 6 hours after IV administration of a single 30-mg/kg dose in a large proportion of treated horses. Adverse effects were minimal.

Abstract

OBJECTIVE To evaluate the effectiveness and safety of dipyrone to control pyrexia in horses with naturally occurring disease under field conditions.

ANIMALS 138 horses with pyrexia and various infections evaluated at 14 veterinary sites in 12 states.

PROCEDURES In the first (effectiveness) phase of this 2-phase study, horses were randomly assigned 3:1 to receive 1 dose of dipyrone (30 mg/kg [13.6 mg/lb], IV) or an equivalent amount of placebo. Effectiveness was defined as a decrease in rectal temperature ≥ 1.1°C (2°F), compared with the pretreatment value, or a rectal temperature of ≤ 38.3°C (101.0°F) 6 hours after treatment administration. Horses deemed to have an appropriate reduction in rectal temperature (regardless of treatment group) by 6 hours were immediately entered into the safety phase of the study, in which dipyrone was administered IV at 30 mg/kg between 0 and 8 times up to every 8 hours on an as-needed basis, as determined by the clinical investigators. Horses were monitored throughout for adverse events.

RESULTS A significantly greater proportion of dipyrone-treated horses (76/99 [77%]) had an effective treatment response than did placebo-treated horses (6/31 [19%]). Posttreatment adverse events were mild and transient. No differences in types or prevalence of gastrointestinal adverse events were evident between treatment groups.

CONCLUSIONS AND CLINICAL RELEVANCE Dipyrone was effective in controlling pyrexia by 6 hours after IV administration of a single 30-mg/kg dose in a large proportion of treated horses. Adverse effects were minimal.

Dipyrone is a nonopioid, atypical NSAID that has been available for human use for > 70 years and has been used as an antipyretic and analgesic. The mechanism of action of the antipyretic effects has not been fully clarified; however, evidence exists that such action is both prostaglandin dependent and prostaglandin independent.1,2 Dipyrone and its active metabolites can cross the blood-brain barrier into the CNS and have direct antipyretic effects unrelated to anti-inflammatory activity.2–4 Control of pyrexia in horses helps to combat its secondary effects, which include an increase in metabolic demand and discomfort that leads to anorexia and a decrease in water intake.4,5

Dipyrone has been approved and is marketed for use in humans and other animals, including horses, in numerous countries in Europe and South America. No FDA-approved medications are currently available to veterinarians in the United States to control pyrexia in horses. Unlike many other NSAIDs, dipyrone has minimal gastrointestinal adverse effects and has antispasmodic effects.3,6,7

A pyrazolone derivative of aminopyrine, dipyrone functions as a prodrug and is immediately hydrolyzed to 4-MAA following administration by parenteral or oral routes.3 The 4-MAA is further metabolized by the liver to secondary metabolites that are primarily excreted by the kidneys. Because dipyrone is present in the circulation for an extremely brief period before metabolism, the 4-MAA molecule is the substance typically assayed in pharmacokinetic evaluations of the drug.3 This molecule is also the substance primarily associated with clinical efficacy.8,9

In 1977, the US FDA withdrew approval of dipyrone for human use because of concerns regarding an association with idiosyncratic agranulocytosis. Although the FDA never approved dipyrone for use in veterinary species, products were widely marketed for use in non–food-producing animals, including horses, at the regulatory discretion of the FDA. However, the FDA received reports of extralabel use of dipyrone in food-producing animals. Consequently, since 1995, all dipyrone products for veterinary use have been withdrawn from the market until an approved product becomes available.10,11 Use of dipyrone in any food-producing animal remains illegal. The withdrawal of dipyrone from the veterinary market was not related to its use in horses, and dipyrone remains available for veterinary use in Europe, Canada, South America, Australia, and New Zealand. Currently, no reports exist of idiosyncratic agranulocytosis in veterinary species secondary to dipyrone use.12

The purpose of the study reported here was to evaluate the effectiveness and safety of dipyrone for the control of pyrexia in horses under field conditions. This was a controlled clinical field effectiveness study that was conducted and reported to the FDA Center for Veterinary Medicine as part of the approval process for a new animal drug.

Materials and Methods

Ethics statements

This study was performed in accordance with Good Clinical Practice Guideline No. 85 as approved by FDA and European Union governing bodies.13 Clinical investigators were licensed and practicing equine veterinarians with adequate qualifications. Investigators were trained on these guidelines and the study protocol prior to participation. Approval from an institutional animal care and use committee was obtained at the one site where applicable. At private equine clinical sites without such a committee, the standard of care for the veterinary profession for humane treatment of animals was followed in addition to the regulatory guidelines.

Enrollment into the study was at the discretion of the clinical investigators and required informed consent of the owner prior to any study procedures. Horses could be withdrawn from the study at any time for medical concerns or for other reasons at the discretion of the clinical investigators or owner.

Clinical investigators received standard compensation for study-related procedures and activities. Owners were not compensated directly; however, the costs of study-related diagnostic testing were covered by the study sponsor in an effort to support the clinical investigators in decisions regarding enrollment and treatment.

Horses

The study was conducted at 14 clinical sites within the United States, including 13 private equine clinics and 1 contract research organization, in 12 states of various geographic characteristics. To be included in the study, horses were required to be patients at any of these clinical sites, ≥ 1 year of age, nonpregnant and nonlactating, free of severe systemic diseases that may interfere with the study objectives, and reasonably expected to complete the first 6 hours of the study. In addition, horses were required to have a rectal temperature ≥ 38.9°C. Horses that qualified for the study were excluded if they had received any of the following medications within the indicated period before the study began: NSAIDs, 24 hours; antimicrobials, 24 hours; corticosteroid drugs, 5 days; and sedatives, 6 hours.

Prior to enrollment, all horses received a physical examination. Baseline blood samples (total, 22.7 mL) were also collected from a jugular vein via 18-gauge, 1.5-inch needles into 3 blood collection tubes: EDTA tube for CBC, serum separator tube for serum biochemical analysis, and sodium citrate tube for coagulation testing. All samples were submitted to a central laboratorya for analysis.

The clinical investigators (PRM and GWW) had sole discretion to withdraw or treat an enrolled horse as medically indicated and to enroll animals that met the inclusion criteria and would not be harmed by a 6-hour phase with restrictions on concurrent medications. Because of the variety of possible causes of pyrexia, clinical investigators were at their discretion to perform diagnostic procedures to identify the cause and direct appropriate treatment.

A total of 138 horses with a median age of 3 years (range, 1 to 32 years) and median body weight of 364 kg met the inclusion criteria and were enrolled in the study. Horses included 74 (54%) mares, 45 (33%) geldings, and 19 (14%) stallions. The most common breeds were Quarter Horse (n = 82 [59%]), Paint (14 [10%]), Arabian (7 [5%]), and Thoroughbred (7 [5%]).

Study design

The study was comprised of 2 phases. The first phase (to evaluate the effectiveness of dipyrone) involved all horses that met the inclusion criteria and was designed as a blinded, controlled, single-dose study, conducted between May and October of 2015. Horses that met certain predefined effectiveness criteria were eligible to continue immediately into the second phase (to evaluate only the safety of dipyrone). This second phase was designed as an unblinded, uncontrolled, multidose study, including only a dipyrone-treated group.

Effectiveness phase

As horses were enrolled in the study, they were randomly assigned to 2 treatment groups in a 3:1 ratio (test treatment:placebo treatment) by means of a random number generator. A centralized block randomization scheme was used with a block size of 4. Treatment groups were identified by 8 treatment codes, with 6 codes corresponding to the test treatment (dipyrone) and 2 codes corresponding to the placebo treatment. Once a horse was randomly enrolled at a study site, a treatment code was assigned through the electronic data capture system.b Site personnel treated the horse with a dose from a bottle of study medication with the assigned treatment code. Both the test (dipyrone) and placebo treatment had the same appearance and coloration, were packaged in identical vials, and had no labeling to indicate the presence or absence of dipyrone. Clinical investigators, site personnel, and horse owners were consequently blinded to treatment identity of the effectiveness phase throughout the study. The blinding to effectiveness phase treatment assignment was maintained until the completion of the statistical analysis.

During the 6-hour effectiveness phase, medications that could have impacted rectal temperature, such as sedatives, or the underlying cause of the disease, such as antimicrobials or corticosteroid drugs, were withheld from all horses. Rectal temperature was first measured with a digital thermometer,c and then the assigned treatment was administered. The test treatment consisted of dipyroned administered IV once at a dose of 30 mg/kg.14 The placebo treatment consisted of an equivalent volume of lactated Ringer solutione and 1% benzyl alcoholf as an excipient, with additives to match the color of the dipyrone, also administered IV. A second rectal temperature was recorded 6 hours later. Effectiveness was defined as a decrease in rectal temperature of ≥ 1.1°C from baseline (ie, at enrollment) or return to normothermia (≤ 38.3°C) by 6 hours after drug administration. Six hours after treatment administration, horses were categorized as to whether treatment had been effective, as defined.

Horses for which treatment (dipyrone or placebo) was deemed effective as previously defined immediately proceeded to the safety phase of the study. Horses that failed to have an adequate decrease in rectal temperature (rectal temperature did not decrease ≥ 1.1°C from baseline) or return to normothermia (≤ 38.3°C) received an additional physical examination, and blood samples for clinicopathologic testing were again collected 24 to 30 hours after initial treatment administration. These horses were removed from the study (ie, did not proceed to the safety phase) and were treated at the discretion of the clinical investigators.

Safety phase

The first 56 horses to complete the effectiveness phase of the study (ie, to receive a 6-hour measurement) were eligible to continue to the safety phase for a total of 5 days, provided that effectiveness was demonstrated in the previous phase. The remaining 82 horses were eligible to continue to the safety phase for a total of 3 days (owing to a change in the proposed drug label indication from 5 days to 3 days), provided that effectiveness was demonstrated in the previous phase. Dipyrone was then administered IV to eligible horses at 30 mg/kg between 0 and 8 times up to every 8 hours on an as-needed basis, as determined by the clinical investigators. No horse included in this phase prior to the change from a maximum 5-day period to a maximum 3-day period received more total doses of dipyrone than the amount permitted after this change. All medications other than NSAIDs were permitted during the safety phase.

Horses were monitored daily for the development of adverse events. Horses that no longer required dipyrone to control pyrexia or that reached the maximum study period received a final physical examination, and blood samples were collected for clinicopathologic testing. All enrolled horses were evaluated for adverse events for the duration of the study. Adverse events included abnormal results of clinicopathologic testing.

Diagnosis

Clinical investigators were required to record the diagnosis or presumptive diagnosis of the underlying condition causing pyrexia at the time each horse exited the study. To reach this decision, clinical investigators considered the clinical signs of the horse, course of the disease, results of any additional diagnostic tests performed, impact of treatment, and any other available variables. Investigators were permitted to report > 1 diagnosis/horse.

Statistical analysis

The individual horse served as the experimental unit. Superiority of treatment over placebo was defined as a significantly (P < 0.05) greater proportion of horses that met predefined effectiveness criteria in the dipyrone group versus the placebo group, as determined by use of the Fisher exact test (2-sided).g

Safety data for all horses enrolled in the study were included as part of the field safety database provided the horses received at least 1 treatment with dipyrone or placebo. Results of clinicopathologic testing were compared between treatment groups by means of ANCOVA, with treatment as a fixed effect and the baseline value as a covariate. The covariate was retained in the model regardless of significance. Owing to the specific nature and diverse etiologies of the endpoint analyzed (pyrexia), accounting for the medical history, disease conditions, and adjunctive treatment for each horse was considered beyond the scope of the study.

Results

Animals

In the effectiveness phase of the study, 104 horses received dipyrone and 34 horses received the placebo. Following completion of the study, 8 (6%) horses were removed from the evaluable group because of protocol deviations, leaving 99 dipyrone-treated horses and 31 placebo-treated horses in the effectiveness analysis.

Effectiveness

Effectiveness of treatment (decrease in rectal temperature of ≥ 1.1°C from baseline or return to normothermia by 6 hours after drug administration) was identified for 76 of the 99 (77%) evaluable dipyrone-treated horses and 6 of the 31 (19%) evaluable placebo-treated horses. The difference in response between groups was significant (P < 0.001).

Safety phase

Fifty-three (38%) horses (26 in the dipyrone group and 27 in the placebo group) failed to have an adequate decrease in rectal temperature during the effectiveness phase, as determined by the attending clinician. Fifty-one horses therefore exited the study without proceeding to the safety phase, and 2 horses were incorrectly entered into the safety phase. Eighty-five horses had a response in the effectiveness phase and continued immediately to the safety phase. Of the 87 horses that entered the safety phase, 59 received dipyrone during the safety phase (68%; 56 treated with dipyrone and 3 treated with placebo in the effectiveness phase) and 28 (32%) received no dipyrone (24 treated with dipyrone and 4 treated with placebo in the effectiveness phase). Mean number of dipyrone doses per horse during this phase was 1.8 (median, 1 dose; range, 0 to 8 doses).

Adverse events

Adverse events for all placebo-treated horses that later received dipyrone in the safety phase were recorded as a placebo-related adverse event only if that event occurred prior to any dipyrone treatment. Few adverse events (minor or transient) were identified during the effectiveness and safety phases of the study, and the nature and distribution of these events were similar between groups. Adverse events observed in at least 2 horses included high serum total bilirubin concentration (n = 2 dipyrone-treated and 0 placebo-treated horses), hyperglycemia (2 and 0), leukocytosis (3 and 1), monocytosis (5 and 1), coagulation abnormality (2 and 0), high serum sorbitol dehydrogenase activity (3 and 1), hyperphosphatemia (2 and 0), lymphocytosis (2 and 0), anemia or low PCV (3 and 0), high blood fibrinogen concentration (2 and 1), diarrhea (1 and 1), loose feces (3 and 1), lymphopenia (3 and 1), nasal discharge (2 and 1), injection site reaction (2 and 0), local swelling at a site other than the injection site (1 and 3), anorexia (1 and 1), and neutrophilia (1 and 1). Two (2%) horses in the dipyrone group were euthanized at the owner's request owing to severity of the underlying disease (septic arthritis and strangulating lipoma of the small intestine), but treatment with dipyrone was not deemed to be associated with this outcome.

Significant (P ≤ 0.10) differences in LS mean values between dipyrone- and placebo-treated horses at study exit were identified for neutrophil count, platelet count, serum aspartate aminotransferase activity, serum creatine kinase activity, and prothrombin time (Table 1). Except for a high LS mean neutrophil count in the placebo group, values for the other variables were within reference ranges. Additional clinicopathologic variables outside of reference ranges at study exit included Hct, monocyte count, serum albumin concentration, and serum globulin concentration in both groups, neutrophil count in the placebo group, and partial thromboplastin time in the dipyrone group (Table 2). The 3 placebo-treated horses that later received dipyrone in the safety phase were included in the dipyrone-treated group for clinicopathologic evaluation.

Table 1—

Least squares mean (SEM) clinicopathologic values at study exit that differed significantly (P ≤ 0.10) between horses with pyrexia of various causes treated with dipyrone (1 to 9 doses at 30 mg/kg [13.6 mg/lb], IV, up to 8 hours apart) or an equivalent volume of placebo (1 dose, IV).

VariableDipyrone (n = 106)Placebo (n = 31)Reference range
Neutrophil count (cells/μL)6,670 (297)7,780 (550)*2,460–7,230
Platelet count (X 103 cells/μL) 215 (6.9) 240 (13)100–350
Prothrombin time (s) 9.6 (0.06) 9.9 (0.11)8.9–11.9
Serum aspartate aminotransferase (U/L) 247 (4.0) 261 (7.6)194–431
Serum creatine kinase (U/L) 232 (22) 336 (40)130–497

Value exceeds the upper reference limit.

Platelet counts are reported for only 90 dipyrone-treated horses and 21 placebo-treated horses owing to automated machine error for some horses.

The time of study exit differed depending on whether horses had an effective treatment outcome following the effectiveness phase and proceeded to the safety phase or had a noneffective outcome. A single dipyrone-treated horse did not have study-exit samples collected and analyzed. The 3 placebo-treated horses that later received dipyrone in the safety phase were included in the dipyrone-treated group for clinicopathologic evaluation.

Table 2—

Mean (SD) values of clinicopathologic variables that were outside reference ranges at study exit for the horses in Table 1.

VariableDipyrone (n = 106)Placebo (n = 31)Reference range
Hct (%) 31.8 (5.4) 31.9 (5.4)32.5–46.5
Monocyte count (cells/μL) 741 (330) 779 (421)0–600
Neutrophil count (cells/μL)6,644 (3,655)7,871 (4,384)2,460–7,230
Partial thromboplastin time (s) 47.6 (9.5) 49.4 (8.4)48.0–77.0
Serum albumin (g/dL)*  2.8 (0.5)  2.8 (0.4)3.0–3.9
Serum globulin (g/dL)  4.3 (1.0)  4.2 (0.9)2.3–4.1

Albumin values are reported for only 105 dipyrone-treated horses because the value for 1 horse was unavailable owing to a laboratory error.

See Table 1 for remainder of key.

Diagnoses

Presumptive or confirmed diagnoses recorded for at least 2 horses included bacterial respiratory infection (n = 43 dipyrone-treated horses and 16 placebo-treated horses), mixed bacterial and viral respiratory infection (25 and 9), viral respiratory infection (9 and 2), immune-mediated disease (8 and 2), musculoskeletal infection (5 and 1), tick-borne bacterial infection (5 and 1), and pyrexia of unknown origin (3 and 0). Presumptive or confirmed diagnoses recorded for 1 horse only included mixed bacterial respiratory infection and generalized bacterial infection, mixed bacterial and viral respiratory infection with a localized infection, bacterial respiratory infection and tick-borne bacterial infection, immune-mediated and generalized bacterial infection, viral gastrointestinal infection, colic, localized bacterial infection, localized infection, and viral respiratory infection with an additional undescribed disease.

Discussion

Results of the present clinical field study indicated that dipyrone effectively controlled pyrexia in horses that received a single 30-mg/kg dose, IV, for 6 hours following administration. Included horses represented multiple breeds, had a variety of naturally occurring causes of pyrexia, and were geographically diverse. These findings were consistent with the few reported for use of dipyrone as an antipyretic in domestic animal species.15 In humans, the antipyretic effect of dipyrone has been well established, particularly in children.16–18

Low numbers of adverse events were reported for horses treated with dipyrone in the effectiveness and safety phases of the study. Of note, no observed increase in gastrointestinal adverse effects was evident following dipyrone versus placebo treatment. The rate of diarrhea or loose feces was similar between treatment groups. Most adverse events were consistent with horses having an infection or inflammation, particularly the observed clinicopathologic abnormalities. Whereas gastrointestinal disturbances may have been a consequence of treatment-associated toxic effects, other possible causes, including the underlying disease or other concomitant medications (eg, antimicrobials), may also have played a role. With the exception of neutrophil count, all clinicopathologic values that differed significantly between treatment and control groups had LS mean values within the reference range. Values identified as outside reference ranges most likely reflected an inflammatory response to the underlying disease process.

Most placebo-treated horses were removed from the study at the end of the effectiveness phase and, therefore, blood samples for clinicopathologic testing had been obtained earlier in the course of the disease than those collected from most dipyrone-treated horses, potentially biasing the clinicopathologic findings in favor of dipyrone treatment. Regardless, the significant differences between groups in clinicopathologic values, and the variables for which no between-group differences were identified but which had LS mean values outside of reference ranges, provided little evidence of a clinical difference between treatment and control groups. Few reports9,19,20 exist of adverse events associated with appropriate dipyrone use in horses. As with NSAIDs, excessive doses may result in adverse events, particularly when other medications are coadministered.21 Overall, findings suggested that dipyrone administered IV at 30 mg/kg was safe in the study conditions reported here.

Horses that continued in the safety phase of the present study received dipyrone on an as-needed basis to control pyrexia. The mean number of doses administered in this phase (1.8; median, 1) was unexpectedly low, likely owing to the concurrent administration of other medications, including antimicrobials.

The most commonly identified cause of pyrexia in the present study was viral or bacterial respiratory disease, and this was not surprising given that the most common infectious causes of pyrexia in horses are respiratory and gastrointestinal infections.5 Indeed, most febrile illnesses in horses are caused by readily diagnosed infectious diseases or resolve without a diagnosis within 2 weeks after onset.5 Although pyrexia is primarily associated with infectious disease in horses, it is also a component of many inflammatory, immunologic, and neoplastic conditions.6 In a retrospective analysis of pyrexia of unknown origin in horses, infection was the most common cause (43%), followed by neoplasia (22%) and immune-mediated disease (6%).22 No attempt was made to control for the various origins of pyrexia in the present study because random allocation should have minimized this and other types of confounding bias.

Results of the study reported here suggested that IV administration of dipyrone at 30 mg/kg effectively controlled pyrexia in horses with naturally occurring disease. The dose was well tolerated and considered safe in the horses that received repeated doses for up to 3 to 5 days. Therefore, dipyrone should provide veterinarians with a safe and effective means to treat horses with pyrexia.

Acknowledgments

Supported by Kindred Biosciences Inc.

This manuscript represents a portion of a new animal drug approval technical section submitted by KindredBio to the FDA Center for Veterinary Medicine.

Presented in abstract form at the 62nd Annual Convention of the American Association of Equine Practitioners, Orlando, Fla, December 2016.

ABBREVIATIONS

4-MAA

4-methylaminoantipyrine

LS

Least squares

Footnotes

a.

Idexx BioResearch, West Sacramento, Calif.

b.

Cloud EDC, ClinCapture, Medrio, San Francisco, Calif.

c.

Dual scale digital thermometer, VetOne, Boise, Idaho.

d.

Zimeta, KindredBio, Burlingame, Calif.

e.

Corden Pharma, Caponago, Italy.

f.

Merck, Darmstadt, Germany.

g.

SAS, version 9.4, SAS Institute Inc, Cary, NC.

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