Materials and Methods
Animals—A total of 103 client-owned dogs with naturally developing hyperadrenocorticism were used in the study. These dogs were part of a clinical trial to evaluate the efficacy of trilostane. Informed owner consent was obtained for all dogs. The protocol for the efficacy trial was reviewed and approved by the US FDA.
Inclusion criteria for the efficacy trial included appropriate clinical signs, physical examination findings, and clinicopathologic data for hyperadrenocorticism, along with abnormal results on a low-dose dexamethasone suppression test (ie, cortisol concentration at 8 hours after dexamethasone administration, > 1.5 μg/dL). Dogs with tumors of the adrenal cortex were identified by use of abdominal ultrasonography. Pretreatment ACTH stimulation tests were performed in all dogs before the initiation of trilostane administration; dogs with pituitary-dependent hyperadrenocorticism were required to have a cortisol concentration after ACTH stimulation of > 19.9 μg/dL, whereas dogs with tumors of the adrenal cortex were required to have a cortisol concentration after ACTH stimulation of > 14.5 μg/dL. The cutoff value for dogs with tumors of the adrenal cortex was lower because a substantial proportion of dogs with this form of hyperadrenocorticism have a more moderate response to exogenously administered ACTH.9,10 Patients with diabetes mellitus, preexisting hepatic compromise, or renal failure were ineligible for the trial; in addition, dogs with distant metastasis of an adrenal gland tumor and that were considered unlikely to survive for at least 12 weeks were also excluded.
ACTH stimulation tests—A pretreatment ACTH stimulation test was performed on each dog < 15 days before starting administration of trilostane. The initial dosage of trilostanea was determined on the basis of body weight in accordance with the manufacturer’s published guidelines.8
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As part of the efficacy trial, ACTH stimulation tests were performed on days 14, 28, 42, and 84 after initiation of trilostane treatment. Most of the dogs received trilostane once daily in the morning, but 14 of 103 dogs received doses of trilostane twice daily (morning and evening) during some part of the trial. All ACTH stimulation tests were started between 4 and 6 hours following administration of the morning dose of trilostane, and adjustments to the trilostane dose were determined by use of the cortisol concentration after ACTH stimulation, as described in the manufacturer’s published guidelines.8
Each ACTH stimulation test was performed in the same manner. A blood sample was collected for measurement of the baseline cortisol concentration immediately before administration of a synthetic ACTH product.b Each blood sample was placed in a serum separator tube, was allowed to clot at 20° to 25°C for 30 minutes, and then was centrifuged for 10 minutes at approximately 1,980 × g. Serum was harvested, transferred to a plain serum tube, and refrigerated at 2°C. The synthetic ACTH product was administered IV at a dose of 0.125 mg for dogs that weighed < 5 kg (< 11 lb) and 0.25 mg for dogs that weighed ≥ 5 kg. A blood sample for measurement of the cortisol concentration after ACTH stimulation was collected 60 minutes after ACTH injection and processed in the same manner as for the blood sample collected before ACTH administration.
Serum samples were shipped on ice via overnight delivery to a commercial veterinary reference laboratory.c Cortisol concentrations were determined by use of a radioimmunoassay method that involved a gammacounter. A standard curve was created for each assay, and 3 concentrations of commercial (control) cortisol were included at the beginning and end of each assay. The laboratory reported cortisol concentrations to the nearest 0.1 μg/dL.
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Statistical analysis—Data were analyzed by use of a commercial software programd; results were considered significant at values of P < 0.01. When appropriate, data sets were tested for normality by use of the D’Agostino and Pearson omnibus normality test. Correlation between paired data points was determined by use of the Spearman method. Median values of selected data sets were compared by use of the Mann-Whitney U test for unpaired data. Reliability of novel hypotheses was tested by use of the Fischer exact method, with results and 95% CIs provided for sensitivity, specificity, PPV, and NPV.
Initially, the paired cortisol measurements for the ACTH stimulation tests performed 14 to 84 days after the start of trilostane administration were investigated for correlation. Subsequently, each cortisol concentration after ACTH stimulation was reviewed by use of the clinical trial guidelines, and control of cortisol release was classified as excessive (cortisol concentration < 1.5 μg/dL after ACTH stimulation), acceptable (cortisol concentration between 1.5 and 9.1 μg/dL after ACTH stimulation), or inadequate (cortisol concentration > 9.1 μg/dL after ACTH stimulation). Data pairs were then reviewed, and an attempt was made to identify a baseline cortisol concentration above which excessive suppression of cortisol synthesis could be safely excluded. Similarly, an attempt was made to identify a baseline cortisol concentration below which the possibility of inadequate control of cortisol synthesis could be safely excluded.
Comparisons between the pretreatment baseline cortisol concentrations and results of the ACTH stimulation tests while dogs were receiving trilostane were also performed. An attempt was made to define a percentage decrease from the pretreatment baseline cortisol concentration that might indicate acceptable control of adrenal gland function. This factor was then combined with the newly defined optimal range for baseline cortisol concentration, and the validity of this novel algorithm was statistically determined.
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