Clinical Studies With GASTROGARD

A series of four dose-confirmation trials, six field trials, two acceptability trials, and four safety trials was conducted to establish the clinical utility of GASTROGARD.⁶

Ulcer Scoring

Ulcers vary in their location, size, depth, and other characteristics. A standardized scoring system is therefore necessary to evaluate healing and to compare severity of lesions among trial subjects. Investigators in both the dose-confirmation trials and the field trials were trained to use a four-point scoring method.⁶ The higher the score, the more severe the lesion.

Dose-Determination Trial

The benefit of GASTROGARD for the treatment of ulcers is based upon the capacity of its active ingredient, omeprazole, to almost completely inhibit acid secretion.⁶ Initially, pharmacodynamic experiments and field trials were conducted to assess the efficacy of various omeprazole pastes in inhibiting gastric acid secretion using several doses. There was a clear indication that at 3 mg/kg/day, ulcer healing and improvement were considerably less than maximum. Further studies led to the conclusion that treatment with GASTROGARD given at 4 mg/kg once daily is the most effective dose for optimal acid suppression in the horse.⁶

Dose Confirmation Trials

Four trials were conducted to evaluate the efficacy of daily doses of 4 mg/kg of GASTROGARD in treating existing ulcers in horses and preventing their recurrence.⁶ The results of these trials were pooled for statistical analysis.

Subjects. Thoroughbred horses at least 2 years old and healthy other than the presence of gastric ulcers were included in trials at sites in Texas, Florida, and Kentucky. When horses followed a typical exercise schedule used by many race-training facilities, ulcers were consistently present over a 56-day period. Exercise consisted of galloping or running at the training track, with distance varied according to the horse's level of training and conditioning. As each horse's condition improved, the length of its runs was increased. Horses were galloped for the required distance 5 days per week, and breezed (run hard for distance) 1 day a week. Day 7 was reserved for rest.⁶

Horses were housed in individual stalls throughout the trial, with feeding that met National Research Council requirements for adult horses in training. Animals were handled in compliance with all applicable local regulations and with due regard for their welfare.⁶

Methods. The dose-confirmation trials were divided into two parts to evaluate both efficacy of treatment as well as prevention of recurrence. In Part 1, involving 100 horses, horses within each trial were grouped into replicates comprising four animals with similar pretrial gastric lesion scores and gender. One randomly selected animal in each replicate was sham dosed using an empty syringe, while the other three received omeprazole 4 mg/kg/day. Dosing was continued for 4 weeks, with endoscopic examination and gastric lesion scoring after 2, 3, and 4 weeks of dosing.⁶

In Part 2, the objective was to determine the omeprazole dosage needed to prevent or reduce ulcer recurrence. The animals that had received omeprazole were regrouped into new replicates of three based on their final gastric lesion scores at the end of Part 1. Treatments at two daily dosages (2 mg/kg/day and 4 mg/kg/day) were randomly allocated to horses within each replicate, with the remaining horse sham dosed. This part of the trial continued for 30 days.6 Investigators, including the endoscopist, in these trials were kept unaware of which animals received omeprazole and of the dosages used.⁶

Statistical Analysis. Changes in ulcer score from baseline were analyzed nonparametrically using a modified Friedman's test (Cochran-Mantel-Haenszel procedure) to assess differences between omeprazole and control after 2, 3, and 4 weeks. Change in ulcer score over the next 30 days was also analyzed using a modified Friedman's test, with contrasts tested using Dunn's procedure to assess differences among omeprazole dosing regimens. The two-sided significance level for all testing was 0.05.⁶

Results: Part 1. GASTROGARD, administered to provide omeprazole at 4 mg/kg (1.8 mg/lb) daily for 4 weeks, effectively healed or reduced the severity of gastric ulcers in 92% of treated horses. In comparison, 32% of sham-dosed horses exhibited healed or less severe ulcers. All horses began the trial with gastric lesion scores >1, and the average pretreatment lesion score was 2.2. More than 44% of the horses had extensive, often coalescing lesions with apparent areas of deep ulceration that resulted in a score of 3. The reduced severity of gastric ulcers compared to baseline was significantly (P<0.01) greater for omeprazole-treated horses than for controls at each endoscopic examination. Ulcers were healed or improved after 4 weeks in horses treated with GASTROGARD.⁶

Prevention of Recurrence: Part 2. In the second part of the study, GASTROGARD at either full or half doses prevented recurrence of gastric ulcers. GASTROGARD (given to provide omeprazole at 4 mg/kg/day or 2 mg/kg/day) or sham dosing was given for 30 days to treated horses that had completed the first part of the study. There was no recurrence of ulcers among 84% of horses receiving prevention with GASTROGARD at either dose, whereas ulcers persisted, recurred, or became more severe in 92%of sham-dosed horses (the proportion of horses with healed ulcers or reduced severity of ulcers was significantly higher for horses continued on omeprazole compared to sham-dosed controls).⁶

The two dosages of omeprazole did not significantly differ in their efficacy at preventing recurrence of ulcers, with 88% and 84% of horses having healed or reduced severity of ulcers at 4 mg/kg/day and 2 mg/kg/day omeprazole, respectively.⁶

When omeprazole treatment stopped, ulcers recurred. At the end of 30 days, 92% of horses that stopped omeprazole treatment had ulcers.⁶

Clinical Field Trials

An additional six studies were conducted to assess the efficacy of omeprazole paste under field conditions.⁶

Subjects. The horses ranged in age from 4 weeks to more than 15 years, and represented a wide variety of breeds, including Standardbreds, Thoroughbreds, Quarter Horses, Appaloosas, Paints, Tennessee Walking Horses, ponies, warmbloods, and crossbreds. Horses enrolled in these trials were otherwise healthy horses confirmed by gastroscopy to have gastric ulcers. The severity of gastric ulcers was scored using the method described in the dose-confirmation trials. Gastric ulcers were not induced specifically, but occurred within the routine management of each facility. Racing, other performance, and non-performance horses were included.6 Animals were maintained on their usual diets, housing, and exercise, which varied among sites and according to the age, condition, and occupation of the horses. Trial sites were located in Indiana, Oklahoma, California, Illinois, Missouri, and Tennessee.⁶

Methods. At each trial facility, horses were grouped into replicates of four, based on type of activity or location. Within each replicate, three horses were randomly selected to receive omeprazole while the remaining horse was sham dosed. Each horse was examined endoscopically prior to the first dose and after week 4, and gastric lesion scores were determined. Each animal was also observed twice daily for changes in condition and health during each trial.⁶

Statistical Analysis. Data including change in gastric ulcer score, body weight, and incidence of health problems were pooled from the six trials. Change in gastric lesion score from baseline to week 4 were analyzed nonparametrically using a modified Friedman's test (Cochran-Mantel-Haenszel procedure). Baseline body weight and weight gain to weeks 2 and 4 were analyzed using mixed-model analysis of variance. In addition, incidence of one or more health problems was also analyzed using the Mantel-Haenszel test. The two-sided significance level for all testing was 0.05.⁶

Results. GASTROGARD administered at 4 mg/kg (1.8 mg/lb) daily for 28 days healed or reduced severity of gastric ulcer lesion severity scores in 99% of omeprazole-treated horses. Among treated animals, none had a lesion score that increased, and only one animal had an unchanged score. In comparison, only 32% of sham-dosed horses had healed ulcers or ulcers that were reduced in severity. Two thirds of the control animals had lesion scores that remained the same or increased during the trial. There were no adverse health effects related to medication.⁶

Acceptability Trials

In the field trials, horses readily accepted GASTROGARD, with >99% of the nearly 3000 doses administered with no loss of paste.6 Two additional field trials were conducted in horses without ulcers to further assess the acceptability of the paste. Each followed the protocols outlined for the previously described field trials, with the omission of the requirement for preexisting ulcers. Subjects included 20 healthy Thoroughbred foals aged 11 to 16 weeks and 20 Thoroughbred yearlings at a facility in Virginia.⁶

The horses readily accepted the paste. No paste was rejected by any of the horses.⁶