Safety of Injectable HPβCD-Diclofenac in Older Patients with Acute Moderate-to-Severe Postoperative Pain: A Pooled Analysis of Three Phase III Trials

Data from three phase III trials of HPβCD-diclofenac were pooled (ClinicalTrials.gov identifiers: NCT00448110, NCT00507026, and NCT00726388). The protocols for all three trials adhered to the International Ethical Guidelines for Biomedical Research Involving Human Subjects, the International Conference on Harmonisation Good Clinical Practice guidelines, and the Helsinki Declaration. Each of the three trials was approved by the appropriate institutional review board and all patients provided written informed consent.

NCT00448110 was a randomized, placebo- and active-controlled trial that included a total of 331 patients aged 18–65 years who experienced moderate-to-severe postoperative pain within 6 h after abdominal or pelvic surgery, and who were randomized 1:1:1:1 to HPβCD-diclofenac 18.75 mg, HPβCD-diclofenac 37.5 mg, ketorolac tromethamine 30 mg, or placebo [4]. The first dose of study drug was administered within the first 6 h after surgery and then every 6 h until patient discharge or discontinuation/withdrawal from the trial. The median number of doses received across the treatment groups was 8 (range 1–13). Overall, 14.8% of patients received study drug for 1 day, 80.6% for 2 days, and 4.5% for 3 days.

NCT00507026 was a randomized, placebo- and active-controlled trial that included a total of 277 patients aged 18–85 years who experienced moderate-to-severe postoperative pain within 6 h after elective orthopedic surgery, and who were randomized 2:1:1 to HPβCD-diclofenac, ketorolac tromethamine, or placebo [5]. Randomized patients were stratified according to anticipated length of stay (≤ 24 versus > 24 h), as well as by risk, with dosages of HPβCD-diclofenac in patients categorized as either ‘non-high risk’, ‘high risk’, or ‘high weight’ (≥ 95 kg and without other risk factors) being 37.5, 18.75, and 50 mg, respectively, and respective ketorolac dosages in the same three groups being 30, 15, and 30 mg, respectively. Patients categorized as high risk were those < 50 kg in weight, ≥ 65 years of age, undergoing medical ulcer therapy, with renal or hepatic insufficiency, or with a history of gastrointestinal bleeding or perforation. The first dose of study drug was administered within the first 6 h after surgery and then every 6 h until patient discharge. Overall, 61% of patients received 1–8 doses of study drug, 30% received 9–12 doses, and 9% received > 13 doses; all patients (100%) received study drug for ≤ 5 days.

NCT00726388 was an open-label, multiple-dose safety study that included a total of 971 patients aged 18–85 years who experienced acute moderate-to-severe postoperative pain following abdominal, orthopedic, abdominal/pelvic, or any other surgery that would qualify for ≥ 2 days of scheduled, parenterally administered NSAIDs [6]. Patients received multiple doses of HPβCD-diclofenac 37.5 mg (for patients weighing < 95 kg, or weighing ≥ 95 kg and with more than one NSAID-related risk factor) or 50 mg (patients weighing ≥ 95 kg and with one or no NSAID-related risk factor) and administration was initiated in the immediate postoperative period as soon as the patient was stable following surgery and according to the study site’s usual practice, and then every 6 h (± 15 minutes) until the patient was completely transitioned to oral analgesics, discharged, discontinued, or had received treatment for 5 days. The median number of doses received across treatment groups was 2 (range 1–5). Overall, 4.2% of patients received study drug for 1 day, 62.5% for 2 days, 22.7% for 3 days, and 10.6% for 4–5 days.

Patients were stratified into three age groups: < 65, 65–74, and ≥ 75 years due to the availability of data from a meaningful number of patients > 75 years of age and as an acknowledgment that many patients aged 65–74 years have a standard of health that is appreciably different from that of the majority of patients > 75 years. General safety was assessed by physical examinations, laboratory tests, vital signs tests, and 12-lead ECG. Treatment-emergent AEs (TEAEs) were defined as those AEs that first occurred or worsened in severity during the course of the study, regardless of their relationship to study drug, and were recorded from baseline or screening through the follow-up periods of 30 days [4] or 30–37 days [5, 6], with TEAEs occurring at or after the first dose of study drug included in the analysis. All TEAEs were assessed by the study-site investigators and coded in accordance with the preferred terms and System Organ Class (SOC) categories defined by the Medical Dictionary for Regulatory Activities (MedDRA) version 12.0.

The analysis included all patients who received at least one dose of HPβCD-diclofenac or placebo as part of one of the three clinical trials described in Sect. 2.1 (patients randomized to a ketorolac tromethamine arm were not included). The baseline characteristics and the incidences of TEAEs in patients receiving HPβCD-diclofenac were presented using descriptive statistics. Comparisons of demographic characteristics and incidences of TEAEs across the three age groups were performed using ANOVA for numerical variables and Cochran–Mantel–Haenszel tests for categorical variables; p values < 0.05 were considered significant. The Cochran–Mantel–Haenszel test is a test of association that takes into account stratification or sources of the data. For the current analysis, the three studies were considered as strata for the Cochran–Mantel–Haenszel test so that information was not lost when analyzing combined data. Cochran–Mantel–Haenszel relative risks (and 95% confidence intervals) were calculated for each of the three age groups by comparing incidences of TEAEs in patients receiving HPβCD-diclofenac with those in patients receiving placebo, adjusted by study. Relative risks were calculated for both the overall SOC categories and any preferred terms whose incidence differed significantly between the three age groups.

A total of 1289 patients were included in the analysis: 878 in the < 65-years group, 282 in the 65–74-years group, and 129 in the ≥ 75-years group. The three age groups differed significantly with regard to mean body weight, gender, racial composition, prevalence of renal impairment, and most frequent type of procedure (Table 1). Mean body weight in the > 75-years group was approximately 10 kg lower than in the other two groups. There was a majority of women in all three age groups, with the < 65-years group having the highest proportion (69.1%). The proportion of white patients increased across the three age groups, as did the prevalence of mild renal impairment. The majority of procedures performed in the two older age groups were orthopedic, whereas procedures performed in the < 65-years group were divided approximately equally between orthopedic and abdominal/pelvic. The mean duration of each procedure was similar across the three age groups (p = 0.3557).

Baseline laboratory test results showed that albumin and overall protein levels were lower with increasing age, whereas blood urea nitrogen and creatinine were higher with increasing age (p < 0.0001 for all; Table 2). Alanine aminotransferase levels were lower with increasing age (p = 0.0006), as were levels of alkaline phosphatase (p = 0.0248), but other markers of liver function were not significantly different. Hematocrit, hemoglobin, erythrocytes, and platelets were lower with increasing age (p < 0.0001 for all).

The proportion of patients who experienced a TEAE was similar in the three age groups (p = 0.4360; Table 3). Overall, TEAEs within the SOC category of ‘Gastrointestinal disorders’ were the most common (49.4–50.4% of subjects across the three age groups), and this was driven predominantly by cases of nausea and constipation. TEAEs within the SOC categories of ‘Injury, poisoning, and procedural complications’ (18.3–34.1% of subjects across the three age groups, driven predominantly by cases of postoperative anemia) and ‘General disorders and administration site conditions’ (20.2–23.4% of subjects, driven predominantly by cases of injection site pain and pyrexia) were the next most common. There was a significant difference in the incidence of TEAEs between the three age groups for the following SOC categories: ‘Blood and lymphatic system disorders’ (driven mainly by an increasing frequency of anemia: 1.5, 3.2, and 3.9% in the < 65, 65–74, and ≥ 75-years age groups, respectively; p = 0.0215); ‘Injury, poisoning, and procedural complications’ (driven mainly by an increasing frequency of postoperative anemia; p < 0.0001); ‘Metabolism and nutrition disorders’ (driven mainly by a higher frequency of hyponatremia in the oldest group: 0.8, 0.4, and 3.9% in the < 65, 65–74, and ≥ 75-years age groups, respectively; p = 0.0089); ‘Nervous system disorders’ (driven mainly by a decreasing frequency of headache; p = 0.0008); ‘Psychiatric disorders’; ‘Renal and urinary disorders’ (driven mainly by an increasing frequency of acute renal failure: 0.1, 0.4, and 3.9% in the < 65, 65–74, and ≥ 75-years age groups, respectively; p < 0.0001); ‘Respiratory, thoracic, and mediastinal disorders’ (driven mainly by a higher frequency of cough in the oldest group: 1.0, 0.7, and 4.7% in the < 65, 65–74, and ≥ 75-years age groups, respectively; p < 0.0028; and ‘Vascular disorders’ (driven mainly by an increasing frequency of hypotension; p = 0.0003). There was also a significant difference between the age groups with regard to the preferred terms of constipation (p = 0.0017), which increased in incidence with increasing age, and flatulence (p = 0.0118), which decreased in incidence with increasing age. The incidence of TEAEs related to postoperative bleeding was low (< 1% for each specific TEAE in the patients receiving HPβCD-diclofenac for all three age groups), with no significant difference between patients receiving HPβCD-diclofenac and those receiving placebo.

Stratification of TEAE data according to severity showed that similar proportions of patients in the < 65, 65–74, and ≥ 75-years age groups experienced mild (32.5, 33.0, and 27.1%, respectively), moderate (43.4, 45.7, and 51.9%, respectively), and severe TEAEs (5.2, 5.0, and 5.4%, respectively). Statistical comparisons after stratification according to the dose of HPβCD-diclofenac received were not possible due to the small number of patients in some of the groups (respective patient numbers in the < 65, 65–74, and ≥ 75 years age groups were 92, 29, and 12 for 18.75 mg; 516, 171, and 99 for 37.5 mg; and 270, 82, and 18 for 50.5 mg), but the overall incidence of TEAEs was similar in the < 65, 65–74, and ≥ 75-years age groups at doses of 18.75 mg (83.7, 79.3, and 75.0%, respectively), 37.5 mg (81.8, 84.2, and 86.9%, respectively), and 50.5 mg (78.9, 84.1, and 77.8%, respectively). Statistical comparisons after stratification according to the type of procedure were not possible due to the small number of patients in the two older groups (patient numbers in the < 65, 65–74, and ≥ 75-years age groups were 418, 38, and 10, respectively, for abdominal/pelvic procedures, and 458, 244, and 119, respectively, for orthopedic procedures), but the overall incidence of TEAEs was similar in the < 65, 65–74, and ≥ 75-years age groups for abdominal/pelvic procedures (83.7, 76.3, and 80.0%, respectively) and orthopedic procedures (78.6, 84.8, and 84.9%, respectively).

For all three age groups, patients who received HPβCD-diclofenac displayed a relative risk of experiencing a TEAE of any type, or a TEAE of a specific SOC category or preferred term whose incidence differed significantly between the three age groups as indicated in Table 3, that was no greater than that of patients who received placebo (Fig. 1). Furthermore, the 95% confidence intervals of the relative risks calculated for each of the three age groups overlapped with one another for every SOC category or preferred term investigated. The time of onset for TEAEs was similar among the three age groups, with the incidence peaking at Day 2 when all TEAEs combined were considered (Fig. 2). The times of onset for the specific preferred terms identified as having a significantly different incidence across the age groups were similar, except for constipation, which peaked at Day 2 in the < 65-years group compared with Days 3 or 4 in the two older groups, and hypotension, which peaked at Day 1 in the > 75-years group compared with Day 2 in the two younger groups.