Initial Experience with the IMPROVE Trial-a Phase III Analgesic Trial for Hospitalized Sickle Cell Painful Episodes

Acute pain is the leading cause of hospitalization in both children and adults with sickle cell disease (SCD). Opioid analgesics are used for pain relief, but are associated with significant adverse effects that are bothersome to patients and may predispose to serious sickle-related pulmonary events. Evidence is limited for the most effective opioid administration strategy that maximizes analgesia and minimizes adverse effects. Patient Controlled Analgesia (PCA) has the potential advantage to allow a patient to optimize pain control without dependence on healthcare providers for administration. PCA generally consists of an opioid given by constant infusion with additional demand doses as needed; the proper dosing for each is largely unknown, particularly at high opioid doses. The SCDCRN conducted a multi-center phase III clinical trial comparing two alternative opioid PCA dosing strategies (HDLI-higher demand dose with low constant infusion or LDHI- lower demand dose and higher constant infusion). The required sample size for the trial was 278 subjects.

SCD patients ≥ age 10 years hospitalized for significant pain (baseline pain VAS ≥ 4.5/10) who had received < 12 hours of previous analgesic therapy and provided informed consent were eligible; patients with renal/hepatic dysfunction, who received large amounts of oral opioids prior to admission, or who had evidence of acute chest syndrome were excluded. Investigators used standardized opioid dosing tables for morphine or hydromorphone, and for participants weighing ±50 kg. Opioid-related symptoms were assessed with a validated daily questionnaire; multimodal assessments of pain, physical function, and sleep were conducted by an assessor blinded to treatment assignment/dose level; because of safety concerns, individuals responsible for making dosing decisions were not blinded. The assigned PCA strategy was continued until patients were transitioned to oral analgesics. An intention to treat analysis was planned for the time to a significant (2.5 cm) improvement in average daily 10 cm pain VAS. Secondary endpoints included total opioid usage and frequency of opioid-related symptoms.

From January 1, 2010 to June 8, 2010, a total of 1050 patients age ≥ 10 years were hospitalized for pain; 216 were ineligible, 796 were missed for logistic/staffing issues at sites, and 38 subjects completed randomization prior to trial closure (due to inadequate time to complete enrollment prior to Network termination in March 2011). Average age of enrolled subjects was 23.9 ± 12.2 years (range 10–52 years), and 53% were female. The HDLI arm had 50% morphine and 40% pediatric subjects (10-17 years); the LDHI arm had 44% morphine and 50% pediatric subjects. Four subjects were withdrawn (1 parent permission withdrawal, 2 inadvertent withdrawals by PI, 1 ineligible). Baseline VAS was high (mean 7.5 cm HDLI, and 7.7 cm LDHI). A reduction in pain intensity during PCA treatment was observed in both treatment arms (mean difference from baseline ± SEM: 2.7 ±1.5 cm HDLI vs 2.8 ±2.0 cm LDHI; time to significant improvement 22.0 ±3.0 hours HDLI vs 22.1 ±3.8 hours LDHI), with 75% of the HDLI subjects and 79% of the LHDI experiencing a significant improvement in pain. Average length of hospitalization was 143.7 ±94.2 hours HDLI vs 102.4 ±42.6 hours LDHI. The reliability or significance of any similarities or differences noted in this descriptive analysis is limited by the small sample size. Opioid utilization in the two treatment arms is currently being analyzed. Opioid-related symptoms were well managed and similar in both treatment arms (mean daily opioid symptom severity score (1-4): 0.9 ± 0.6 HDLI vs 0.8 ± 0.6 LDHI). Four episodes of serious hypoxia, likely relate to exacerbation of pulmonary hypertension, developed in adult subjects during the study (2 HDLI, 2 LDHI).

The premature closure of the study limits potential conclusions regarding safety and efficacy, or superiority of either treatment regimen. The data gathered will help resolve potential design issues related to the complexity of running an inpatient opiod PCA trial and help guide modification of subject selection and enrollment, optimization of opioid dosing and monitoring, and endpoint assessments. Given the clinical priority of adequate pain management and the challenges of opioid PCA therapy, completion of this trial is imperative. Supported by NHLBI.

Dampier:Anthera Pharmaceuticals Inc:; Glycomimetics Inc:.Telen:GlycoMimetics: Consultancy, clinical trial sponsorship.