Effectiveness and Safety of Intrathecal Ziconotide: Final Results of the Patient Registry of Intrathecal Ziconotide Management (PRIZM).

BACKGROUND AND OBJECTIVES: The Patient Registry of Intrathecal Ziconotide Management evaluated the long-term effectiveness and safety of intrathecal ziconotide. METHODS: The study was a prospective, multicenter observational study of intrathecal ziconotide in US clinical practice. Patients were adults with severe chronic pain that warranted intrathecal therapy. Ziconotide was initiated as the single agent in the pump; however, other intrathecal medications were permitted. The primary efficacy outcome was ≥30% reduction in numeric pain rating scale score from baseline at week 12. A secondary outcome was patient global impression of change. Adverse events were solicited at each visit. RESULTS: The registry enrolled 93 patients. Seventy-four and 28 patients completed 12 weeks and 18 months of treatment, respectively. In the overall patient population, 17.4% had ≥30% pain reduction from baseline at week 12, with a mean reduction in pain of 10.9%. At month 18, 38.5% of patients had ≥30% pain reduction from baseline, with a mean pain reduction of 24.7%. Patient-rated improvement was reported in 67% of patients at week 12 and 71% at month 18. Almost all patients experienced adverse events, the most common of which were nausea (25.8%), confusional state (22.6%), and dizziness (20.4%). CONCLUSIONS: Final study analyses showed that intrathecal ziconotide provided clinically meaningful pain relief in 17.4% and 38.5% of patients at week 12 and month 18, respectively. At these same time points, patient-rated improvement was reported in at least two-thirds of patients. The safety profile was consistent with that listed in the ziconotide prescribing information.

Effectiveness and Safety of Intrathecal Ziconotide: Interim Analysis of the Patient Registry of Intrathecal Ziconotide Management (PRIZM).

BACKGROUND: The Patient Registry of Intrathecal Ziconotide Management (PRIZM) evaluated long-term effectiveness, safety, and tolerability of intrathecal ziconotide treatment in clinical practice. METHODS: Patient Registry of Intrathecal Ziconotide Management was an open-label, long-term, multicenter, observational study of adult patients with severe chronic pain. This interim analysis (data through July 10, 2015) of ziconotide as the first vs. not first intrathecal agent in pump included change from baseline in the Numeric Pain Rating Scale (NPRS; primary efficacy measure) and Patient Global Impression of Change (PGIC) scores. RESULTS: Enrollment closed at 93 patients; data collection was ongoing at the time of this interim analysis. Fifty-one patients (54.8%) received ziconotide as the first agent in pump (FIP+), whereas 42 (45.2%) did not (FIP-). Mean (SD) baseline NPRS scores were 7.4 (1.9) and 7.9 (1.6) in FIP+ and FIP- patients, respectively. Mean (SEM) percentage changes in NPRS scores were -29.4% (5.5%) in FIP+ patients (n = 26) and +6.4% (7.7%) in FIP- patients (n = 17) at month 6 and -34.4% (9.1%) in FIP+ patients (n = 14) and -3.4% (10.2%) in FIP- patients (n = 9) at month 12. Improvement from baseline, measured by PGIC score, was reported in 69.2% of FIP+ (n = 26) and 35.7% of FIP- (n = 14) patients at month 6 and 85.7% of FIP+ (n = 7) and 71.4% of FIP- (n = 7) patients at month 12. The most common adverse events (≥ 10% of patients overall as of the data cut) were nausea (19.6% vs. 7.1% of FIP+ vs. FIP- patients, respectively), confusional state (9.8% vs. 11.9%), and dizziness (13.7% vs. 7.1%). CONCLUSIONS: Greater improvements in efficacy outcomes were observed when ziconotide was initiated as first-line intrathecal therapy vs. not first intrathecal agent in pump. The adverse event profile was consistent with the ziconotide prescribing information.

Pain intensity rating training: results from an exploratory study of the ACTTION PROTECCT system.

Clinical trial participants often require additional instruction to prevent idiosyncratic interpretations regarding completion of patient-reported outcomes. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership developed a training system with specific, standardized guidance regarding daily average pain intensity ratings. A 3-week exploratory study among participants with low-back pain, osteoarthritis of the knee or hip, and painful diabetic peripheral neuropathy was conducted, randomly assigning participants to 1 of 3 groups: training with human pain assessment (T+); training with automated pain assessment (T); or no training with automated pain assessment (C). Although most measures of validity and reliability did not reveal significant differences between groups, some benefit was observed in discriminant validity, amount of missing data, and ranking order of least, worst, and average pain intensity ratings for participants in Group T+ compared with the other groups. Prediction of greater reliability in average pain intensity ratings in Group T+ compared with the other groups was not supported, which might indicate that training produces ratings that reflect the reality of temporal pain fluctuations. Results of this novel study suggest the need to test the training system in a prospective analgesic treatment trial.

PEARL-HF: prevention of hyperkalemia in patients with heart failure using a novel polymeric potassium binder, RLY5016.

The treatment of heart failure has seen considerable advances in the past decades. In particular, a therapeutic focus on the renin-angiotensin-aldosterone system has provided significant improvements in outcomes. Multiple inhibition points in the renin-angiotensin-aldosterone system, including direct renin inhibitors, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and mineralocorticoid receptor antagonists, have the common feature of either blocking aldosterone production (direct renin inhibitor, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker) or the mineralocorticoid receptor. As a consequence of this inhibition, sodium and water reabsorption is blocked, and potassium (K(+)) excretion is reduced. Hyperkalemia may result from the use of multiple renin-angiotensin-aldosterone inhibitors or blockers, particularly in patients with heart failure and concomitant chronic kidney disease. Interventions to reliably control serum K(+) during renin-angiotensin-aldosterone inhibition have not been available to date, and would be of particular value with the use of mineralocorticoid receptor antagonists that have been shown to reduce mortality in patients with heart failure and a reduced left ventricular ejection fraction. In this review, we examine the PEARL-HF study, which has tested the combined use of RLY5016, a novel nonabsorbed K(+) binding polymer, with spironolactone in heart failure patients receiving standard care but with previous documented hyperkalemia or chronic kidney disease. RLY5016 significantly lowered serum K(+) levels from baseline relative to placebo, lowered the incidence of hyperkalemia and allowed a higher proportion of heart failure patients to receive spironolactone at a dose of 50 mg/day.

Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial.

AIMS: To evaluate efficacy and safety of RLY5016 (a non-absorbed, orally administered, potassium [K+]-binding polymer) on serum K+ levels in patients with chronic heart failure (HF) receiving standard therapy and spironolactone. METHODS AND RESULTS: One hundred and five patients with HF and a history of hyperkalaemia resulting in discontinuation of a renin-angiotensin-aldosterone system inhibitor/blocker and/or beta-adrenergic blocking agent or chronic kidney disease (CKD) with an estimated glomerular filtration rate of <60 mL/min were randomized to double-blind treatment with 30 g/day RLY5016 or placebo for 4 weeks. Spironolactone, initiated at 25 mg/day, was increased to 50 mg/day on Day 15 if K+ was ≤5.1 mEq/L. Endpoints included the change from baseline in serum K+ at the end of treatment (primary); the proportion of patients with hyperkalaemia (K+ >5.5 mEq/L); and the proportion titrated to spironolactone 50 mg/day. Safety assessments included adverse events (AEs) and clinical laboratory tests. RLY5016 (n= 55) and placebo (n= 49) patients had similar baseline characteristics. At the end of treatment, compared with placebo, RLY5016 had significantly lowered serum K+ levels with a difference between groups of -0.45 mEq/L (P < 0.001); a lower incidence of hyperkalaemia (7.3% RLY5016 vs. 24.5% placebo, P= 0.015); and a higher proportion of patients on spironolactone 50 mg/day (91% RLY5016 vs. 74% placebo, P= 0.019). In patients with CKD (n= 66), the difference in K+ between groups was -0.52 mEq/L (P= 0.031), and the incidence of hyperkalaemia was 6.7% RLY5016 vs. 38.5% placebo (P= 0.041). Adverse events were mainly gastrointestinal, and mild or moderate in severity. Adverse events resulting in study withdrawal were similar (7% RLY5016, 6% placebo). There were no drug-related serious AEs. Hypokalaemia (K+ <3.5 mEq/L) occurred in 6% of RLY5016 patients vs. 0% of placebo patients (P= 0.094). CONCLUSION: RLY5016 prevented hyperkalaemia and was relatively well tolerated in patients with HF receiving standard therapy and spironolactone (25-50 mg/day).

Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial.

OBJECTIVES: The purpose of this study was to determine if ranolazine improves angina in stable coronary patients with persisting symptoms despite maximum recommended dose of amlodipine. BACKGROUND: Ranolazine is a unique antianginal agent that has been effective in stable angina, but it has not been studied in the setting of maximum recommended doses of conventional antianginal agents. METHODS: Stable patients with coronary disease and > or =3 anginal attacks per week despite maximum recommended dosage of amlodipine (10 mg/day) were randomized to 1,000 mg ranolazine or placebo twice a day for 6 weeks. Primary end point was the frequency of angina episodes per week during the double-blind treatment phase. Efficacy was also assessed by nitroglycerin consumption per week and the Seattle Angina Questionnaire (SAQ). Adjustment for multiple testing of secondary end points used a hierarchic closed testing procedure. Efficacy was assessed in subgroups based on baseline angina frequency, concomitant long-acting nitrate use, gender, and age. Safety was assessed by adverse events and electrocardiogram evaluations. RESULTS: A total of 565 patients were randomized: 281 patients to ranolazine and 284 patients to placebo. Baseline characteristics were similar between treatment groups. At baseline, angina frequency averaged 5.63 +/- 0.18 episodes/week, and nitroglycerin consumption averaged 4.72 +/- 0.21 tablets/week. Compared with placebo, ranolazine significantly reduced frequency of angina episodes (2.88 +/- 0.19 on ranolazine vs. 3.31 +/- 0.22 on placebo; p = 0.028) and nitroglycerin consumption (2.03 +/- 0.20 on ranolazine vs. 2.68 +/- 0.22; p = 0.014), with treatment effect that appeared consistent across subgroups. The median angina weekly episode rate at baseline was 4.5 per week. Subgroup analysis showed statistically significant reductions of angina frequency, nitroglycerin use, and SAQ angina frequency for patients with a baseline frequency >4.5 per week but only of angina frequency for those with baseline frequency < or =4.5 per week. Patients with more frequent angina appeared to have a more pronounced treatment effect. No hemodynamic changes were observed. Ranolazine was well tolerated. CONCLUSIONS: Ranolazine significantly reduced frequency of angina and nitroglycerin consumption compared with placebo and was well tolerated. (The ERICA [Efficacy of Ranolazine In Chronic Angina] Trial; http://clinicaltrials.gov; NCT00091429).