Background/Purpose: Pregabalin (PGB) is currently approved for the treatment of fibromyalgia (FM) for twice daily dosing over a range of 300-450 mg/day. A pregabalin controlled-release (PGB CR) formulation was developed to enable once daily (QD) dosing.

Methods: The study involved 4 phases: baseline (BL; 1 week), single blind (SB; 6 weeks), double blind treatment (DB; 13 weeks), and a 1-week double blind taper. The SB starting dose was 165 mg/day and was escalated during the first 3 weeks, up to 495 mg/day based on efficacy and tolerability. Dosing was QD following an evening meal. Patients with ≥50% reduction in average daily pain score at the end of SB compared to BL were randomized (1:1) in the DB phase to continue PGB CR treatment at the optimized dose (330 to 495 mg/day) or to matching placebo (PBO). The primary endpoint (EP) of time to Loss of Therapeutic Response (LTR) was assessed during DB and defined as < 30% pain response relative to BL (SB) or discontinuation due to lack of efficacy or an adverse event (AE).  Secondary endpoints included measures of pain relief, global assessment, functional status, tiredness, and sleep.  A total of 290 SB patients were planned to provide the 74 LTR events needed to achieve 90% power to detect a difference in the primary EP.  However, there was insufficient power, a priori, to detect differences in the secondary endpoints of this study.

Results: 441 patients, ≥18 years of age, meeting the American College of Rheumatology 1990 criteria for FM (Wolfe F, et al. Arthritis Rheum. 1990; 33(2):160-172) were enrolled. The majority were white (80%), female (89%) and an average age of 48 years. Of the 441 patients, 121 (27%) completed SB, had ≥50% pain response and were treated in DB.  Seventy-five LTR events occurred. The median time from randomization to LTR (Kaplan-Meier analysis) was 58 days in the PGB CR group and 22 days in the PBO group (p=0.021). During the DB phase 34/63 (54.0%) PGB CR and 41/58 (70.7%) of PBO patients met LTR criteria.  There was no statistically significant difference between DB treatments for the secondary endpoints with the exception of benefit from treatment; a domain of the Benefit, Satisfaction and Willingness to Continue scale: more patients reported “much benefit” in the PGB CR group (p=0.0296). While not significant, trends favoring PGB CR treatment were seen in the Fibromyalgia Impact Questionnaire Total Score, Patient Global Impression of Change, and the Sleep Quality domain of the Subjective Sleep Questionnaire. In PGB CR patients the most common AEs during SB were dizziness, somnolence, and headache; and during DB were dizziness, peripheral edema, and insomnia. The most common AEs in PBO patients were dizziness, somnolence, dry mouth, and peripheral edema. The majority of AEs were mild to moderate in severity. Five patients experienced serious adverse events (SAE) during SB and 1 event (glossitis) was considered related to PGB CR; 2 PGB CR patients experienced an SAE during DB.  No deaths occurred.

Conclusion: PGB CR was effective in improving the time to and the number of LTR events in FM patients. PGB CR was well-tolerated in most patients and results were consistent with the known safety profile of PGB.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/once-daily-controlled-release-pregabalin-in-fibromyalgia-patients-a-phase-3-double-blind-randomized-withdrawal-placebo-controlled-study/