Preliminary experience using milnacipran in patients with juvenile fibromyalgia: lessons from a clinical trial program

Abstract

Background: There are no approved medications for juvenile fibromyalgia (JFM), a disorder that is often under-diagnosed. The effects of milnacipran, a drug approved for the management of fibromyalgia (FM) in adults, was assessed in a clinical trial program for JFM.

Methods: Patients, ages 13-17 years who met the Yunus and Masi criteria for JFM and/or 1990 American College of Rheumatology criteria for FM, were enrolled in a responder-enriched, randomized withdrawal trial. After receiving open-label milnacipran (8 weeks), patients with ≥50 % improvement in pain underwent double-blind randomization (1:2) to either placebo or continuing treatment with milnacipran (8 weeks). All patients, including those who did not meet the randomization criteria for double-blind withdrawal, were allowed to enter an extension study with open-label milnacipran (up to 52 weeks). The primary endpoint was loss of therapeutic response (LTR) during the double-blind period. Additional outcome measures included the Patient Global Impression of Severity (PGIS), Pediatric Quality of Life Inventory (PedsQL: Generic Core Scales, Multidimensional Fatigue Scale), and Multidimensional Anxiety Scale for Children (MASC). Safety assessments included adverse events (AEs), vital signs, electrocardiograms, and laboratory tests.

Results: The milnacipran program was terminated early due to low enrollment. Because only 20 patients were randomized into the double-blind withdrawal period, statistical analyses were not conducted for the LTR endpoint. However, 116 patients entered the open-label period of the initial study and 57 participated in the open-label extension study. Their experience provides preliminary information about the use of milnacipran in JFM patients. During both open-label periods, there were mean improvements in pain severity, PGIC, PedsQL, and MASC scores. No unexpected safety issues were detected. The most commonly reported treatment-emergent AEs were nausea, headache, vomiting, and dizziness. Mean increases in heart rate and blood pressure were observed, and were consistent with the AE profile in adults with FM.

Conclusions: The open-label findings provide preliminary evidence that milnacipran may improve symptoms of JFM, with a safety and tolerability profile that is consistent with the experience in adult FM patients. Future trial designs for JFM should consider the relatively low recognition of this condition compared to adult FM and the difficulties with enrollment.

Trial registration: NCT01328002 ; NCT01331109.

Figures

Fig. 1

Study flow. *Reasons for ineligibility occurring in >1 patient: current severe psychiatric illness (12 patients); did not have a mean daily pain rating of ≥3 to ≤ 9 in the week prior to the baseline visit (8 patients); did not meet Yunus and Masi criteria or ACR criteria (6 patients); had positive drug screen for illegal substances (4 patients); unwilling, unable, or inadvisable to discontinue prohibited medications during washout (3 patients). DB = double blind, ITT = intent to treat, OL = open label

Fig. 2

Mean changes from baseline in outcome measures during the extension study. Baseline was defined as pre-treatment values (i.e., patients’ scores prior to receiving the first dose of milnacipran in the open-label period of the randomized withdrawal study). For each visit in the extension study, baseline only includes pre-treatment values for those patients who completed that particular study visit. The n-values represent numbers of patients with valid assessments at baseline and at each extension study visit; graph only includes study visits that had >1 patient. *CDI was primarily used as a safety outcome. CDI = Children’s Depression Inventory, MASC = Multidimensional Anxiety Scale for Children, PedsQL = Pediatric Quality of Life Inventory, PGIS = Patient Global Impression of Severity