This randomized, double-blind, placebo-controlled phase 3 trial was conducted at 89 sites in the United States, Australia, and Canada. Patients were randomized 1:1 to receive oral ruxolitinib phosphate tablets or matched placebo. The starting dose of ruxolitinib was 15 mg or 20 mg twice daily, depending on baseline platelet count (100 to 200×109/l or >200×109/l, respectively). The dose was adjusted for lack of efficacy or excess toxicity per protocol (Appendix ). Unblinding of therapy and crossover from placebo to ruxolitinib was permitted for protocol-defined worsening splenomegaly (Appendix ). The prospectively defined data cutoff occurred when half the patients remaining in the study completed the week 36 visit, and all completed the week 24 evaluation or discontinued treatment. Data for placebo-treated patients after crossover are not included in these analyses, except for the intent-to-treat (ITT) analysis of overall survival.
The primary endpoint was the proportion of patients achieving a ≥35% reduction in spleen volume from baseline to week 24, measured by magnetic resonance imaging (MRI) or computed tomography. Secondary endpoints included duration of maintenance of spleen volume reduction, proportion of patients with ≥50% reduction in Total Symptom Score (TSS) from baseline to week 24 using the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary (Appendix ),10 ,11 change in TSS from baseline to week 24, and overall survival. The overall survival analysis was updated at the time of a planned data cutoff 4 months after the primary analysis. Patients completed the MFSAF every night; this electronic diary evaluated, on a scale of 0 (absent) to 10 (worst imaginable), night sweats, itching, abdominal discomfort, pain under the ribs on the left side, feeling of fullness (early satiety), muscle/bone pain, and inactivity. TSS was the sum of individual symptom scores, excluding inactivity. Exploratory endpoints included changes in body weight and JAK2V617F allele burden, achievement of transfusion independence,12 (link) and additional patient-reported outcomes (Appendix ).
The study was designed to enroll 240 patients, providing 97% power to detect a treatment difference in spleen volume response at a 2-sided alpha level of 0.05 assuming ≥30% response rate for ruxolitinib and ≤10% response rate for placebo. Analyses were conducted in accordance with intent-to-treat (ITT) principles. For all applicable variables, however, patients with missing baseline values were excluded from analyses of change and percent change from baseline. In analyses of change from baseline to week 24, patients who discontinued or crossed over before week 24 were counted as nonresponders (for response measures of spleen volume reduction and symptom improvement). Comparative secondary efficacy variables were tested in a fixed-sequence-testing procedure at an alpha level of 0.05. Durability of spleen response and survival were analyzed using the Kaplan-Meier method. The statistical analysis plan is posted on NEJM.org.
This study was funded by Incyte Corporation. The first author (S.V.) and a coauthor (V.S.) wrote the initial draft of the manuscript. Medical writing assistance with an early draft was provided by Daniel Hutta, Ph.D., of Articulate Science, LLC, and funded by Incyte Corporation. All coauthors contributed to subsequent drafts and decided to submit for publication. Data were analyzed at Incyte Corporation (W.S.). All authors vouch for the accuracy and completeness of reported data and for fidelity of this report to the protocol.
The primary endpoint was the proportion of patients achieving a ≥35% reduction in spleen volume from baseline to week 24, measured by magnetic resonance imaging (MRI) or computed tomography. Secondary endpoints included duration of maintenance of spleen volume reduction, proportion of patients with ≥50% reduction in Total Symptom Score (TSS) from baseline to week 24 using the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary (
The study was designed to enroll 240 patients, providing 97% power to detect a treatment difference in spleen volume response at a 2-sided alpha level of 0.05 assuming ≥30% response rate for ruxolitinib and ≤10% response rate for placebo. Analyses were conducted in accordance with intent-to-treat (ITT) principles. For all applicable variables, however, patients with missing baseline values were excluded from analyses of change and percent change from baseline. In analyses of change from baseline to week 24, patients who discontinued or crossed over before week 24 were counted as nonresponders (for response measures of spleen volume reduction and symptom improvement). Comparative secondary efficacy variables were tested in a fixed-sequence-testing procedure at an alpha level of 0.05. Durability of spleen response and survival were analyzed using the Kaplan-Meier method. The statistical analysis plan is posted on NEJM.org.
This study was funded by Incyte Corporation. The first author (S.V.) and a coauthor (V.S.) wrote the initial draft of the manuscript. Medical writing assistance with an early draft was provided by Daniel Hutta, Ph.D., of Articulate Science, LLC, and funded by Incyte Corporation. All coauthors contributed to subsequent drafts and decided to submit for publication. Data were analyzed at Incyte Corporation (W.S.). All authors vouch for the accuracy and completeness of reported data and for fidelity of this report to the protocol.
