Background: Momelotinib (MMB) is a JAK1/2 inhibitor that displays potent in vitro inhibitory activity against cells dependent on JAK2, including cells with the JAK2V617F mutation. In a completed phase I/II study of MMB which enrolled 166 subjects with myelofibrosis (MF) (CCL09101), the rate of spleen response was 39%, and the rate of anemia response was 53% (Pardanani et al, Blood 2013). Assessment at 3 months showed improvement of constitutional symptoms. Most common treatment-related adverse events were thrombocytopenia (46%), peripheral neuropathy (44%), diarrhea (25%), dizziness (24%), and nausea (22%). Dizziness is believed to be part of the first-dose effect of MMB. Methods: 420 subjects with primary (PMF), post-polycythemia vera (PPV-MF), or post-essential thrombocythemia MF (PET-MF) will be randomized in a 1:1 manner to receive either MMB plus ruxolitinib (RUX) placebo, or RUX plus MMB placebo in this double-blind, active-controlled study for 24 weeks, with the option for eligible subjects to subsequently continue open-label MMB treatment for up to an additional 168 weeks. Key inclusion criteria include palpable splenomegaly ≥ 5 cm, high risk or intermediate-2 risk MF, or intermediate-1 risk MF with symptoms, and platelet count ≥ 50 x 10⁹/L. Prior use of a JAK inhibitor is not allowed. The primary endpoint is Splenic Response Rate at Week 24, defined as the proportion of subjects achieving ≥ 35% reduction in spleen volume at Week 24 as measured by MRI or CT scan. Secondary endpoints include Response Rate in Total Symptom Score at Week 24 defined as the proportion of subjects who achieves ≥ 50% reduction from baseline in total symptom score to Week 24 as measured by the modified MPNSAF TSS diary. The Data Monitoring Committee last reviewed the trial in November 2014 and recommended that the trial continue as planned. Clinical trial registry number: NCT01969838. Clinical trial information: NCT01969838