To Evaluate Efficacy and Safety of Parsaclisib and Ruxolitinib in Participants With Myelofibrosis Who Have Suboptimal Response to Ruxolitinib (LIMBER-304)

Participants had an MRI of the upper and lower abdomen and pelvis to determine the spleen volume. A CT scan was substituted for participants who were not candidates for MRI or when MRI was not readily available.

Time frame: Baseline; Week 24

Population: Intent-to-Treat (ITT) Population: all randomized participants. Participants were analyzed if they had both Baseline and Week 24 measurements, or discontinued treatment before 03MAR2023 or switched treatment before Week 24, or reached Week 24 before 03MAR2023 but were missing Week 24 assessments. For participants who switched to parsaclisib plus ruxolitinib treatment early, data was truncated at the time of switch.

Symptoms of myelofibrosis were assessed using the MFSAF v4.0 diary. The MFSAF v4.0 is composed of 7 individual symptom scores (fatigue, night sweats, itchiness, abdominal discomfort, pain under left ribs, early satiety, bone pain), each collected daily using a 0- (no symptoms) to 10-point (worst imaginable symptoms) scale. The daily TSS (0 to 70) is the sum of the 7 individual symptom scores collected in a day. A higher TSS corresponds to more severe symptoms. The TSS was marked as missing if there were any missing individual scores. Observations with missing dates were excluded from the analysis. The Baseline/Week 24 total score was defined as the average of the daily total scores from the last 7 days before the first dose of parsaclisib, placebo, or ruxolitinib/the Week 24 visit. The Baseline/Week 24 total score was marked as missing if there were ≥4 out of the 7 daily TSSs missing. Change from Baseline was calculated as the Week 24 value minus the Baseline value.

Time frame: Baseline; Week 24

Population: ITT Population. Only participants with data available were analyzed.

The duration of ≥25% reduction from Baseline in spleen volume was defined as the interval between the first spleen volume measurement that was a ≥25% reduction from Baseline and the date of the first measurement that was no longer a ≥25% reduction from Baseline. If the end date was not observed before the database cutoff, the duration was censored at the last assessment.

Time frame: up to 898 days

Population: ITT Population. Only those participants who had at least 1 measurement of ≥25% reduction from Baseline were to be analyzed. At the time of study termination, only a limited number of ≥25% reduction in spleen volume responses were observed; therefore, as specified in the Statistical Analysis Plan, analysis of duration of a 25% reduction in spleen volume was not performed.

An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it is considered drug related. A TEAE is defined as an AE reported for the first time or the worsening of a pre-existing event after the first dose of study treatment. The severity of AEs was assessed using Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grades 1 through 5. Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: moderate; minimal, local or noninvasive intervention indicated; limiting instrumental activities of daily living (ADL). Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4: life-threatening urgent intervention indicated. Grade 5: death related to AE.

Time frame: up to 917 days

Population: Safety Population

An adverse event (AE) is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it is considered drug related. An AE could therefore be any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE is defined as an AE reported for the first time or the worsening of a pre-existing event after the first dose of study treatment.

Time frame: up to 917 days

Population: Safety Population: all randomized participants who received at least 1 dose of parsaclisib, placebo, or ruxolitinib. Treatment groups for this population were determined according to the actual treatment the participant received regardless of assigned study drug treatment.

Overall survival was defined as the interval between the randomization date and the date of death due to any cause.

Time frame: up to 917 days

Population: ITT Population

Symptoms of myelofibrosis were assessed using the MFSAF v4.0 diary. The MFSAF v4.0 is composed of 7 individual symptom scores (fatigue, night sweats, itchiness, abdominal discomfort, pain under left ribs, early satiety, bone pain), each collected daily using a 0- (no symptoms) to 10-point (worst imaginable symptoms) scale. The daily TSS (0 to 70) is the sum of the 7 individual symptom scores collected in a day. A higher TSS corresponds to more severe symptoms. The TSS was marked as missing if there were any missing individual scores. Observations with missing dates were excluded from the analysis. The Baseline/Week 24 total score was defined as the average of the daily total scores from the last 7 days before the first dose of parsaclisib, placebo, or ruxolitinib/the Week 24 visit. The Baseline/Week 24 total score was marked as missing if there were ≥4 out of the 7 daily TSSs missing.

Time frame: Baseline; Week 24

Population: ITT Population. Participants were analyzed if they had both Baseline and Week 24 measurements, or discontinued treatment before 03MAR2023 or switched treatment before Week 24, or reached Week 24 before 03MAR2023 but were missing Week 24 assessments. For participants who switched to parsaclisib plus ruxolitinib treatment early, data was truncated at the time of switch.

The time to the first ≥25% reduction in spleen volume is defined as the time from randomization to the first time participants had ≥25% reduction in spleen volume. Participants with a Baseline and post-Baseline MRI or CT scan who did not have ≥25% reduction in spleen volume at the time of analysis were censored at the time of the last MRI or CT scan. If the participants had no Baseline or post-Baseline MRI or CT scan, they were censored at the date of randomization.

Time frame: up to 898 days

Population: ITT Population

Symptoms were assessed using the MFSAF v4.0 diary. The MFSAF v4.0 is composed of 7 individual symptom scores (fatigue, night sweats, itchiness, abdominal discomfort, pain under left ribs, early satiety, bone pain), each collected daily using a 0- (no symptoms) to 10-point (worst imaginable symptoms) scale. The daily TSS (0 to 70) is the sum of the 7 individual symptom scores collected in a day. A higher TSS corresponds to more severe symptoms. The TSS was marked as missing if there were any missing individual scores. Observations with missing dates were excluded from the analysis. The Baseline/Week 24 total score was defined as the average of the daily total scores from the last 7 days before the first dose of parsaclisib, placebo, or ruxolitinib/the Week 24 visit. The Baseline/Week 24 total scores was marked as missing if there were ≥4 out of the 7 daily TSSs missing. The 95% confidence interval was calculated using the Brookmeyer and Crowley's method with log-log transformation.

Time frame: Baseline; up to Week 24

Population: ITT Population. For participants who switched to parsaclisib plus ruxolitinib treatment early, data was truncated at the time of switch. Participants with valid, calculated Baseline TSS and at least 1 postbaseline TSS who did not have a ≥50% reduction in TSS at the time of analysis were censored at the time of the last valid calculated TSS. If the participants had no valid, calculated Baseline or postbaseline TSS, they were censored at the date of randomization.