CINC424AGB02

Novartis Pharma AG

CH-4002, Basel, Switzerland,

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111 ,

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111 ,

No

No

No

Final

28 Jan 2014

No

Yes

28 Jan 2014

No

To evaluate the efficacy of daily oral doses of 15mg BID or 20mg BID of INC424 in patients with PMF, PPV-MF, or PET-MF, based on the proportion of patients experiencing treatment success at the 48 week timepoint. Treatment success was defined as: - 50% or greater reduction in palpable spleen length versus Baseline at the 48-week time point  and/or  - 50% or greater improvement in total symptom scores (derived from MF symptom assessment form [MFSAF] questionnaire) versus Baseline at the 48-week time point

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

01 May 2012

No

No

United Kingdom: 48

48

48

0

0

0

0

0

0

15

31

2

Treatment (overall period)

Not applicable

Ruxolitinib

INC424

Tablet

Oral use

Starting dose (Patients with platelet counts less than 100,000 L were ineligible for the study): - Patients with a Baseline platelet count of > 200,000/μL began dosing at 20 mg per os (p.o.) BID (four 5 mg tablets BID). - Patients with a Baseline platelet count between 100,000 – 200,000/μL (inclusive) began dosing at 15 mg p.o. BID (three 5 mg tablets BID). Dose could be increased by 5 mg BID (for optimization of dosing) after at least Week 4 (Month 1) for patients who met all of the following conditions: - Palpable spleen length below the costal margin that decreased by less than 40% at the Week 4 visit relative to Baseline. - Platelet count at the Week 4 blood draw was > 150,000/μL and platelet count had never been below 150,000/μL at a prior laboratory evaluation while receiving ruxolitinib. - ANC levels had remained at or above 1000/μL since enrollment in the study. Guidance was provided for decreasing, interruption or discontinuation of study drug.

Treatment

Full Analysis Set and Safety Set

The Full Analysis set (FAS) consisted of all patients who received at least one administration of study drug and had at least one post-Baseline efficacy assessment. The Safety set consisted of all patients who received at least one dose of study drug and had at least one post-Baseline safety assessment. The statement that a patient had no AEs constituted a safety assessment. Patients who had received at least one dose of study drug but who had no post-treatment safety data of any kind were be excluded from the safety population.

Oral INC424 at a dose of 15 or 20 mg twice daily

Full Analysis Set and Safety Set

The Full Analysis set (FAS) consisted of all patients who received at least one administration of study drug and had at least one post-Baseline efficacy assessment. The Safety set consisted of all patients who received at least one dose of study drug and had at least one post-Baseline safety assessment. The statement that a patient had no AEs constituted a safety assessment. Patients who had received at least one dose of study drug but who had no post-treatment safety data of any kind were be excluded from the safety population.

Treatment success was defined as a 50% or greater reduction in palpable spleen length versus baseline at 48 weeks and/or a 50% or greater improvement in total symptom score (derived from the MF symptom assessment form (MFSAF) questionnaire) versus baseline at the week 48 time point. The MFSAF assesses the following symptoms (all scored from absent (0) to worst imaginable (10)): general fatigue, abdominal pain (and discomfort), inactivity (ability to move and walk around), cough, night sweats, itching (pruritus), bone pain (diffuse not joint pain or arthritis), fever, change in appetite/unintentional weight loss (or gain) in past 6 months, overall quality of life (QoL). Full analysis set (FAS): The FAS included all participants who received at least one administration of study drug and had at least one post-baseline efficacy assessment.

Primary

Baseline versus 48 week end of treatment.

Response to treatment and disease progression was assessed by physical examination, specifically assessing changes in spleen size by palpation. Disease response and progression was evaluated using the International Working Group for myelofibrosis Research and Treatment Response Criteria. Only participants from the full analysis set (FAS), who had evaluable measurements at both baseline and the post-baseline week time point, was included in the analysis for that time point. The FAS included all participants who received at least one administration of study drug and had at least one post-baseline efficacy assessment.

Secondary

Week 48.

The MF-SAF consists of seven questions about key symptoms and impact of MF. Questions are scored on a scale of 0–10, with higher scores indicating more severe symptoms and greater inactivity. Questions 1–6, which together comprise a Total Symptom Score (TSS), investigate the following symptoms: night sweats, pruritus/itching, abdominal discomfort, pain under the ribs, early satiety and bone/muscle pain. Question 7 asks patients to report levels of inactivity. The TSS reflects the sum of the scores of these symptoms excluding inactivity, with the maximum possible score being 60 (most severe symptom experienced). Only participants from the full analysis set (FAS), who had evaluable measurements at both baseline and the post-baseline week time point, was included in the analysis for that time point. The FAS included all participants who received at least one administration of study drug and had at least one post-baseline efficacy assessment.

Secondary

Baseline, week 4, week 12, week 24, week 48

The EQ-5D is a standardized instrument used for measuring health outcomes in a wide range of health conditions and treatment. It consists of a descriptive system and a visual analogue scale (EQ-VAS). The descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The EQ-VAS records the participant's self-rated health on a vertical, VAS where the endpoints are labeled 'best imaginable health state' and 'worst imaginable health state'. The EQ-5D health state was converted to a single summary index by applying a formula that attaches a weight to each of the levels in each dimension. The final EQ5D preference index scores range from 0 to 1 with higher scores indicating better health. Only participants from the full analysis set (FAS), who had evaluable measurements at both baseline and the post-baseline week time point, was included in

Secondary

Baseline, week 4, week 12, week 24, week 48

Medical resource utilization (MRU) was assessed according to the number of hospitalizations. Only participants from the full analysis set (FAS), who had evaluable measurements at the post-baseline week time point, were included in the analysis for that time point. The FAS included all participants who received at least one administration of study drug and had at least one post-baseline efficacy assessment.

Secondary

week 12, week 24, week 26, week 48

MRU was assessed according to the mean duration of hospitalization visits. Participants from the full analysis set, who were hospitalized between baseline and week 48, were included in the analysis.

Secondary

Week 48

MRU was assessed according to the number of accidents and emergency room visits Only participants from the full analysis set (FAS), who had evaluable measurements at each timeframe, e.g. from baseline to week 12, were included in the analysis for that timeframe. The FAS included all participants who received at least one administration of study drug and had at least one post-baseline efficacy assessment.

Secondary

baseline to week 12, week 12 to week 24, week 24 to week 36, week 36 to week 48

Transfusion dependency status from baseline through the end of study was assessed. New onset of transfusion dependency was defined as the use of 2 or more units of red blood cell products during the 8 weeks prior to a study visit. New onset of transfusion independency was defined as the use of 0 or 1 unit of red blood cell products during the 8 weeks prior to a study visit. Full analysis set was used for analysis. Full analysis set (FAS): The FAS included all participants who received at least one administration of study drug and had at least one post-baseline efficacy assessment.

Secondary

Baseline (BL), end of treatment (up to 28 days post last treatment) (EOT)

MRU was assessed according to the number of GP, specialists', and urgent care visits. Only participants from the full analysis set (FAS), who had evaluable measurements at each timeframe, e.g. from baseline to week 12, were included in the analysis for that timeframe. The FAS included all participants who received at least one administration of study drug and had at least one post-baseline efficacy assessment.

Secondary

Baseline to week 12, week 12 to, week 24, week 24 to week 36, week 36 to week 48

Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

16.1

Ruxolitinib