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Phase 2, Randomized, Multi-Center, Double-Blind, Dose-Ranging, Placebo Controlled, Adaptive Design Study to Evaluate the Efficacy and Safety/Pharmacokinetics of BMS-986142 in Subjects With Moderate to Severe Rheumatoid Arthritis With an Inadequate Response to Methotrexate With or Without TNF Inhibitors

Efficacy and Safety Study of BMS-986142 in Patients With Moderate to Severe Rheumatoid Arthritis

247

BMS: BMS-986142 Baseline measures Number analyzed; Placebo:75, BMS 100mg:73, BMS 200mg:73, BMS 350mg:26, Total:247 Age (years), mean (SD); Placebo:58.6 (11.61), BMS 100mg:57.6 (13.01), BMS 200mg:55.2 (13.13), BMS 350mg:52.9 (13.16), Total:56.7 (12.72) Sex (%) Male; Placebo:11 (14.67), BMS 100mg:6 (8.22), BMS 200mg:11 (15.07), BMS 350mg:5 (19.23), Total:33 (13.36) Female; Placebo:64 (85.33), BMS 100mg:67 (91.78), BMS 200mg:62 (84.93), BMS 350mg:21 (80.77), Total:214 (86.64) Ethnicity (NIH/OMB) (%) Hispanic or Latino; Placebo:22 (29.33), BMS 100mg:24 (32.88), BMS 200mg:28 (38.36), BMS 350mg:10 (38.46), Total:84 (34.01) Not Hispanic or Latino; Placebo:27 (36), BMS 100mg:24 (32.88), BMS 200mg:25 (34.25), BMS 350mg:8 (30.77), Total:84 (34.01) Unknown or Not Reported; Placebo:26 (34.67), BMS 100mg:25 (34.25), BMS 200mg:20 (27.4), BMS 350mg:8 (30.77), Total:79 (31.98) Race/Ethnicity (%) White; Placebo:52 (69.33), BMS 100mg: 54 (73.97), BMS 200mg:58 (79.45), BMS 350mg:24 (92.31), Total:188 (76.11) Black or African American; Placebo:6 (8), BMS 100mg: 9 (12.33), BMS 200mg:5 (6.85), BMS 350mg:1 (3.85), Total:21 (8.5) Asian; Placebo:14 (18.67), BMS 100mg:8 (10.96), BMS 200mg:8 (10.96), BMS 350mg:1 (3.85), Total:31 (12.55) Other; Placebo:3 (4), BMS 100mg:2 (2.74), BMS 200mg:2 (2.74), BMS 350mg:0 (0), Total:7 (2.83)

Out of 508 participants who signed the informed consent form and were enrolled in the study; 248 participants were randomized, and 247 participants were administered study drug (1 participant did not take any double-blind study medication). Treated; Placebo: 75, BMS 100mg: 73, BMS 200mg: 73, BMS 350mg: 26 Completed; Placebo: 66, BMS 100mg: 62, BMS 200mg: 66, BMS 350mg: 18 Not Completed; Placebo: 9, BMS 100mg: 11, BMS 200mg: 7, BMS 350mg: 8 Reasons for not completed Withdrawal by Subject; Placebo: 4, BMS 100mg: 5, BMS 200mg: 3, BMS 350mg: 1 Administrative Reason by Sponsor; Placebo: 0, BMS 100mg: 1, BMS 200mg: 0, BMS 350mg: 4 Adverse Event; Placebo: 0, BMS 100mg: 0, BMS 200mg: 1, BMS 350mg: 1 Lack of Efficacy; Placebo: 1, BMS 100mg: 1, BMS 200mg: 0, BMS 350mg: 0 Lost to Follow up; Placebo: 0, BMS 100mg: 0, BMS 200mg: 1, BMS 350mg: 1 Poor/Non-Compliance; Placebo: 0, BMS 100mg: 2, BMS 200mg: 1, BMS 350mg: 0 Participant no longer met study criteria; Placebo: 0, BMS 100mg: 1, BMS 200mg: 0, BMS 350mg: 0 Other than specified above; Placebo: 4, BMS 100mg: 1, BMS 200mg: 1, BMS 350mg: 1

Total All-Cause Mortality; Placebo: 0/75 (0%), BMS 100mg: 0/73 (0%), BMS 200mg: 0/73 (0%), BMS 350mg: 0/26 (0%) Serious Adverse Events Total; Placebo: 4/75 (5.33%), BMS 100mg: 2/73 (2.74%), BMS 200mg: 0/73 (0%), BMS 350mg: 0/26 (0%) Cardiac disorders Angina pectoris A *; Placebo: 0/75 (0%), BMS 100mg: 1/73 (1.37%), BMS 200mg: 0/73 (0%), BMS 350mg: 0/26 (0%) Gastrointestinal disorders Intestinal obstruction A *; Placebo: 0/75 (0%), BMS 100mg: 1/73 (1.37%), BMS 200mg: 0/73 (0%), BMS 350mg: 0/26 (0%) Mouth ulceration A *; Placebo: 1/75 (1.33%), BMS 100mg: 0/73 (0%), BMS 200mg: 0/73 (0%), BMS 350mg: 0/26 (0%) Injury, poisoning and procedural complications Open globe injury A *; Placebo: 1/75 (1.33%), BMS 100mg: 0/73 (0%), BMS 200mg: 0/73 (0%), BMS 350mg: 0/26 (0%) Musculoskeletal and connective tissue disorders Rheumatoid arthritis A *; Placebo: 1/75 (1.33%), BMS 100mg: 0/73 (0%), BMS 200mg: 0/73 (0%), BMS 350mg: 0/26 (0%) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Endometrial adenocarcinoma A *; Placebo: 1/75 (1.33%), BMS 100mg: 0/73 (0%), BMS 200mg: 0/73 (0%), BMS 350mg: 0/26 (0%) Other Adverse Events Total; Placebo: 11/75 (14.67%), BMS 100mg: 12/73 (16.44%), BMS 200mg: 17/73 (23.29%), BMS 350mg: 14/26 (53.85%) Blood and lymphatic system disorders Anaemia A *; Placebo: 1/75 (1.33%), BMS 100mg: 1/73 (1.37%), BMS 200mg: 3/73 (4.11%), BMS 350mg: 2/26 (7.69%) Infections and infestations Nasopharyngitis A *; Placebo: 2/75 (2.67%), BMS 100mg: 4/73 (5.48%), BMS 200mg: 3/73 (4.11%), BMS 350mg: 0/26 (0%) Urinary tract infection A *; Placebo: 1/75 (1.33%), BMS 100mg: 5/73 (6.85%), BMS 200mg: 6/73 (8.22%), BMS 350mg: 5/26 (19.23%) Investigations Alanine aminotransferase increased A *; Placebo: 3/75 (4%), BMS 100mg: 0/73 (0%), BMS 200mg: 1/73 (1.37%), BMS 350mg: 5/26 (19.23%) Aspartate aminotransferase increased A *; Placebo: 2/75 (2.67%), BMS 100mg: 0/73 (0%), BMS 200mg: 1/73 (1.37%), BMS 350mg: 2/26 (7.69%) Blood alkaline phosphatase increased A *; Placebo: 0/75 (0%), BMS 100mg: 0/73 (0%), BMS 200mg: 0/73 (0%), BMS 350mg: 4/26 (15.38%) Metabolism and nutrition disorders Dyslipidaemia A *; Placebo: 2/75 (2.67%), BMS 100mg: 1/73 (1.37%), BMS 200mg: 3/73 (4.11%), BMS 350mg: 6/26 (23.08%) Nervous system disorders Headache A *; Placebo: 2/75 (2.67%), BMS 100mg: 2/73 (2.74%), BMS 200mg: 4/73 (5.48%), BMS 350mg: 2/26 (7.69%) *, events were collected by systematic assessment A, term from MedDRA 21.0

Primary outcome measures: Percentage of Paticipants Achieving American College of Rheumatology 20% (ACR20) and 70% (ACR70) Responses at Week 12 Paticipants Analyzed; Placebo:75, BMS 100mg:73, BMS 200mg:73, BMS 350mg:26 ACR20 (95%CI) Placebo: 30.7% (20.2 to 41.1), BMS 100mg: 35.6% (24.6 to 46.6), BMS 200mg: 42.5% (31.1 to 53.8), BMS 350mg: 30.8% (13.0 to 48.5) Difference from Placebo group BMS 100mg: 4.9% (-10.2 to 20.1), BMS 200mg: 11.8% (-3.6 to 27.2), BMS 350mg: 0.1% (-3.6 to 27.2) ACR70 (95%CI) Placebo: 4.0% (0.8 to 11.2), BMS 100mg: 4.1% (0.9 to 11.5), BMS 200mg: 9.6% (2.8 to 16.3), BMS 350mg: 3.8% (0.1 to 19.6) Difference from Placebo group BMS 100mg: 0.1% (-16 to 16.5), BMS 200mg: 5.6% (-10.5 to 21.9), BMS 350mg: -0.2% (-22.2 to 22.2)

3.Secondary outcome measure: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response Over Time From Baseline to Week 12 Participants Analyzed; Placebo: 75, BMS 100mg: 73, BMS 200mg: 73, BMS 350mg: 26 ACR20_Over time (95%CI); Baseline (Day 1) Placebo:0.0 (NA to NA), BMS 100mg: 0.0 (NA to NA), BMS 200mg: 0.0 (NA to NA), BMS 350mg: 0.0 (NA to NA) Day 15 Placebo:10.7 (3.7 to 17.7), BMS 100mg: 13.7 (5.8 to 21.6), BMS 200mg: 24.7 (14.8 to 34.5), BMS 350mg: 15.4 (4.4 to 34.9) Day 29 Placebo:18.7 (9.8 to 27.5), BMS 100mg: 23.3 (13.6 to 33.0), BMS 200mg: 21.9 (12.4 to 31.4), BMS 350mg: 26.9 (9.9 to 44.0) Day 57 Placebo:28.0 (17.8 to 38.2), BMS 100mg: 41.1 (29.8 to 52.4), BMS 200mg: 39.7 (28.5 to 51.0), BMS 350mg: 15.4 (4.4 to 34.9) Day 85 Placebo:30.7 (20.2 to 41.1), BMS 100mg: 35.6 (24.6 to 46.6), BMS 200mg: 42.5 (31.1 to 53.8), BMS 350mg: 30.8 (13.0 to 48.5) NA, not estimable 4.Secondary outcome measure: Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response Over Time From Baseline to Week 12 Participants Analyzed; Placebo: 75, BMS 100mg: 73, BMS 200mg: 73, BMS 350mg: 26 ACR50_Over time (95%CI); Baseline (Day 1) Placebo:0 (NA to NA), BMS 100mg: 0 (NA to NA), BMS 200mg: 0 (NA to NA), BMS 350mg: 0 (NA to NA) Day 15 Placebo:2.7 (0.3 to 9.3), BMS 100mg: 4.1 (0.9 to 11.5), BMS 200mg: 5.5 (1.5 to 13.4), BMS 350mg: 3.8 (0.1 to 19.6) Day 29 Placebo:2.7 (0.3 to 9.3), BMS 100mg: 4.1 (0.9 to 11.5), BMS 200mg: 6.8 (1.1 to 12.6), BMS 350mg: 7.7 (0.9 to 25.1) Day 57 Placebo:9.3 (2.7 to 15.9), BMS 100mg: 12.3 (4.8 to 19.9), BMS 200mg: 13.7 (5.8 to 21.6), BMS 350mg: 7.7 (0.9 to 25.1) Day 85 Placebo:9.3 (2.7 to 15.9), BMS 100mg: 13.7 (5.8 to 21.6), BMS 200mg: 16.4 (7.9 to 24.9), BMS 350mg: 11.5 (2.4 to 30.2) NA, not estimable 5.Secondary outcome measure: Percentage of Participants Achieving American College of Rheumatology 70% Response Over Time From Baseline to Week 12 Participants Analyzed; Placebo: 75, BMS 100mg: 73, BMS 200mg: 73, BMS 350mg: 26 ACR70_Over time (95%CI); Baseline (Day 1) Placebo: 0 (NA to NA), BMS 100mg: 0 (NA to NA), BMS 200mg: 0 (NA to NA), BMS 350mg: 0 (NA to NA) Day 15 Placebo:1.3 (0.0 to 7.2), BMS 100mg: 0.0 (0.0 to 4.9), BMS 200mg: 1.4 (0.0 to 7.4), BMS 350mg: 0.0 (0.0 to 13.2) Day 29 Placebo:0.0 (NA to NA), BMS 100mg: 0.0 (NA to NA), BMS 200mg: 0.0 (NA to NA), BMS 350mg: 0.0 (NA to NA) Day 57 Placebo:1.3 (0.0 to 7.2), BMS 100mg: 5.5 (1.5 to 13.4), BMS 200mg: 5.5 (1.5 to 13.4), BMS 350mg: 3.8 (0.1 to 19.6) Day 85 Placebo:4.0 (0.8 to 11.2), BMS 100mg: 4.1 (0.9 to 11.5), BMS 200mg: 9.6 (2.8 to 16.3), BMS 350mg: 3.8 (0.1 to 19.6) NA, not estimable 6.Secondary outcome measure: Percentage of Participants Achieving < 2.6 Response in Disease Activity Score for 28 Joints -C-Reactive Protein (DAS28--CRP) Score at Week 12 Participants Analyzed; Placebo: 75, BMS 100mg: 73, BMS 200mg: 73, BMS 350mg: 26 DAS28--CRP (95%CI); Placebo: 6.7 (1.0 to 12.3), BMS 100mg: 9.6 (2.8 to 16.3), BMS 200mg: 11.0 (3.8 to 18.1), BMS 350mg: 0.0 (0.0 to 13.2) 7.Secondary outcome measure: Percentage of Participants Achieving < 2.6 Response in Disease Activity Score for 28 Joints Erythrocyte Sedimentation Rate (DAS28--ESR) Score at Week 12 Participants Analyzed; Placebo: 75, BMS 100mg: 73, BMS 200mg: 73, BMS 350mg: 26 DAS28--ESR (95%CI); Placebo: 0.0 (0.0 to 4.8), BMS 100mg: 6.8 (1.1 to 12.6), BMS 200mg: 1.4 (0.0 to 7.4), BMS 350mg: 0.0 (0.0 to 13.2) 8.Secondary outcome measure: Percentage of Participants Achieving <= 2.8 Response in Clinical Disease Activity Index (CDAI) Score at Week 12 Participants Analyzed; Placebo: 75, BMS 100mg: 73, BMS 200mg: 73, BMS 350mg: 26 CDAI (95%CI); Placebo: 0.0 (0.0 to 4.8), BMS 100mg: 6.8 (1.1 to 12.6), BMS 200mg: 6.8 (1.1 to 12.6), BMS 350mg: 0.0 (0.0 to 13.2) 9.Secondary outcome measure: Percentage of Participants Achieving <= 3.3 Response in Simple Disease Activity Index (SDAI) Score at Week 12 Participants Analyzed; Placebo: 75, BMS 100mg: 73, BMS 200mg: 73, BMS 350mg: 26 SDAI (95%CI); Placebo: 0.0 (0.0 to 4.8), BMS 100mg: 6.8 (1.1 to 12.6), BMS 200mg: 6.8 (1.1 to 12.6), BMS 350mg: 0.0 (0.0 to 13.2) 10.Secondary outcome measure: Percentage of Participants Achieving Boolean Remission Criteria at Week 12 Participants Analyzed; Placebo: 75, BMS 100mg: 73, BMS 200mg: 73, BMS 350mg: 26 Boolean Remission Criteria (95%CI); Placebo: 1.3 (0.0 to 7.2), BMS 100mg: 4.1 (0.9 to 11.5), BMS 200mg: 4.1 (0.9 to 11.5), BMS 350mg: 0.0 (0.0 to 13.2) 11.Secondary outcome measure: Change From Baseline in DAS28-CRP Score Over Time up to Week 12 Participants Analyzed; Placebo: 64, BMS 100mg: 63, BMS 200mg: 64, BMS 350mg: 15 DAS28-CRP_Change (95%CI); Placebo: -1.1 (0.141), BMS 100mg: -1.1 (0.176), BMS 200mg: -1.4 (0.168), BMS 350mg: -1.4 (0.194) 12.Secondary outcome measure: Change From Baseline in DAS28-ESR Score Over Time up to Week 12 Participants Analyzed; Placebo: 64, BMS 100mg: 63, BMS 200mg: 65, BMS 350mg: 14 DAS28-ESR_Change, Mean (SE); Placebo: -1.1 (0.149), BMS 100mg: -1.1 (0.166), BMS 200mg: -1.4 (0.161), BMS 350mg: -1.5 (0.247) 13.Secondary outcome measure: Change From Baseline in CDAI Score Over Time up to Week 12 Participants Analyzed; Placebo: 65, BMS 100mg: 61, BMS 200mg: 68, BMS 350mg: 16 CDAI_Over Time, Mean (SE); Placebo: -14.9 (1.591), BMS 100mg: -13.6 (2.030), BMS 200mg: -16.0 (1.828), BMS 350mg: -17.6 (2.519) 14.Secondary outcome measure: Change From Baseline in SDAI Score Over Time up to Week 12 Participants Analyzed; Placebo: 64, BMS 100mg: 61, BMS 200mg: 64, BMS 350mg: 15 SDAI Score Over Time, Mean (SE); Placebo: -14.8 (1.628), BMS 100mg: -13.9 (2.090), BMS 200mg: -16.6 (1.954), BMS 350mg: -18.9 (3.218) 15.Secondary Outcome Measure: Number of Participants With Adverse Events (AEs), and Serious AEs (SAEs) Participants Analyzed; Placebo: 75, BMS 100mg: 73, BMS 200mg: 73, BMS 350mg: 26 Participants With Adverse Events (AEs) and Serious AEs (SAEs), Number (%); AEs; Placebo:36 (48), BMS 100mg: 39 (53.42), BMS 200mg: 39 (53.42), BMS 350mg: 19 (73.08) SAEs; Placebo:4 (5.33), BMS 100mg: 2 (2.74), BMS 200mg: 0 (0), BMS 350mg: 0 (0) 16.Secondary Outcome Measure: Trough Observed Plasma Concentration (Ctrough) of BMS-986142 Participants Analyzed; BMS 100mg: 73, BMS 200mg: 73, BMS 350mg: 26 Ctrough of BMS-986142, ng/mL, Geometric Mean (Geometric Coefficient of Variation); Week 4, Number Analyzed, BMS 100mg: 60 participants, BMS 200mg: 61 participants, BMS 350mg: 16 participants; BMS 100mg: 47.9 (119.0%), BMS 200mg: 111.8 (101.7%), BMS 350mg: 195.9 (91.9%) Week 8, Number Analyzed, BMS 100mg: 54 participants, BMS 200mg: 60 participants, BMS 350mg: 18 participants; BMS 100mg: 41.2 (95.3%), BMS 200mg: 92.2 (124.5%), BMS 350mg: 283.0 (133.3%) Week 12, Number Analyzed, BMS 100mg: 55 participants, BMS 200mg: 52 participants, BMS 350mg: 13 participants; BMS 100mg: 28.4 (123.0%), BMS 200mg: 75.6 (155.4%), BMS 350mg: 169.5 (83.2%)

BMS-986142 at all doses administered appeared to be safe in all the RA subjects. BMS-986142 100/200 mg doses administered tended to show higher response rates in ACR20/70 achievements than placebo group (not statistically significant). No deaths were reported. Of the 6 subjects with a SAE (Placebo, 4; 100mg, 2), none were assessed as drug related. BMS-986142 350 mg dose was discontinued due to elevations in ALT and AST, as well as due to a lack of benefit in efficacy compared to placebo.

No

Bristol-Myers Squibb K.K.

mg-jp-clinical_trial@bms.com

Bristol-Myers Squibb K.K.

mg-jp-clinical_trial@bms.com

completed

July. 28, 2016

Interventional

Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment

treatment purpose

2

Diagnosed with active rheumatoid arthritis (RA) by standard criteria at least 16 weeks before screening, have functional ACR class I-III
Have an inadequate response to methotrexate
In addition to an inadequate response to methotrexate have an inadequate response or intolerance to 1 but not more than 2 TNF inhibitors
Have a minimum of 6 swollen and 6 tender joints (from 66/68 joint count)
Have hsCRP of not less than 0.8 mg/dL (8mg/L) [by central laboratory values] or an ESR not less than 28 mm/hr
Willing to use effective birth control for the entire length of the study

Diagnosed with juvenile Rheumatoid Arthritis
Have been treated with other biologic treatment than a TNF inhibitor
Active systemic bacterial, viral or fungal infection or evidence of prior or current Hepatitis B or C infection or HIV infection, latent bacterial, viral or fungal infections
Have been treated with Intramuscular or Intra-articular glucocorticosteroids within 4 weeks of randomization
Taking Oral steroids at dose above 10 mg/day of prednisone (or prednisone equivalents)
Have other autoimmune disease other than RA like lupus, multiple sclerosis
Have significant concurrent medical condition at the time of screening or baseline visit

Both

Rheumatoid Arthritis

investigational material(s)
Generic name etc : BMS-986142
INN of investigational material : -
Therapeutic category code : 399 Agents affecting metabolism, n.e.c.
Dosage and Administration for Investigational material : BMS-986142 at dose level 1+ Methotrexate as specified. BMS-986142 at dose level 2 + Methotrexate as specified.

control material(s)
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : Placebo + Methotrexate dose as specified

efficacy
Proportion of subjects who achieve ACR70 response rate [ Time Frame: At week 12 ] [ Designated as safety issue: No ]
Proportion of subjects who achieve ACR20 response rate [ Time Frame: At week 12 ] [ Designated as safety issue: No

safety
efficacy
pharmacokinetics
Proportion of subjects who achieve ACR20 [ Time Frame: Baseline to week 12 ] [ Designated as safety issue: No ]
Proportion of subjects who achieve ACR50 [ Time Frame: Baseline to week 12 ] [ Designated as safety issue: No ]
Proportion of subjects who achieve ACR70 [ Time Frame: Baseline to week 12 ] [ Designated as safety issue: No ]
Proportion of subjects who achieve DAS28- C-reactive protein (CRP) less than 2.6 [ Time Frame: Baseline to week 12 ] [ Designated as safety issue: No ]
Proportion of subjects who achieve DAS28- erythrocyte sedimentation rate (ESR) less than 2.6 [ Time Frame: Baseline to week 12 ] [ Designated as safety issue: No ]
Proportion of subjects who achieve clinical disease activity index (CDAI) less than or equal to 2.8 [ Time Frame: Baseline to week 12 ] [ Designated as safety issue: No ]
Proportion of subjects who achieve simplified disease index (SDAI) less than or equal to 3.3 [ Time Frame: Baseline to week 12 ] [ Designated as safety issue: No ]
Proportion of subjects who achieve Boolean Remission [ Time Frame: Baseline to week 12 ] [ Designated as safety issue: No ]
Change from baseline in DAS28-CRP score [ Time Frame: Upto week 12 ] [ Designated as safety issue: No ]
Change from baseline in DAS28-ESR score [ Time Frame: Upto week 12 ] [ Designated as safety issue: No ]
Change from baseline in CDAI score [ Time Frame: Upto week 12 ] [ Designated as safety issue: No ]
Change from baseline in SDAI score [ Time Frame: Upto week 12 ] [ Designated as safety issue: No ]
Change from baseline in rheumatoid arthritis magnetic resonance imaging scoring system (RAMRIS) scores of synovitis [ Time Frame: Upto week 12 ] [ Designated as safety issue: No ]
Change from baseline in RAMRIS scores of osteitis (bone marrow edema) [ Time Frame: Upto week 12 ] [ Designated as safety issue: No ]
Change from baseline in RAMRIS scores of bone erosion [ Time Frame: Upto week 12 ] [ Designated as safety issue: No ]
Change from baseline in RAMRIS scores of cartilage loss (joint-space narrowing) [ Time Frame: Upto week 12 ] [ Designated as safety issue: No ]
Incidence of Adverse Events (AEs), Serious AEs, pre-established events of special Interest, vital signs, electrocardiogram (ECG), abnormalities in general laboratory tests [ Time Frame: Upto week 16 ] [ Designated as safety issue: Yes ]
Plasma concentration of BMS-986142 [ Time Frame: Upto week 12 ] [ Designated as safety issue: No ]

May. 09, 2016