Efficacy and Safety Study of Apremilast to Treat Active Psoriatic Arthritis (PsA) (PALACE4)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Celgene Corporation
ClinicalTrials.gov Identifier:
NCT01307423
First received: November 29, 2010
Last updated: December 13, 2013
Last verified: December 2013
  Purpose

The purpose of this study is to determine whether apremilast is safe and effective in the treatment of patients with psoriatic arthritis who have not been previously treated with DMARDs.

Apremilast is proposed to improve signs and symptoms of psoriatic arthritis (tender and swollen joints, pain, physical function) in treated patients.


Condition Intervention Phase
Psoriatic Arthritis
Drug: Apremilast 20mg
Drug: Apremilast 30mg
Drug: Placebo + 20mg Apremilast
Drug: Placebo + 30mg Apremilast
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy And Safety Study Of TWO DOSES OF Apremilast (CC-10004) In Subjects With Active Psoriatic Arthritis Who Have Not Been Previously Treated With Disease Modifying Anti-rheumatic Drugs

Resource links provided by NLM:


Further study details as provided by Celgene Corporation:

Primary Outcome Measures:
  • American College of Rheumatology criteria for 20% improvement (ACR 20) [ Time Frame: 0 to 16 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects in each treatment group who achieve the American College of Rheumatology criteria for a 20% improvement (ACR 20)


Secondary Outcome Measures:
  • Adverse Events [ Time Frame: up to 5 years ] [ Designated as safety issue: Yes ]
    type, frequency , severity and relationship to Apremilast

  • Physical Function [ Time Frame: Change from baseline at 16 weeks ] [ Designated as safety issue: No ]
    Change from baseline in physical function (Health Assessment Questionnaire-Disability Index (HAQ-DI)

  • ACR 20 [ Time Frame: Change from baseline after 24 weeks ] [ Designated as safety issue: No ]
    Proportion of subjects who achieve the ACR 20, compared with baseline, after 24 weeks of treatment

  • Physical Function HAQ-DI [ Time Frame: Change from baseline at 24 weeks ] [ Designated as safety issue: No ]
    Change from baseline in the physical function (HAQ-DI)

  • Physical Function [ Time Frame: Change from baseline at 16 weeks ] [ Designated as safety issue: No ]
    Change from baseline in the physical function domain score of the Medical Outcome Study Short Form 36 - Item Health Survey, version 2

  • Psoriatic Arthritis Response Criteria [ Time Frame: after 16 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects who achieve the modified Psoriatic Arthritis Response Criteria (PsARC)

  • Pain Assessment [ Time Frame: change from baseline to 16 weeks ] [ Designated as safety issue: No ]
    Change from baseline in subject's assessment of pain using the Visual Analog Scale (VAS)

  • Maastricht Ankylosing Spondylitits Entheses Score [ Time Frame: change from baseline to 16 weeks ] [ Designated as safety issue: No ]
    Change from baseline in the Maastricht Ankylosing Spondylitis Entheses Score (MASES) in subjects with pre-existing enthesopathy

  • Dactylitis [ Time Frame: Change from baseline to 16 weeks ] [ Designated as safety issue: No ]
    Change from baseline in the dactylitis severity score in subjects with pre-existing datylitis

  • Clinical Disease Activity Index [ Time Frame: change from baseline to 16 weeks ] [ Designated as safety issue: No ]
    Change from baseline in the Clinical Disease Activity Index (CDAI) after 16 weeks of treatment

  • Disease Activity Score [ Time Frame: change from baseline to 16 weeks ] [ Designated as safety issue: No ]
    Change in baseline in the Disease Activity Score (DAS28) after 16 weeks of treatment

  • Functional Assessment of Chronic Illness Therapy - Fatigue [ Time Frame: change from baseline to 16 weeks ] [ Designated as safety issue: No ]
    Change from baseline in the Functional Assessment nof Chronic Illness Therapy - Fatigue (FACIT-Fatigue) score

  • Physical Function [ Time Frame: change from baseline to 24 weeks ] [ Designated as safety issue: No ]
    Change from baseline in the physical function domain score of the SF-36

  • Psoriatic Arthritis Response Criteria [ Time Frame: after 24 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects who achieve the modified Psoriatic Arthritis Response Criteria (PsARC)

  • Pain Assessment [ Time Frame: change from baseline to 24 weeks ] [ Designated as safety issue: No ]
    Change from baseline in subject's assessment of pain using the Visual Analog Scale

  • Maastricht Ankylosing Spondylitits Entheses Score [ Time Frame: change from baseline to 24 weeks ] [ Designated as safety issue: No ]
    Change from baseline in the Maastricht Ankylosing Spondylitis Entheses Score (MASES) in subjects with pre-existing enthesopathy

  • Dactylitis [ Time Frame: Change from baseline to 24 weeks ] [ Designated as safety issue: No ]
    Change from baseline in the Dactylitis severity score in subjects with pre-existing Dactylitis

  • Clinical Disease Activity Index [ Time Frame: change from baseline to 24 weeks ] [ Designated as safety issue: No ]
    Change from baseline in the Clinical disease Activity Index (CDAI) after 16 weeks of treatment

  • Disease Activity Score [ Time Frame: change from baseline to 24 weeks ] [ Designated as safety issue: No ]
    Change in baseline in the Disease Activity Score (DAS28) after 16 weeks of treatment

  • Functional Assessment of Chronic Illness Therapy- Fatigue [ Time Frame: Change from baseline to 24 weeks ] [ Designated as safety issue: No ]
    Change from baseline in the Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-Fatigue) score

  • Maastricht Ankylosing Spondylitits Entheses Score [ Time Frame: after 16 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects with pre-existing enthesopathy whose Maastricht Ankylosing Spondylitis Entheses Score improves by > or equal to 20 %

  • Dactylitis [ Time Frame: after 16 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects with pre-existing dactylitis whose dactylitis severity score improves by > or = to 1

  • European League Against Rheumatism (EULAR) response [ Time Frame: after 16 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects with good or moderate European League Against Rheumatism (EULAR) response

  • Maastricht Ankylosing Spondylitits Entheses Score [ Time Frame: after 24 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects with pre-existing enthesopathy whose Maastricht Ankylosing Spondylitis Entheses Score improves by > or equal to 20 %

  • Dactylitis [ Time Frame: after 24 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects with pre-existing dactylitis whose dactylitis severity score improves by > or = to 1

  • European League Against Rheumatism (EULAR) response [ Time Frame: after 24 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects with good or moderate European League Against Rheumatism (EULAR) response

  • ACR 50 [ Time Frame: after 16 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects who achieve an ACR 50

  • ACR 70 [ Time Frame: after 16 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects who achieve an ACR 70

  • ACR 50 [ Time Frame: after 25 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects who achieve an ACR 50

  • ACR 70 [ Time Frame: after 24 weeks of treatment ] [ Designated as safety issue: No ]
    proportion of subjects who achieve an ACR 70

  • Maastricht Ankylosing Spondylitits Entheses Score [ Time Frame: after 16 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects with pre-existing enthesopathy whose Maastricht Ankylosing Spondylitis Entheses Score improves to 0

  • Dactylitis [ Time Frame: after 16 weeks of treatment ] [ Designated as safety issue: No ]
    Proprotion of subjects with pre-existing Dactylitis whose Dactylitis severity score improves to 0

  • Maastricht Ankylosing Spondylitits Entheses Score [ Time Frame: after 24 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects with pre-existing enthesopathy whose Maastricht Ankylosing Spondylitits Entheses Score improves to 0

  • Dactylitis [ Time Frame: after 24 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects with pre-existing Dactylitis whose Dactylitis severity score improves to 0

  • ACR 20 [ Time Frame: Change from baseline after 52 weeks ] [ Designated as safety issue: No ]
    Proportion of subjects who achieve the ACR 20, compared with baseline

  • Physical Function [ Time Frame: change from baseline at 52 weeks ] [ Designated as safety issue: No ]
    Change from baseline in the physical function (HAQ-DI)

  • Physical Function [ Time Frame: Change from baseline at 52 weeks ] [ Designated as safety issue: No ]
    Change from baseline in the physical function domain score of the Medical Outcome Study Short Form 36- Item Health Survey, Version 2

  • Psoriatic Arthritis Response Criteria [ Time Frame: after 52 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects who achieve the modified Psoriatic Arthritis Response Criteria (PsARC)

  • Pain Assessment [ Time Frame: change from baseline to 52 weeks ] [ Designated as safety issue: No ]
    Change from baseline in subject's assessment of pain using the Visual Analog Scale

  • Maastricht Ankylosing Spondylitits Entheses Score [ Time Frame: change from baseline to 52 weeks ] [ Designated as safety issue: No ]
    Change from baseline in the Maastricht Ankylosing Spondylitis Entheses Score (MASES) in subjects with pre-existing enthesopathy

  • Dactylitis [ Time Frame: change from baseline to 52 weeks ] [ Designated as safety issue: No ]
    Change from baseline in the Dactylitis severity score in subjects with pre-existing Dactylitis

  • Clinical Disease Activity Index [ Time Frame: change from baseline to 52 weeks ] [ Designated as safety issue: No ]
    Change from baseline in the Clinical disease Activity Index (CDAI) after 16 weeks of treatment

  • Disease Activity Score [ Time Frame: change from baseline to 52 weeks ] [ Designated as safety issue: No ]
    Change in baseline in the Disease Activity Score (DAS28) after 16 weeks of treatment

  • Functional Assessment of Chronic Illness Therapy- Fatigue [ Time Frame: Change from baseline to 52 weeks ] [ Designated as safety issue: No ]
    Change from baseline in the Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-Fatigue) score

  • Maastricht Ankylosing Spondylitits Entheses Score [ Time Frame: after 52 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects with pre-existing enthesopathy whose Maastricht Ankylosing Spondylitits Entheses Score improveds by > or = to 20%

  • Dactylitis [ Time Frame: after 52 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects with pre-existing datylitis whos dactylitis severity score improves by > or = to 1

  • European League Against Rheumatism (EULAR) response [ Time Frame: after 52 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects with good or moderate European League Against Rheumatism (EULAR) response

  • ACR 50 [ Time Frame: after 52 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects who achieve an ACR 50 Safety Issue: No

  • ACR 70 [ Time Frame: after 52 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects who achieve an ACR 70

  • Maastricht Ankylosing Spondylitits Entheses Score [ Time Frame: after 52 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects with pre-existing enthesopathy whose Maastricht Ankylosing Spondylitits Entheses Score improves to 0

  • Dactylitis [ Time Frame: after 52 weeks of treatment ] [ Designated as safety issue: No ]
    Proportion of subjects with pre-existing dactylitis whose dactylitis severity score improves to 0

  • Work Limitations [ Time Frame: after 16, 24 or 52 weeks of treatment ] [ Designated as safety issue: No ]
    Change in the Work Limitations Questionnaire-25 (WLQ-25) score in each treatment group

  • Medical Outcomes Study [ Time Frame: after 16, 24 or 52 weeks' treatment ] [ Designated as safety issue: No ]
    Change in the Medical Outcomes Study (MOS) Sleep score in each treatment group

  • EuroQol 5 Dimensions [ Time Frame: after 16, 24 or 52 weeks' treatment ] [ Designated as safety issue: No ]
    Change in the EuroQual-5 Dimensions (EQ-5D) score in each treatment group

  • Health related quality of life [ Time Frame: after 2, 3, 4 or 5 years' treatment ] [ Designated as safety issue: No ]
    Change in the Work Limitations Questionnaire-25 score , Medical Outcomes Study Sleep Score and the EuroQol-5 Dimensions score in each treatment group


Enrollment: 529
Study Start Date: November 2010
Estimated Study Completion Date: July 2017
Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Apremilast 20mg
Apremilast 20mg twice daily, orally
Drug: Apremilast 20mg
Apremilast 20mg twice daily, orally
Other Name: CC-10004
Experimental: Apremilast 30mg
Apremilast 30mg twice daily, orally
Drug: Apremilast 30mg
Apremilast 30mg twice daily, orally
Other Name: CC-10004
Placebo Comparator: Placebo + 20mg Apremilast
Placebo + 20mg Apremilast tablets administered twice daily
Drug: Placebo + 20mg Apremilast
Placebo + 20mg Apremilast
Other Names:
  • Placebo
  • CC-10004
Placebo Comparator: Placebo + 30mg Apremilast
Placebo + 30mg Apremilast tablets administered twice daily
Drug: Placebo + 30mg Apremilast
Placebo + 30 mg Apremilast
Other Names:
  • Placebo
  • CC-10004

Detailed Description:

Psoriatic arthritis (PsA) is an inflammatory arthritis that occurs in 6-39% of psoriasis patients. The immunopathogenesis of PsA, which mirrors but is not identical to that seen in psoriatic plaques, reflects a complex interaction among resident dendritic, fibroblastic and endothelial cells, and inflammatory cells attracted to the synovium by cytokines and chemokines. Apremilast (CC-10004) is a novel oral agent that modulates multiple inflammatory pathways through targeted phosphodiesterase type 4 (PDE4) enzyme inhibition. Therefore, apremilast has the potential to be effective in the treatment of PsA.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study:

  1. Male or female, aged ≥ 18 years at time of consent.
  2. Must understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted.
  3. Able to adhere to the study visit schedule and other protocol requirements.
  4. Have a documented diagnosis of Psoriatic Arthritis (PsA, by any criteria) of ≥ 3 months duration.
  5. Meet the Classification Criteria for Psoriatic Arthritis (CASPAR) criteria for PsA at time of screening.
  6. Have ≥ 3 swollen AND ≥ 3 tender joints.
  7. Have not been previously treated with disease-modifying antirheumatic drugs (DMARDS) (small molecules or biologics)
  8. Be receiving treatment on an outpatient basis.
  9. If taking oral corticosteroids, must be on a stable dose of prednisone ≤ 10 mg/day or equivalent for at least 1 month prior to screening.
  10. If taking nonsteroidal anti-inflammatory drugs (NSAIDs) or narcotic analgesics, must be on stable dose for at least 2 weeks prior to screening and until they have completed the Week 24 study visit.
  11. Low potency topical corticosteroids (Appendix M or locally available equivalent) will be allowed as background therapy for treatment of psoriasis on the face, axillae and groin in accordance with the manufacturers' suggested usage during the course of the study. Subjects with scalp psoriasis will be permitted to use coal tar shampoo and/or salicylic acid scalp preparations on scalp lesions. A non-medicated skin emollient (eg, Eucerin cream) will also be permitted for body lesions only. Subjects must not use these treatments within 24 hours prior to the clinic visit.
  12. Meet the following laboratory criteria:

    • White blood cell count ≥ 3000/mm3 (≥ 3.0 x 109/L) and < 14,000/mm3 (< 14 x 109/L)
    • Platelet count ≥ 100,000/mm3 (≥ 100 x 109/L)
    • Serum creatinine ≤ 1.5 mg/dL(≤ 132.6 μmol/L)
    • Aspartate aminotransferase/Serum glutamic oxaloacetic transaminase (AST/SGOT) and Alanine aminotransferase/Serum glutamic pyruvic transaminase (ALT/SGPT) ≤ 2 x upper limit of normal (ULN)
    • Total bilirubin ≤ 2 mg/dL (≤ 34 μmol/L)
    • Hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L)
    • Hemoglobin A1c ≤ 9.0%
  13. Male subjects (including those who have had a vasectomy) who engage in activity in which conception is possible must use barrier contraception (latex condom or any nonlatex condom NOT made out of natural [animal] membrane [eg, polyurethane]) while on IP and for at least 28 days after the last dose of IP.
  14. Females of childbearing potential (FCBP) must have a negative pregnancy test at Screening and Baseline. FCBP who engage in activity in which conception is possible must use 2 forms of contraception while on investigational product (IP) and for at least 28 days after the last dose of IP: one highly effective form (ie, hormonal, intrauterine device [IUD], tubal ligation, vasectomized partner) and one additional form (latex condom or any nonlatex condom NOT made out of natural [animal] membrane [eg, polyurethane], diaphragm, sponge). If one highly effective form of contraception cannot be used, then 2 forms of barrier contraception must be used, ie, latex condom or any nonlatex condom NOT made out of natural (animal) membrane (eg, polyurethane) with either of the following: sponge with spermicide or diaphragm with spermicide.

Exclusion Criteria:

  1. History of clinically significant (as determined by the Investigator) cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic disease, or other major uncontrolled disease.
  2. Any condition, including the presence of laboratory abnormalities that places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
  3. Clinically significant abnormality on 12-lead electrocardiography (ECG) at Screening.
  4. Pregnant or breast feeding.
  5. History of allergy to any component of the IP.
  6. Hepatitis B surface antigen positive at screening.
  7. Hepatitis C antibody positive at screening.
  8. AST/SGOT and/or ALT/SGPT > 1.5 x ULN and total bilirubin > ULN or albumin < lower limit of normal (LLN).
  9. History of positive Human Immunodeficiency Virus (HIV), or congenital or acquired immunodeficiency (eg, Common Variable Immunodeficiency Disease).
  10. Active tuberculosis or a history of incompletely treated tuberculosis.
  11. Clinically significant abnormality based upon chest radiograph with at least PA view (radiograph must be taken within 12 weeks prior to Screening or during the Screening visit). An additional lateral view is strongly recommended but not required.
  12. Active substance abuse or a history of substance abuse within 6 months prior to Screening.
  13. Bacterial infections requiring treatment with oral or injectable antibiotics, or significant viral or fungal infections, within 4 weeks of Screening. Any treatment for such infections must have been completed at least 4 weeks prior to Screening.
  14. Malignancy or history of malignancy (except for treated [ie, cured] basal cell or squamous cell in situ skin carcinomas and treated [ie, cured] cervical intraepithelial neoplasia [CIN] or carcinoma in situ of the cervix).
  15. Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.
  16. Erythrodermic, guttate, or pustular psoriasis.
  17. Topical therapy for psoriasis, except as noted in the Inclusion Criteria, within 2 weeks of randomization (including but not limited to topical corticosteroids, topical retinoids or vitamin D analog preparations, tacrolimus, pimecrolimus, or anthralin).
  18. Rheumatic autoimmune disease other than PsA, including systemic lupus erythematosis (SLE), mixed connective tissue disease (MCTD), scleroderma, or polymyositis.
  19. Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis (Appendix Q).
  20. Prior history of or current inflammatory joint disease other than PsA (eg, gout, reactive arthritis, RA, ankylosing spondylitis, Lyme disease).
  21. Prior use of disease modifying antirheumatic drugs (DMARDS; small molecules or biologics).
  22. Use of the following systemic therapy(ies) within 4 weeks of randomization, including but not limited to corticosteroids (except as noted in inclusion criteria), oral retinoids and fumaric acid esters.
  23. Use of phototherapy within 4 weeks of randomization (ie, UVB, PUVA).
  24. Previous treatment with any cell depleting therapies, including investigational agents (eg, rituximab, CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, and anti-CD20).
  25. Treatment with intravenous gamma globulin, plasmapheresis, or Prosorba® column within 6 months of baseline.
  26. Any previous treatment with alkylating agents such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation.
  27. Prior treatment with apremilast.
  28. Use of any investigational drug within 4 weeks of randomization, or 5 pharmacokinetic/ pharmacodynamic half lives, if known (whichever is longer).
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01307423

  Show 162 Study Locations
Sponsors and Collaborators
Celgene Corporation
Investigators
Study Director: Douglas Hough, MD Celgene Corporation
  More Information

No publications provided

Responsible Party: Celgene Corporation
ClinicalTrials.gov Identifier: NCT01307423     History of Changes
Other Study ID Numbers: CC-10004-PSA-005, 2010-020324-22
Study First Received: November 29, 2010
Last Updated: December 13, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board
Canada: Health Canada
Australia: National Health and Medical Research Council
Belgium: Federal Agency for Medicinal Products and Health Products
Bulgaria: Ministry of Health
Czech Republic: Ethics Committee
Estonia: Ravimiamet State Agency of Medicines
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Hungary: Research Ethics Medical Committee
Italy: National Monitoring Centre for Clinical Trials - Ministry of Health
Lithuania: State Medicines Control Agency under the Ministry of Health of the Republic of Lithuania
New Zealand: Ministry of Health
Poland: Ministry of Health
Romania: Ministry of Public Health
Russia: Ministry of Health of the Russian Federation
South Korea: Korea Food and Drug Administration (KFDA)
Taiwan: Department of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Celgene Corporation:
psoriasis
Arthritis
Psoriatic Arthritis
inflammation
skin condition
inflammatory cells
apremilast
CC-10004
phosphodiesterase type 4

Additional relevant MeSH terms:
Arthritis
Arthritis, Psoriatic
Joint Diseases
Musculoskeletal Diseases
Spondylarthropathies
Spondylarthritis
Spondylitis
Spinal Diseases
Bone Diseases
Psoriasis
Skin Diseases, Papulosquamous
Skin Diseases
Antirheumatic Agents
Thalidomide
Therapeutic Uses
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Leprostatic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents

ClinicalTrials.gov processed this record on April 17, 2014