Molecular Effects of Apremilast in the Synovium of Psoriatic Arthritis Patients

NCT04645420 | Completed

• 4 other identifiers: P1200_46AP-CL-PSA-PI-131462019-003887-392020/24AOU/424
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

This study assess the genomics profiles in synovial biopsies obtained prior to, and 24 weeks after an immunomodulator agent (Apremilast) in patients with active psoriatic arthritis who are naive to treatment with a conventional synthetic DMARDs (such as methotrexate).

Conditions

Psoriatic Arthritis

Keywords

Biologics; Apremilast; Synovium; Genomics; Psoriatic disease

Outcome Measures

Primary Outcomes (1)

• Quantitative measurement of the molecular changes in relation to the up-regulated or down-regulated genes in the synovium.

  The primary endpoint of the study is not the efficacy of the drug, but the molecular changes it induce in the synovium. In a first set of analyses, the magnitude of fold-changes in global gene expression profiles between baseline and W24 will be analysed. The higher values correspond to the high intensity in the up-regulation or down-regulation of the gene expression.

  24 weeks

Secondary Outcomes (3)

• Comparison between the magnitude of molecular changes (up-regulation or down-regulation of the genes) and clinical changes (improvement or worsening of the swollen joints count).

  24 weeks

• Comparison between the magnitude of molecular changes (up-regulation or down-regulation of the genes) and imaging changes on Grey Scale ultrasound (GSUS).

  24 weeks

• Comparison between the magnitude of molecular changes (up-regulation or down-regulation of the genes) and imaging changes on Power Doppler ultrasound (PDUS).

  24 weeks

Study Arms (1)

Apremilast

EXPERIMENTAL

15 PsA patients with active disease and naïve to conventional synthetic and biologic disease modifying anti-rheumatic drugs. Treatment with apremilast orally in the whole group (n = 15). Escalating dose the first Week (10 mg once day1, 10 mg bid day2, 10 mg-20 mg day3, 20 mg bid day4, 20 mg-30 mg day5, 30 mg bid on day6), and 30 mg bid from day7 until week24.

Procedure: Global gene expression profiles obtained from synovial biopsies.

Interventions

Global gene expression profiles obtained from synovial biopsies. PROCEDURE

Global gene expression profiles obtained from synovial biopsies before and after 24 weeks of treatment with the drug in each patient.

Also known as: No other intervention

Apremilast

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients who meet ALL the following criteria can be enrolled:
• Patient must be able to understand and communicate with the investigator and comply with the requirements of the study and must give a written, signed and dated informed consent before any study assessment is performed.
• Male or non-pregnant, non-nursing female patients at least 18 years of age.
• With a diagnosis of active PsA according to CASPAR criteria
• Naïve to csDMARD and bDMARD,
• At least 1 swollen joint at screening or baseline (despite NSAIDs therapy) with ability to perform a synovial biopsy at W0.
• Concomitant oral steroids (no more than 10 mg/day of prednisolone), NSAIDs, or painkillers is permitted if started prior to the study and remain at a stable dose at least 4 weeks before the baseline.
• Allowed concomitant medications are to remain stable through week 24.
• At least one joint (small or large) to biopsy in order to get synovial tissue. Small joints must have an US scoring \> 2 on grey-scale score/power Doppler.

You may not qualify if:

• Contraindications for needle-arthroscopy.
• Patients with hypersensitivity to apremilast or to one of its excipients
• Prior csDMARD or bDMARD therapy,
• Women who are pregnant, breastfeeding or planning on becoming pregnant for the 24 weeks of the drug administration,
• Non-menopausal women who are not using an adequate contraception method,
• Patients with conditions/concomitant diseases making them non evaluable for the primary endpoint
• Impossibility to meet specific protocol requirements (e.g. blood sampling)
• Patient is the Investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol
• Uncooperative or any condition that could make the patient potentially noncompliant to the study procedures
• Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks before baseline.
• Any intramuscular corticosteroid injection within 4 weeks before baseline.
• A history of active tuberculosis (TB).

Sponsors & Collaborators

• Cliniques universitaires Saint-Luc- Université Catholique de Louvain: lead
• Amgen: collaborator

Study Sites (1)

Adrien NZEUSSEU TOUKAP

Brussels, 1200, Belgium

Location

Related Publications (23)

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• Wong K, Gladman DD, Husted J, Long JA, Farewell VT. Mortality studies in psoriatic arthritis: results from a single outpatient clinic. I. Causes and risk of death. Arthritis Rheum. 1997 Oct;40(10):1868-72. doi: 10.1002/art.1780401021.

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  PMID: 19493586 BACKGROUND

• Schett G, Sloan VS, Stevens RM, Schafer P. Apremilast: a novel PDE4 inhibitor in the treatment of autoimmune and inflammatory diseases. Ther Adv Musculoskelet Dis. 2010 Oct;2(5):271-8. doi: 10.1177/1759720X10381432.

  PMID: 22870453 BACKGROUND

• Busa S, Kavanaugh A. Drug safety evaluation of apremilast for treating psoriatic arthritis. Expert Opin Drug Saf. 2015 Jun;14(6):979-85. doi: 10.1517/14740338.2015.1031743. Epub 2015 Mar 31.

  PMID: 25827658 BACKGROUND

• Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol. 2012 Jun 15;83(12):1583-90. doi: 10.1016/j.bcp.2012.01.001. Epub 2012 Jan 10.

  PMID: 22257911 BACKGROUND

• Gooderham M, Papp K. Selective Phosphodiesterase Inhibitors for Psoriasis: Focus on Apremilast. BioDrugs. 2015 Oct;29(5):327-39. doi: 10.1007/s40259-015-0144-3.

  PMID: 26481941 BACKGROUND

• Schafer PH, Truzzi F, Parton A, Wu L, Kosek J, Zhang LH, Horan G, Saltari A, Quadri M, Lotti R, Marconi A, Pincelli C. Phosphodiesterase 4 in inflammatory diseases: Effects of apremilast in psoriatic blood and in dermal myofibroblasts through the PDE4/CD271 complex. Cell Signal. 2016 Jul;28(7):753-63. doi: 10.1016/j.cellsig.2016.01.007. Epub 2016 Jan 22.

  PMID: 26806620 BACKGROUND

• Edwards CJ, Blanco FJ, Crowley J, Birbara CA, Jaworski J, Aelion J, Stevens RM, Vessey A, Zhan X, Bird P. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3). Ann Rheum Dis. 2016 Jun;75(6):1065-73. doi: 10.1136/annrheumdis-2015-207963. Epub 2016 Jan 20.

  PMID: 26792812 BACKGROUND

• Papp K, Reich K, Leonardi CL, Kircik L, Chimenti S, Langley RG, Hu C, Stevens RM, Day RM, Gordon KB, Korman NJ, Griffiths CE. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol. 2015 Jul;73(1):37-49. doi: 10.1016/j.jaad.2015.03.049.

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• Paul C, Cather J, Gooderham M, Poulin Y, Mrowietz U, Ferrandiz C, Crowley J, Hu C, Stevens RM, Shah K, Day RM, Girolomoni G, Gottlieb AB. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2). Br J Dermatol. 2015 Dec;173(6):1387-99. doi: 10.1111/bjd.14164. Epub 2015 Nov 7.

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• Ritchlin CT, Colbert RA, Gladman DD. Psoriatic Arthritis. N Engl J Med. 2017 Mar 9;376(10):957-970. doi: 10.1056/NEJMra1505557. No abstract available.

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• Nzeusseu Toukap A, Galant C, Theate I, Maudoux AL, Lories RJ, Houssiau FA, Lauwerys BR. Identification of distinct gene expression profiles in the synovium of patients with systemic lupus erythematosus. Arthritis Rheum. 2007 May;56(5):1579-88. doi: 10.1002/art.22578.

  PMID: 17469140 BACKGROUND

• Lauwerys BR, Hernandez-Lobato D, Gramme P, Ducreux J, Dessy A, Focant I, Ambroise J, Bearzatto B, Nzeusseu Toukap A, Van den Eynde BJ, Elewaut D, Gala JL, Durez P, Houssiau FA, Helleputte T, Dupont P. Heterogeneity of synovial molecular patterns in patients with arthritis. PLoS One. 2015 Apr 30;10(4):e0122104. doi: 10.1371/journal.pone.0122104. eCollection 2015.

  PMID: 25927832 BACKGROUND

• De Groof A, Ducreux J, Humby F, Nzeusseu Toukap A, Badot V, Pitzalis C, Houssiau FA, Durez P, Lauwerys BR. Higher expression of TNFalpha-induced genes in the synovium of patients with early rheumatoid arthritis correlates with disease activity, and predicts absence of response to first line therapy. Arthritis Res Ther. 2016 Jan 20;18:19. doi: 10.1186/s13075-016-0919-z.

  PMID: 26792343 BACKGROUND

• Badot V, Galant C, Nzeusseu Toukap A, Theate I, Maudoux AL, Van den Eynde BJ, Durez P, Houssiau FA, Lauwerys BR. Gene expression profiling in the synovium identifies a predictive signature of absence of response to adalimumab therapy in rheumatoid arthritis. Arthritis Res Ther. 2009;11(2):R57. doi: 10.1186/ar2678. Epub 2009 Apr 23.

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• Badot V, Durez P, Van den Eynde BJ, Nzeusseu-Toukap A, Houssiau FA, Lauwerys BR. Rheumatoid arthritis synovial fibroblasts produce a soluble form of the interleukin-7 receptor in response to pro-inflammatory cytokines. J Cell Mol Med. 2011 Nov;15(11):2335-42. doi: 10.1111/j.1582-4934.2010.01228.x.

  PMID: 21129157 BACKGROUND

• Gutierrez-Roelens I, Galant C, Theate I, Lories RJ, Durez P, Nzeusseu-Toukap A, Van den Eynde B, Houssiau FA, Lauwerys BR. Rituximab treatment induces the expression of genes involved in healing processes in the rheumatoid arthritis synovium. Arthritis Rheum. 2011 May;63(5):1246-54. doi: 10.1002/art.30292.

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• Ducreux J, Durez P, Galant C, Nzeusseu Toukap A, Van den Eynde B, Houssiau FA, Lauwerys BR. Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23. doi: 10.1002/art.38202.

  PMID: 24449571 BACKGROUND

Related Links

• Federal Agency for Medicines and Health Products (famhp/afmps/fagg). Otezla (apremilast): nouvelles recommandations importantes concernant les idées et comportements suicidaires.
• Otezla (apremilast): Nieuw belangrijk advies met betrekking tot suïcidale ideatie en suïcidaal gedrag (28 oktober 2016).

MeSH Terms

Conditions

Arthritis, Psoriatic

Condition Hierarchy (Ancestors)

Spondylarthropathies; Spondylarthritis; Spondylitis; Spinal Diseases; Bone Diseases; Musculoskeletal Diseases; Arthritis; Joint Diseases; Psoriasis; Skin Diseases, Papulosquamous; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Adrien NZEUSSEU TOUKAP, MD

  Cliniques universitaires Saint-Luc- Université Catholique de Louvain

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Open Label

Study Record Dates

• First Submitted: October 30, 2020
• First Posted: November 27, 2020
• Study Start: November 12, 2020
• Primary Completion: January 10, 2023
• Study Completion: February 10, 2023
• Last Updated: September 21, 2023

Record last verified: 2023-09

Locations

BE (1)