Pain Modulation in Rheumatoid Arthritis (RA) - Influence of Adalimumab

NCT01197144 | Completed

• 2 other identifiers: MR201001142009-017163-42
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this study is to obtain increased knowledge concerning central pain and fatigue processing in rheumatoid arthritis, and how these conditions are influenced by treatment with Tumor Necrosis Factor (TNF) blockade with adalimumab.

Conditions

Arthritis, Rheumatoid; Pain; Fatigue

Keywords

TNF; functional Magnetic Resonance Imaging; Autonomic; Vagus; adalimumab

Outcome Measures

Primary Outcomes (1)

• Pain processing as measured by Blood Oxygen Level Dependent (BOLD) patterns in functional Magnetic Resonance Imaging (fMRI) of the brain

  The main purpose of the study is to investigate effects of treatment/placebo on central nervous pain processing, measured with fMRI.

  4 weeks

Secondary Outcomes (1)

• Fatigue Visual Analogue Scale (VAS)

  4 weeks

Study Arms (3)

Adalimumab

ACTIVE COMPARATOR

Treatment with adalimumab 40 mg sc eow for 4 weeks

Drug: adalimumab

Placebo

PLACEBO COMPARATOR

Treatment with placebo s c eow for 4 weeks

Drug: Placebo

Healthy Controls

NO INTERVENTION

Healthy volunteers, age ≥18. Will perform all the same pain assessments, blood sampling and baseline fMRI as RA patients Exclusion criteria: For fMRI - left handedness and all forms of metallic implants. * Fulfilling ACR criteria for fibromyalgia. * Severe ischemic heart disease. * Concurrent treatment for depression/anxiety with antidepressant drugs. * Concurrent neurological disease. * Other reason as evaluated by the P.I.

Interventions

adalimumab DRUG

Subcutaneous, 40 mg every other week for 4 weeks

Also known as: ATC code L04AB04, CAS 331731-18-1

Adalimumab

Placebo DRUG

Subcutaneous, every other week for 4 weeks

Also known as: Placebo, no other name

Placebo

Eligibility Criteria

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

You may qualify if:

• Age ≥18
• Fulfilling American College of Rheumatology (ACR) criteria for RA.
• Disease duration ≤ 5 years.
• Either under treatment with methotrexate (in a maximum tolerable up to 20 mg/week orally or subcutaneously), or previous treatment with methotrexate withdrawn due to documented side effects.
• Patients should be bio-naïve.
• Disease activity: Disease Activity Score (DAS28)\>3.2 and Swollen joint count (SJC)\>1 and Tender Joint Count (TJC)\>1.

You may not qualify if:

• For fMRI - left handedness and all forms of metallic implants.
• Fulfilling ACR criteria for fibromyalgia.
• Severe ischemic heart disease.
• Concurrent treatment for depression/anxiety with antidepressant drugs.
• Contraindication to adalimumab.
• Active or latent tuberculosis.
• Chronic infections including hepatitis B or C.
• Malignancy, multiple sclerosis, Systemic lupus erythematosus.
• Other reason as evaluated by the PI.

Sponsors & Collaborators

• Karolinska Institutet: lead
• Abbott: collaborator
• Swedish Foundation for Strategic Research: collaborator
• The Swedish Research Council: collaborator

Study Sites (2)

Dep of Rheumatology

Stockholm, SE-171 76, Sweden

Location

MR Centre, Dep of Clinical Neuroscience

Stockholm, SE-171 76, Sweden

Location

Related Publications (24)

• Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, Fischkoff SA, Chartash EK. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 2004 May;50(5):1400-11. doi: 10.1002/art.20217.

  PMID: 15146409 BACKGROUND

• Weinblatt ME, Keystone EC, Furst DE, Kavanaugh AF, Chartash EK, Segurado OG. Long term efficacy and safety of adalimumab plus methotrexate in patients with rheumatoid arthritis: ARMADA 4 year extended study. Ann Rheum Dis. 2006 Jun;65(6):753-9. doi: 10.1136/ard.2005.044404. Epub 2005 Nov 24.

  PMID: 16308341 BACKGROUND

• Yount S, Sorensen MV, Cella D, Sengupta N, Grober J, Chartash EK. Adalimumab plus methotrexate or standard therapy is more effective than methotrexate or standard therapies alone in the treatment of fatigue in patients with active, inadequately treated rheumatoid arthritis. Clin Exp Rheumatol. 2007 Nov-Dec;25(6):838-46.

  PMID: 18173917 BACKGROUND

• Thompson PW, Carr AJ. Pain in the rheumatic diseases. Ann Rheum Dis. 1997 Jun;56(6):395. doi: 10.1136/ard.56.6.395. No abstract available.

  PMID: 9227173 BACKGROUND

• Neumann L, Buskila D. Epidemiology of fibromyalgia. Curr Pain Headache Rep. 2003 Oct;7(5):362-8. doi: 10.1007/s11916-003-0035-z.

  PMID: 12946289 BACKGROUND

• Leffler AS, Kosek E, Lerndal T, Nordmark B, Hansson P. Somatosensory perception and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from rheumatoid arthritis. Eur J Pain. 2002;6(2):161-76. doi: 10.1053/eujp.2001.0313.

  PMID: 11900476 BACKGROUND

• Evrengul H, Dursunoglu D, Cobankara V, Polat B, Seleci D, Kabukcu S, Kaftan A, Semiz E, Kilic M. Heart rate variability in patients with rheumatoid arthritis. Rheumatol Int. 2004 Jul;24(4):198-202. doi: 10.1007/s00296-003-0357-5. Epub 2003 Sep 11.

  PMID: 14523570 BACKGROUND

• Goldstein RS, Bruchfeld A, Yang L, Qureshi AR, Gallowitsch-Puerta M, Patel NB, Huston BJ, Chavan S, Rosas-Ballina M, Gregersen PK, Czura CJ, Sloan RP, Sama AE, Tracey KJ. Cholinergic anti-inflammatory pathway activity and High Mobility Group Box-1 (HMGB1) serum levels in patients with rheumatoid arthritis. Mol Med. 2007 Mar-Apr;13(3-4):210-5. doi: 10.2119/2006-00108.Goldstein.

  PMID: 17597834 BACKGROUND

• Cohen H, Neumann L, Kotler M, Buskila D. Autonomic nervous system derangement in fibromyalgia syndrome and related disorders. Isr Med Assoc J. 2001 Oct;3(10):755-60.

  PMID: 11692551 BACKGROUND

• Tracey KJ. The inflammatory reflex. Nature. 2002 Dec 19-26;420(6917):853-9. doi: 10.1038/nature01321.

  PMID: 12490958 BACKGROUND

• Uceyler N, Valenza R, Stock M, Schedel R, Sprotte G, Sommer C. Reduced levels of antiinflammatory cytokines in patients with chronic widespread pain. Arthritis Rheum. 2006 Aug;54(8):2656-64. doi: 10.1002/art.22026.

  PMID: 16871547 BACKGROUND

• Salemi S, Rethage J, Wollina U, Michel BA, Gay RE, Gay S, Sprott H. Detection of interleukin 1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha in skin of patients with fibromyalgia. J Rheumatol. 2003 Jan;30(1):146-50.

  PMID: 12508404 BACKGROUND

• Bazzichi L, Rossi A, Massimetti G, Giannaccini G, Giuliano T, De Feo F, Ciapparelli A, Dell'Osso L, Bombardieri S. Cytokine patterns in fibromyalgia and their correlation with clinical manifestations. Clin Exp Rheumatol. 2007 Mar-Apr;25(2):225-30.

  PMID: 17543146 BACKGROUND

• Watkins LR, Maier SF. Immune regulation of central nervous system functions: from sickness responses to pathological pain. J Intern Med. 2005 Feb;257(2):139-55. doi: 10.1111/j.1365-2796.2004.01443.x.

  PMID: 15656873 BACKGROUND

• Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci. 2009 Jan;10(1):23-36. doi: 10.1038/nrn2533.

  PMID: 19096368 BACKGROUND

• Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, Beattie MS, Malenka RC. Control of synaptic strength by glial TNFalpha. Science. 2002 Mar 22;295(5563):2282-5. doi: 10.1126/science.1067859.

  PMID: 11910117 BACKGROUND

• Johnston IN, Milligan ED, Wieseler-Frank J, Frank MG, Zapata V, Campisi J, Langer S, Martin D, Green P, Fleshner M, Leinwand L, Maier SF, Watkins LR. A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J Neurosci. 2004 Aug 18;24(33):7353-65. doi: 10.1523/JNEUROSCI.1850-04.2004.

  PMID: 15317861 BACKGROUND

• Inglis JJ, Notley CA, Essex D, Wilson AW, Feldmann M, Anand P, Williams R. Collagen-induced arthritis as a model of hyperalgesia: functional and cellular analysis of the analgesic actions of tumor necrosis factor blockade. Arthritis Rheum. 2007 Dec;56(12):4015-23. doi: 10.1002/art.23063.

  PMID: 18050216 BACKGROUND

• Baliki MN, Chialvo DR, Geha PY, Levy RM, Harden RN, Parrish TB, Apkarian AV. Chronic pain and the emotional brain: specific brain activity associated with spontaneous fluctuations of intensity of chronic back pain. J Neurosci. 2006 Nov 22;26(47):12165-73. doi: 10.1523/JNEUROSCI.3576-06.2006.

  PMID: 17122041 BACKGROUND

• Kulkarni B, Bentley DE, Elliott R, Julyan PJ, Boger E, Watson A, Boyle Y, El-Deredy W, Jones AK. Arthritic pain is processed in brain areas concerned with emotions and fear. Arthritis Rheum. 2007 Apr;56(4):1345-54. doi: 10.1002/art.22460.

  PMID: 17393440 BACKGROUND

• Schweinhardt P, Kalk N, Wartolowska K, Chessell I, Wordsworth P, Tracey I. Investigation into the neural correlates of emotional augmentation of clinical pain. Neuroimage. 2008 Apr 1;40(2):759-766. doi: 10.1016/j.neuroimage.2007.12.016. Epub 2007 Dec 23. Erratum In: Neuroimage. 2011 May 1;56(1):384.

  PMID: 18221890 BACKGROUND

• Ochsner KN, Ludlow DH, Knierim K, Hanelin J, Ramachandran T, Glover GC, Mackey SC. Neural correlates of individual differences in pain-related fear and anxiety. Pain. 2006 Jan;120(1-2):69-77. doi: 10.1016/j.pain.2005.10.014. Epub 2005 Dec 20.

  PMID: 16364548 BACKGROUND

• Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain. 2005 Aug;9(4):463-84. doi: 10.1016/j.ejpain.2004.11.001. Epub 2005 Jan 21.

  PMID: 15979027 BACKGROUND

• Sandstrom A, Ellerbrock I, Lofgren M, Altawil R, Bileviciute-Ljungar I, Lampa J, Kosek E. Distinct aberrations in cerebral pain processing differentiating patients with fibromyalgia from patients with rheumatoid arthritis. Pain. 2022 Mar 1;163(3):538-547. doi: 10.1097/j.pain.0000000000002387.

  PMID: 34224497 DERIVED

MeSH Terms

Conditions

Arthritis, Rheumatoid; Pain; Fatigue

Interventions

Adalimumab

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Lars Klareskog, Professor

  Karolinska Institutet

  STUDY CHAIR

• Jon Lampa, MD, PhD

  Karolinska Institutet

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD, Associate Professor

Study Record Dates

• First Submitted: September 3, 2010
• First Posted: September 9, 2010
• Study Start: October 1, 2010
• Primary Completion: November 28, 2016
• Study Completion: November 28, 2016
• Last Updated: October 22, 2020

Record last verified: 2020-10

Locations

SE (2)