Relevance of Monitoring Blood and Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases

NCT03122431 | Completed Phase 4 Results

• 1 other identifier: HPLC-Rheumatic diseases
• Study Type: interventional
• Target: 93
• Locations: 1 country
• Sites: 1

Brief Summary

No drug treatment is completely free of risk and lack of response, adverse events and poor adherence may affect its effectiveness. Within this context, this project aims to evaluate the importance of monitoring blood levels and salivary drug used in rheumatic autoimmune diseases in the monitoring of adherence to therapy. In addition, this project intends to use the monitoring of drug levels, based on pharmacokinetic studies and pharmacokinetics/pharmacodynamics modeling, to broaden the understanding of the possible cellular, tissue and immunological mechanisms involved in efficacy and adverse effects of these drugs with the prospect of reducing the damage and maintain therapeutic efficacy. The high-performance liquid chromatography (HPLC) coupled to mass spectrometry, which will be used to evaluate hydroxychloroquine, thalidomide, glucocorticoids, is considered the gold standard technology to qualitative and quantitative analysis of drugs in blood and its comparison with the dosage in the saliva is an improvement in simplification of the process. For biological agents the focus will be on the understanding the loss of efficacy and the possible role of anti-TNF antibodies using ELISA capture methodology.This project will be divided into four sections with their respective sub-projects according to the medications that will be studied: hydroxychloroquine, thalidomide, biologic agents and glucocorticoids.

Conditions

Systemic Lupus Erythematosus (SLE); Juvenile SLE; Cutaneous Lupus

Outcome Measures

Primary Outcomes (2)

• Serum Levels of Thalidomide

  Serum levels of thalidomide by liquid chromatography and tandem mass spectrometry (HPLC-MS/MS)

  12 months

• Serum Levels of Hydroxycloroquine

  Serum levels of hydroxycloroquine by LCMS

  12 months

Study Arms (3)

SLE/cutaneous lupus with thalidomide

OTHER

This subproject includes only one arm of lupus patients with active and refractory cutaneous disease and eligible for Thalidomide 100mg/day for 12 months.

Drug: Thalidomide

Inactive SLE with standard dose of HCQ

ACTIVE COMPARATOR

This subproject includes one arm of lupus patients with inactive disease, in which will be maintained on standard dose of Hydroxychloroquine (400mg/day).

Drug: standard dose of HCQ

Inactive SLE with reduced dose of HCQ

ACTIVE COMPARATOR

This subproject includes one arm of lupus patients with inactive disease: in which the dose will be reduced to 400mg 3 times a week (Hydroxychloroquine reduced).

Drug: Hydroxychloroquine reduced

Interventions

Thalidomide DRUG

Thalidomide 100 mg/day

Also known as: Thalidomide 100 mg

SLE/cutaneous lupus with thalidomide

Hydroxychloroquine reduced DRUG

Hydroxychloroquine 2.5 mg/kg/day

Also known as: HCQ reduced

Inactive SLE with reduced dose of HCQ

standard dose of HCQ DRUG

Hydroxychloroquine 5.0 mg/kg/day

Also known as: HCQ standard

Inactive SLE with standard dose of HCQ

Eligibility Criteria

• Age: 5 Years - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• SLE diagnosis according to 1997 ACR criteria
• Active and refractory cutaneous lupus lesions
• Male gender (using contraceptive barrier method) or confirmed infertility for female gender
• Normal electroneuromyography at study entry

You may not qualify if:

• Alcoholism
• History of peripheral neuropathy
• Previous history of thrombophilia or positive antiphospholipid antibodies
• Renal and/or central nervous system and/or hematological activity
• HCQ reduced subproject:
• SLE diagnosis according to 1997 ACR criteria
• Use of hydroxychloroquine (5 to 6.5mg/kg/day) for ≥5 years
• SLEDAI-2K \<4
• Alcoholism
• Renal dialysis
• Concomitant infectious process
• Acute and chronic liver diseases
• Concomitant use of some drugs that interact with HCQ (cimetidine, antacids, digoxin, aminoglycosides, penicillamine, neostigmine, pyridostigmine)
• Signs of Retinopathy
• HCQ high subproject:

Sponsors & Collaborators

• University of Sao Paulo General Hospital: lead
• Fundação de Amparo à Pesquisa do Estado de São Paulo: collaborator

Study Sites (1)

Hospital das Clinicas da Faculdade de Medicina da USP

São Paulo, 05403-000, Brazil

Location

Related Publications (20)

• Albrecht J, Taylor L, Berlin JA, Dulay S, Ang G, Fakharzadeh S, Kantor J, Kim E, Militello G, McGinnis K, Richardson S, Treat J, Vittorio C, Van Voorhees A, Werth VP. The CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index): an outcome instrument for cutaneous lupus erythematosus. J Invest Dermatol. 2005 Nov;125(5):889-94. doi: 10.1111/j.0022-202X.2005.23889.x.

  PMID: 16297185 BACKGROUND

• Bai N, Cui XY, Wang J, Sun CG, Mei HK, Liang BB, Cai Y, Song XJ, Gu JK, Wang R. Determination of thalidomide concentration in human plasma by liquid chromatography-tandem mass spectrometry. Exp Ther Med. 2013 Feb;5(2):626-630. doi: 10.3892/etm.2012.847. Epub 2012 Nov 30.

  PMID: 23404219 BACKGROUND

• Bernstein HN. Ocular safety of hydroxychloroquine. Ann Ophthalmol. 1991 Aug;23(8):292-6.

  PMID: 1952638 BACKGROUND

• Briani C, Zara G, Rondinone R, Della Libera S, Ermani M, Ruggero S, Ghirardello A, Zampieri S, Doria A. Thalidomide neurotoxicity: prospective study in patients with lupus erythematosus. Neurology. 2004 Jun 22;62(12):2288-90. doi: 10.1212/01.wnl.0000130499.91775.2c.

  PMID: 15210897 BACKGROUND

• Coelho A, Souto MI, Cardoso CR, Salgado DR, Schmal TR, Waddington Cruz M, de Souza Papi JA. Long-term thalidomide use in refractory cutaneous lesions of lupus erythematosus: a 65 series of Brazilian patients. Lupus. 2005;14(6):434-9. doi: 10.1191/0961203305lu2124oa.

  PMID: 16038106 BACKGROUND

• Costedoat-Chalumeau N, Amoura Z, Hulot JS, Hammoud HA, Aymard G, Cacoub P, Frances C, Wechsler B, Huong du LT, Ghillani P, Musset L, Lechat P, Piette JC. Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus. Arthritis Rheum. 2006 Oct;54(10):3284-90. doi: 10.1002/art.22156.

  PMID: 17009263 BACKGROUND

• Costedoat-Chalumeau N, Pouchot J, Guettrot-Imbert G, Le Guern V, Leroux G, Marra D, Morel N, Piette JC. Adherence to treatment in systemic lupus erythematosus patients. Best Pract Res Clin Rheumatol. 2013 Jun;27(3):329-40. doi: 10.1016/j.berh.2013.07.001.

  PMID: 24238690 BACKGROUND

• Costedoat-Chalumeau N, Dunogue B, Morel N, Le Guern V, Guettrot-Imbert G. Hydroxychloroquine: a multifaceted treatment in lupus. Presse Med. 2014 Jun;43(6 Pt 2):e167-80. doi: 10.1016/j.lpm.2014.03.007. Epub 2014 May 19.

  PMID: 24855048 BACKGROUND

• Cuadrado MJ, Karim Y, Sanna G, Smith E, Khamashta MA, Hughes GR. Thalidomide for the treatment of resistant cutaneous lupus: efficacy and safety of different therapeutic regimens. Am J Med. 2005 Mar;118(3):246-50. doi: 10.1016/j.amjmed.2004.04.030.

  PMID: 15745722 BACKGROUND

• Frances C, Cosnes A, Duhaut P, Zahr N, Soutou B, Ingen-Housz-Oro S, Bessis D, Chevrant-Breton J, Cordel N, Lipsker D, Costedoat-Chalumeau N. Low blood concentration of hydroxychloroquine in patients with refractory cutaneous lupus erythematosus: a French multicenter prospective study. Arch Dermatol. 2012 Apr;148(4):479-84. doi: 10.1001/archdermatol.2011.2558.

  PMID: 22508872 BACKGROUND

• Giannini F, Volpi N, Rossi S, Passero S, Fimiani M, Cerase A. Thalidomide-induced neuropathy: a ganglionopathy? Neurology. 2003 Mar 11;60(5):877-8. doi: 10.1212/01.wnl.0000049462.03800.b1. No abstract available.

  PMID: 12629253 BACKGROUND

• Gladman DD, Ibanez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002 Feb;29(2):288-91.

  PMID: 11838846 BACKGROUND

• Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997 Sep;40(9):1725. doi: 10.1002/art.1780400928. No abstract available.

  PMID: 9324032 BACKGROUND

• Jallouli M, Galicier L, Zahr N, Aumaitre O, Frances C, Le Guern V, Liote F, Smail A, Limal N, Perard L, Desmurs-Clavel H, Le Thi Huong D, Asli B, Kahn JE, Pourrat J, Sailler L, Ackermann F, Papo T, Sacre K, Fain O, Stirnemann J, Cacoub P, Leroux G, Cohen-Bittan J, Sellam J, Mariette X, Blanchet B, Hulot JS, Amoura Z, Piette JC, Costedoat-Chalumeau N; Plaquenil Lupus Systemic Study Group. Determinants of hydroxychloroquine blood concentration variations in systemic lupus erythematosus. Arthritis Rheumatol. 2015 May;67(8):2176-84. doi: 10.1002/art.39194.

  PMID: 25989906 BACKGROUND

• Knop J, Bonsmann G, Happle R, Ludolph A, Matz DR, Mifsud EJ, Macher E. Thalidomide in the treatment of sixty cases of chronic discoid lupus erythematosus. Br J Dermatol. 1983 Apr;108(4):461-6. doi: 10.1111/j.1365-2133.1983.tb04600.x.

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• Kyriakis KP, Kontochristopoulos GJ, Panteleos DN. Experience with low-dose thalidomide therapy in chronic discoid lupus erythematosus. Int J Dermatol. 2000 Mar;39(3):218-22. doi: 10.1046/j.1365-4362.2000.00953.x.

  PMID: 10759967 BACKGROUND

• Michaelides M, Stover NB, Francis PJ, Weleber RG. Retinal toxicity associated with hydroxychloroquine and chloroquine: risk factors, screening, and progression despite cessation of therapy. Arch Ophthalmol. 2011 Jan;129(1):30-9. doi: 10.1001/archophthalmol.2010.321.

  PMID: 21220626 BACKGROUND

• Morita S, Takahashi T, Yoshida Y, Yokota N. Population Pharmacokinetics of Hydroxychloroquine in Japanese Patients With Cutaneous or Systemic Lupus Erythematosus. Ther Drug Monit. 2016 Apr;38(2):259-67. doi: 10.1097/FTD.0000000000000261.

  PMID: 26587870 BACKGROUND

• Tsakonas E, Joseph L, Esdaile JM, Choquette D, Senecal JL, Cividino A, Danoff D, Osterland CK, Yeadon C, Smith CD. A long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group. Lupus. 1998;7(2):80-5. doi: 10.1191/096120398678919778.

  PMID: 9541091 BACKGROUND

• Zanetti CB, Pedrosa T, Kupa LVK, Aikawa NE, Borba EF, Vendramini MBG, Silva CA, Pasoto SG, Bonfa E. Hydroxychloroquine blood levels in stable lupus nephritis under low dose (2-3 mg/kg/day): 12-month prospective randomized controlled trial. Clin Rheumatol. 2021 Jul;40(7):2745-2751. doi: 10.1007/s10067-021-05600-2. Epub 2021 Jan 24.

  PMID: 33486596 DERIVED

MeSH Terms

Conditions

Lupus Erythematosus, Systemic

Interventions

Thalidomide; Hydroxychloroquine

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Chloroquine; Aminoquinolines; Quinolines

Results Point of Contact

• Title: Prof Eloisa Bonfa
• Organization: Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo

eloisa.bonfa@hc.fm.usp.br

551130617490

Study Officials

• Eloisa Bonfa, MD, PhD

  University of Sao Paulo

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This study includes 3 subprojects that will assess serum drug levels for efficacy and toxicity. In the first two subprojects, hydroxychloroquine will be studied in SLE population. In the third subproject, thalidomide and SLE and cutaneous lupus will be studied.

Study Record Dates

• First Submitted: April 17, 2017
• First Posted: April 20, 2017
• Study Start: June 5, 2017
• Primary Completion: December 30, 2020
• Study Completion: March 30, 2021
• Last Updated: December 16, 2021
• Results First Posted: December 16, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will not share

Locations

BR (1)