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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT03122431
Other study ID # HPLC-Rheumatic diseases
Secondary ID
Status Completed
Phase Phase 4
First received
Last updated
Start date June 5, 2017
Est. completion date March 30, 2021

Study information

Verified date May 2021
Source University of Sao Paulo General Hospital
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


Description:

No drug treatment is completely free of risk and lack of response, adverse events and poor adherence may affect its effectiveness. There is also a large inter-individual variability in response to treatments with regard to efficacy and toxicity, and for many drugs, there is also a period of weeks to months to establish its efficacy. 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. The implementation of this methodology dedicated to research in our center, with the necessary training of human resources, will enable the standardization and availability of this advanced technology to other muldisciplinary projects in various areas of science. 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 thematic 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.


Recruitment information / eligibility

Status Completed
Enrollment 93
Est. completion date March 30, 2021
Est. primary completion date December 30, 2020
Accepts healthy volunteers No
Gender All
Age group 5 Years to 64 Years
Eligibility Thalidomide subproject: Inclusion Criteria: - 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 Exclusion Criteria: - 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: Inclusion Criteria: - SLE diagnosis according to 1997 ACR criteria - Use of hydroxychloroquine (5 to 6.5mg/kg/day) for =5 years - SLEDAI-2K <4 Exclusion Criteria: - 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: Inclusion Criteria: - SLE diagnosis according to 1997 ACR criteria - No use of hydroxychloroquine for = 6 months - LES/LESJ in activity (SLEDAI=6) Exclusion Criteria: - 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

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Thalidomide
Thalidomide 100 mg/day
Hydroxychloroquine reduced
Hydroxychloroquine 2.5 mg/kg/day
standard dose of HCQ
Hydroxychloroquine 5.0 mg/kg/day

Locations

Country Name City State
Brazil Hospital das Clinicas da Faculdade de Medicina da USP São Paulo

Sponsors (2)

Lead Sponsor Collaborator
University of Sao Paulo General Hospital Fundação de Amparo à Pesquisa do Estado de São Paulo

Country where clinical trial is conducted

Brazil, 

References & Publications (19)

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. — View Citation

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. Epub 2012 Nov 30. — View Citation

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

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. — View Citation

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. — View Citation

Costedoat-Chalumeau N, Amoura Z, Hulot JS, Hammoud HA, Aymard G, Cacoub P, Francès 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. — View Citation

Costedoat-Chalumeau N, Dunogué 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. Review. — View Citation

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. Review. — View Citation

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. — View Citation

Francès 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. — View Citation

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. — View Citation

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

Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997 Sep;40(9):1725. — View Citation

Jallouli M, Galicier L, Zahr N, Aumaître O, Francès C, Le Guern V, Lioté 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, Sacré 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Tsakonas E, Joseph L, Esdaile JM, Choquette D, Senécal 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. — View Citation

* Note: There are 19 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary Serum Levels of Thalidomide Serum levels of thalidomide by liquid chromatography and tandem mass spectrometry (HPLC-MS/MS) 12 months
Primary Serum Levels of Hydroxycloroquine Serum levels of hydroxycloroquine by LCMS 12 months
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