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

NCT ID: NCT03122431

Last Updated: 2021-12-16

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

93 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-06-05

Study Completion Date

2021-03-30

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Systemic Lupus Erythematosus (SLE) Juvenile SLE Cutaneous Lupus

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

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.
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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SLE/cutaneous lupus with thalidomide

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

Group Type OTHER

Thalidomide

Intervention Type DRUG

Thalidomide 100 mg/day

Inactive SLE with standard dose of HCQ

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

Group Type ACTIVE_COMPARATOR

standard dose of HCQ

Intervention Type DRUG

Hydroxychloroquine 5.0 mg/kg/day

Inactive SLE with reduced dose of HCQ

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).

Group Type ACTIVE_COMPARATOR

Hydroxychloroquine reduced

Intervention Type DRUG

Hydroxychloroquine 2.5 mg/kg/day

Interventions

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Thalidomide

Thalidomide 100 mg/day

Intervention Type DRUG

Hydroxychloroquine reduced

Hydroxychloroquine 2.5 mg/kg/day

Intervention Type DRUG

standard dose of HCQ

Hydroxychloroquine 5.0 mg/kg/day

Intervention Type DRUG

Other Intervention Names

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Thalidomide 100 mg HCQ reduced HCQ standard

Eligibility Criteria

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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


* SLE diagnosis according to 1997 ACR criteria
* Use of hydroxychloroquine (5 to 6.5mg/kg/day) for ≥5 years
* SLEDAI-2K \<4


* SLE diagnosis according to 1997 ACR criteria
* No use of hydroxychloroquine for ≥ 6 months
* LES/LESJ in activity (SLEDAI≥6)

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:


* 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:


* 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
Minimum Eligible Age

5 Years

Maximum Eligible Age

64 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Fundação de Amparo à Pesquisa do Estado de São Paulo

OTHER_GOV

Sponsor Role collaborator

University of Sao Paulo General Hospital

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Eloisa Bonfa, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Sao Paulo

Locations

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Hospital das Clinicas da Faculdade de Medicina da USP

São Paulo, , Brazil

Site Status

Countries

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Brazil

References

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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.

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PMID: 16038106 (View on PubMed)

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.

Reference Type BACKGROUND
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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.

Reference Type BACKGROUND
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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.

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Reference Type BACKGROUND
PMID: 15745722 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 22508872 (View on PubMed)

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

Reference Type BACKGROUND
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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.

Reference Type BACKGROUND
PMID: 9324032 (View on PubMed)

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Reference Type BACKGROUND
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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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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.

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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.

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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.

Reference Type DERIVED
PMID: 33486596 (View on PubMed)

Provided Documents

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Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

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HPLC-Rheumatic diseases

Identifier Type: -

Identifier Source: org_study_id