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| Name | Class |
|---|---|
| Fundação de Amparo à Pesquisa do Estado de São Paulo | OTHER_GOV |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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). |
|
| 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). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Thalidomide | Drug | Thalidomide 100 mg/day |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
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Thalidomide subproject:
Inclusion Criteria:
Exclusion Criteria:
HCQ reduced subproject:
Inclusion Criteria:
Exclusion Criteria:
HCQ high subproject:
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Eloisa Bonfa, MD, PhD | University of Sao Paulo | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hospital das Clinicas da Faculdade de Medicina da USP | São Paulo | 05403-000 | Brazil |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 16297185 | Background | 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. | |
| 23404219 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Inactive SLE With Standard Dose of HCQ | Lupus nephritis patients on stable inactive disease for at least 6 months prescribed full 2016-AAO dose of HCQ (4-5.5 mg/kg/day, real body weight). |
| FG001 | Inactive SLE With Reduced Dose of HCQ |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 1, 2017 |
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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.
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| Hydroxychloroquine reduced | Drug | Hydroxychloroquine 2.5 mg/kg/day |
|
|
| standard dose of HCQ | Drug | Hydroxychloroquine 5.0 mg/kg/day |
|
|
| 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. |
| 1952638 | Background | Bernstein HN. Ocular safety of hydroxychloroquine. Ann Ophthalmol. 1991 Aug;23(8):292-6. |
| 15210897 | 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. |
| 16038106 | 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. |
| 17009263 | 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. |
| 24238690 | 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. |
| 24855048 | 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. |
| 15745722 | 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. |
| 22508872 | 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. |
| 12629253 | 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. |
| 11838846 | Background | Gladman DD, Ibanez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002 Feb;29(2):288-91. |
| 9324032 | 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. |
| 25989906 | 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. |
| 6838771 | 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. |
| 10759967 | Background | 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. |
| 21220626 | 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. |
| 26587870 | 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. |
| 9541091 | 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. |
| 33486596 | Derived | 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. |
Lupus nephritis patients on stable inactive disease for at least 6 months prescribed reduced 2016-AAO dose of HCQ (2-3.0 mg/kg/day, real body weight) |
| FG002 | SLE/Cutaneous Lupus With Thalidomide | Adult patients with CLE (biopsy proven)/SLE (American College of Rheumatology classification criteria, 1997) treated with thalidomide. Inclusion criteria:
7) normal serum vitamin B12 levels; 8) negative tests for hepatitis B/C and HIV; 9) negative antiphospholipid antibodies. Exclusion criteria:
|
| COMPLETED |
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| NOT COMPLETED |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Inactive SLE With Standard Dose of HCQ | Lupus nephritis patients on stable inactive disease for at least 6 months prescribed full 2016-AAO dose of HCQ (4-5.5 mg/kg/day, real body weight). |
| BG001 | Inactive SLE With Reduced Dose of HCQ | Lupus nephritis patients on stable inactive disease for at least 6 months prescribed reduced 2016-AAO dose of HCQ (2-3.0 mg/kg/day, real body weight). |
| BG002 | 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. |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median | Standard Deviation | years |
| ||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| |||||||||||
| Race/Ethnicity, Customized | Count of Participants | Participants |
| |||||||||||
| Drug blood levels | Baseline hydroxychloroquine levels in this arm were not measured. | Mean | Standard Deviation | ng/mL |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Serum Levels of Thalidomide | Serum levels of thalidomide by liquid chromatography and tandem mass spectrometry (HPLC-MS/MS) | Posted | Mean | Standard Deviation | ng/mL | 12 months |
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| ||||||||||||||||||||||||||
| Primary | Serum Levels of Hydroxycloroquine | Serum levels of hydroxycloroquine by LCMS | Posted | Mean | Standard Deviation | ng/mL | 12 months |
|
|
12 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | SLE/Cutaneous Lupus With Thalidomide | SLE/cutaneous lupus with thalidomide arm (12 months). | 0 | 20 | 0 | 20 | 12 | 20 |
| EG001 | Inactive SLE With Standard Dose of HCQ | Lupus nephritis patients on stable inactive disease for at least 6 months prescribed full 2016-AAO dose of HCQ (4-5.5 mg/kg/day, real body weight). | 0 | 41 | 0 | 41 | 0 | 41 |
| EG002 | Inactive SLE With Reduced Dose of HCQ | Lupus nephritis patients on stable inactive disease for at least 6 months prescribed reduced 2016-AAO dose of HCQ (2-3.0 mg/kg/day, real body weight). | 0 | 32 | 0 | 32 | 0 | 32 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Only sensory peripheral neuropathy | Nervous system disorders | Systematic Assessment | Only sensory peripheral neuropathy evaluated by nerve conduction study |
|
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof Eloisa Bonfa | Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo | 551130617490 | eloisa.bonfa@hc.fm.usp.br |
| Nov 10, 2021 |
| Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Apr 1, 2017 | Nov 10, 2021 | ICF_001.pdf |
| ID | Term |
|---|---|
| D008180 | Lupus Erythematosus, Systemic |
| ID | Term |
|---|---|
| D003240 | Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D013792 | Thalidomide |
| D006886 | Hydroxychloroquine |
| ID | Term |
|---|---|
| D010797 | Phthalimides |
| D010795 | Phthalic Acids |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
| D010881 | Piperidones |
| D010880 | Piperidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D054833 | Isoindoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D002738 | Chloroquine |
| D000634 | Aminoquinolines |
| D011804 | Quinolines |
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| Non-Caucasian |
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