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

Sponsor
University of Sao Paulo General Hospital (Other)
Overall Status
Completed
CT.gov ID
NCT03122431
Collaborator
Fundação de Amparo à Pesquisa do Estado de São Paulo (Other)
93
1
3
45.8
2

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
93 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
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.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.
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Relevance of Monitoring Blood Levels Compared to Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases: Adherence and Understanding the Possible Underlying Mechanisms Involved in Effectiveness and in Adverse Effects
Actual Study Start Date :
Jun 5, 2017
Actual Primary Completion Date :
Dec 30, 2020
Actual Study Completion Date :
Mar 30, 2021

Arms and Interventions

Arm Intervention/Treatment
Other: 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.

Drug: Thalidomide
Thalidomide 100 mg/day
Other Names:
  • Thalidomide 100 mg
  • Active Comparator: 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).

    Drug: standard dose of HCQ
    Hydroxychloroquine 5.0 mg/kg/day
    Other Names:
  • HCQ standard
  • Active Comparator: 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).

    Drug: Hydroxychloroquine reduced
    Hydroxychloroquine 2.5 mg/kg/day
    Other Names:
  • HCQ reduced
  • Outcome Measures

    Primary Outcome Measures

    1. Serum Levels of Thalidomide [12 months]

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

    2. Serum Levels of Hydroxycloroquine [12 months]

      Serum levels of hydroxycloroquine by LCMS

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    5 Years to 64 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Hospital das Clinicas da Faculdade de Medicina da USP São Paulo Brazil 05403-000

    Sponsors and Collaborators

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

    Investigators

    • Principal Investigator: Eloisa Bonfa, MD, PhD, University of Sao Paulo

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    University of Sao Paulo General Hospital
    ClinicalTrials.gov Identifier:
    NCT03122431
    Other Study ID Numbers:
    • HPLC-Rheumatic diseases
    First Posted:
    Apr 20, 2017
    Last Update Posted:
    Dec 16, 2021
    Last Verified:
    May 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Inactive SLE With Standard Dose of HCQ Inactive SLE With Reduced Dose of HCQ SLE/Cutaneous Lupus With Thalidomide
    Arm/Group Description 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). 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) Adult patients with CLE (biopsy proven)/SLE (American College of Rheumatology classification criteria, 1997) treated with thalidomide. Inclusion criteria: absence of pregnancy potential for females; agreement of male patients to use condoms throughout the treatment period with thalidomide and up to 30 days after its ending, even though they had already undergone vasectomy; active skin lesions; no response to previous use of HCQ, prednisone 20 mg/day, and immunosuppressants/dapsone or indication of thalidomide according to the attending physician; 5) agreement of recruited patients to participate in the study according to signed informed consent form, and agreement to thalidomide use according to signed responsibility term at starting treatment and at each renewal of the prescription; 6) a normal NCS; 7) normal serum vitamin B12 levels; 8) negative tests for hepatitis B/C and HIV; 9) negative antiphospholipid antibodies. Exclusion criteria: other associated autoimmune diseases, such as Sjogren's syndrome; previous or current alcoholism; diabetes mellitus; history of PN; previous use of thalidomide; previous or current use of leflunomide, TNF-alpha inhibitors, chemotherapy and other neurotoxic drugs; history of cancer or thrombosis; current renal or nervous system lupus activities, autoimmune haemolytic anaemia and/or thrombocytopenia <50,000/mm3; inability to understand the study.
    Period Title: Overall Study
    STARTED 41 32 20
    COMPLETED 41 32 9
    NOT COMPLETED 0 0 11

    Baseline Characteristics

    Arm/Group Title Inactive SLE With Standard Dose of HCQ Inactive SLE With Reduced Dose of HCQ SLE/Cutaneous Lupus With Thalidomide Total
    Arm/Group Description 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). 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). This subproject includes only one arm of lupus patients with active and refractory cutaneous disease and eligible for Thalidomide 100mg/day for 12 months. Total of all reporting groups
    Overall Participants 41 32 20 93
    Age (years) [Median (Standard Deviation) ]
    Median (Standard Deviation) [years]
    37
    (10.5)
    37
    (6.9)
    44.8
    (7.6)
    37
    (8.7)
    Sex: Female, Male (Count of Participants)
    Female
    39
    95.1%
    29
    90.6%
    17
    85%
    85
    91.4%
    Male
    2
    4.9%
    3
    9.4%
    3
    15%
    8
    8.6%
    Race/Ethnicity, Customized (Count of Participants)
    Caucasian
    13
    31.7%
    6
    18.8%
    9
    45%
    28
    30.1%
    Non-Caucasian
    28
    68.3%
    26
    81.3%
    11
    55%
    65
    69.9%
    Drug blood levels (ng/mL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ng/mL]
    1343.5
    (521.5)
    1404.9
    (492.0)
    1374.2
    (506.8)

    Outcome Measures

    1. Primary Outcome
    Title Serum Levels of Thalidomide
    Description Serum levels of thalidomide by liquid chromatography and tandem mass spectrometry (HPLC-MS/MS)
    Time Frame 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title SLE/Cutaneous Lupus With Thalidomide
    Arm/Group Description Adult patients with CLE (biopsy proven)/SLE (American College of Rheumatology classification criteria, 1997) treated with thalidomide.
    Measure Participants 20
    Mean (Standard Deviation) [ng/mL]
    415.1
    (326.0)
    2. Primary Outcome
    Title Serum Levels of Hydroxycloroquine
    Description Serum levels of hydroxycloroquine by LCMS
    Time Frame 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Inactive SLE With Standard Dose of HCQ Inactive SLE With Reduced Dose of HCQ
    Arm/Group Description 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). 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)
    Measure Participants 41 32
    Mean (Standard Deviation) [ng/mL]
    991.6
    (576.3)
    569.0
    (533.4)

    Adverse Events

    Time Frame 12 months
    Adverse Event Reporting Description
    Arm/Group Title SLE/Cutaneous Lupus With Thalidomide Inactive SLE With Standard Dose of HCQ Inactive SLE With Reduced Dose of HCQ
    Arm/Group Description SLE/cutaneous lupus with thalidomide arm (12 months). 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). 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).
    All Cause Mortality
    SLE/Cutaneous Lupus With Thalidomide Inactive SLE With Standard Dose of HCQ Inactive SLE With Reduced Dose of HCQ
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/20 (0%) 0/41 (0%) 0/32 (0%)
    Serious Adverse Events
    SLE/Cutaneous Lupus With Thalidomide Inactive SLE With Standard Dose of HCQ Inactive SLE With Reduced Dose of HCQ
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/20 (0%) 0/41 (0%) 0/32 (0%)
    Other (Not Including Serious) Adverse Events
    SLE/Cutaneous Lupus With Thalidomide Inactive SLE With Standard Dose of HCQ Inactive SLE With Reduced Dose of HCQ
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 12/20 (60%) 0/41 (0%) 0/32 (0%)
    Nervous system disorders
    Only sensory peripheral neuropathy 12/20 (60%) 12 0/41 (0%) 0 0/32 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Prof Eloisa Bonfa
    Organization Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo
    Phone 551130617490
    Email eloisa.bonfa@hc.fm.usp.br
    Responsible Party:
    University of Sao Paulo General Hospital
    ClinicalTrials.gov Identifier:
    NCT03122431
    Other Study ID Numbers:
    • HPLC-Rheumatic diseases
    First Posted:
    Apr 20, 2017
    Last Update Posted:
    Dec 16, 2021
    Last Verified:
    May 1, 2021