Systemic Lupus
Conditions
Keywords
Arsenic trioxide, Systemic Lupus, clinically, biologically active
Brief summary
Primary objectives : * To investigate the safety and the tolerability of ATO by IV infusions to patients with SLE, * To determine the maximum tolerated dose of ATO. Secondary objectives : * Evaluation of the clinical and biological response of the SLE to ATO, * Time of relapse in case of positive response, * Determination of the efficacy, * Pharmacokinetic study of ATO.
Interventions
DRUGArsenic trioxide
The study duration was 30 months (24 months recruitment + 6 months follow-up).Thirteen patients will be successively included in this study at 6 different dose levels of arsenic trioxide (0.075, 0.10, 015, 0.20, 0.25 and 0.30 mg / kg / day). The treatment should be administered by IV infusion over 2 hours of D1 to D4 (conventional hospitalization) and at D8, D11, D15, D18, D22 and D25. The protocol starts at the dose of 0.10 mg / kg / day. The stage at the dose of 0.075mg/kg/day is planned in case of toxicity with the first stage at the dose of 0.10mg/kg/day. The course of study is as follows : * Pre-inclusion between D-35 and D-15 * Ten injections during the first month distributed as follows : conventional hospitalization from D1 to D4 (one injection per day) and daily hospitalization day for injections at D8, D11, D15, D18, D22 and D25. * A telephone contact between D32 and D34 * A consultation at D40 then monthly consultation at D60, D90, D120, D150 and D180
Sponsors
Medsenic Company
Nantes University Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Systemic Lupus meeting the ACR (American College of Rheumatology) criteria, progressive either SLEDAI activity score ≥ 4, despite a corticosteroid therapy ≥ 10 mg / d associated with hydroxychloroquine (in the absence of contraindication or intolerance) and / or an immunosuppressive treatment at a stable dose, * Insured, * Availability for hospitalization required by the protocol (conventional and daily hospitalizations).
Exclusion criteria
* Inability to give their signed informed consent form, * Performans status \> 2 * QTcorrected space before treatment \> 0.45 seconds * Hemoglobin less than 11g/dL * Neutrophils rate below 1 200 / mm3 * Platelets rate below 100 Giga / mm3 * Previous history of arrhythmia or heart rhythm disorder or other rhythm trouble by referring cardiologist * Heart disorder (progressive pericarditis, valvular disease, ...) according to cardiologist * Family previous history of arrhythmias * Taking drugs that potentially prolong the QT * Hypersensitivity to the active substance of Trisenox® or any of the excipients * Serum potassium ≤ 4 milliequivalent / L * Magnesemia ≤ 1,8 mg / dl * Increase corticosteroids beyond 20 mg / day within 15 days before inclusion * Immunosuppressive treatments, thalidomide introduced within the last 3 months * Biotherapy (rituximab, belimumab, ...) introduced within 6 months prior to inclusion * Pregnancy or lactation * For women of childbearing age, men and their partner : unless effective contraception for the duration of participation in the study that is 7 months * Creatinine clearance \<50 ml / min, * Hepatocellular insufficiency (TP \<50%), and / or AST (aspartate aminotransferase) / ALT (alanine aminotransferase) / ALP (alkaline phosphatase) \> 2N * HBsAg positive, DNA detectable HbS * Infection with HIV, HBV (hepatitis B virus) or HCV (hepatitis C virus) * Renal or progressive central neurological impairment with possible alternative therapeutic (to be discussed with the principal investigator and scientific board meeting) * Peripheral neuropathy * Unweaned alcoholism * Minor * Patients older than 65 years * Patient having been professionally exposed to arsenic (cleaning electronic circuits for example) * Guardianship patients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cardiac adverse events whatever grade and any adverse event of grade 3 or 4 | 30 days after the last infusion | The definition of toxicity will be based on Common Terminology Criteria for Adverse Events, version 4 of the U.S. Department of Health and Human Services, National Institutes of Health / National Cancer Institute. The investigators will consider the occurrence of a significant toxicity if at least one of the following events is observed : * Any symptomatic toxicity (and / or abnormality) cardiac and / or QTc prolongation \> 480 msec., * Apart from cardiac toxicity, toxicity of any grade 3 or 4 and irreversible toxicity (within 30 days) of any grade 1 or 2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Anti-nuclear antibodies (ANA). | 30 months | The modification of anti-nuclear antibodies (ANA). |
| Anti-native DNA | 30 months | The modification of anti-native DNA. |
| C3 complement | 30 monhs | The modification of C3 complement. |
| C4 complement | 30 months | The modification of C4 complement. |
| Sedimentation rate | 30 months | Analysis of Sedimentation rate. |
| Serum creatinine | 30 months | Analysis of serum creatinine. |
| Proteinuria/creatinuria ratio | 30 months | Analysis of proteinuria/creatinuria ratio. |
| Composite response of SLE | 30 months | Combined clinical response using the composite response of SLE or SRI (SLE Responder Index) (SLEDAI + BILAG (British Isles Lupus Assessment Group) + PGA) : a positive response is defined by a reduction of SELENA SLEDAI of at least 4 points, no worsening ( \> 0,3 point) of the physician's global assessment (PGA), no new score A and no more than one new score B about BILAG. This composite index is now the benchmark tool for evaluating therapeutic protocols in SLE. |
| Quantitation of immunoglobulins | 30 months | Analysis of quantitation of immunoglobulins. |
| Quality of life | 30 months | Assessment of quality of life wih questionnaires SF36 and LupusQol. |
| Steroids | 30 months | Reduction of the dose of steroids throughout the study. |
| Immunosuppressive treatments | 30 months | Cessation of immunosuppressive treatments. |
| Response time | 30 months | Response time in case of positive response. |
| Time to relapse | 30 months | Time to relapse in case of positive response. |
| Blood test of arsenic | D1, D2, D3, D4, D8, D11, D15, D18, D22 and D25 (before and after each infusion) | Pharmacokinetic study of arsenic plasma with analysis of potential correlations blood rates/ toxicity and response. |
| Serum protein electrophoresis | 30 months | Analysis of serum protein electrophoresis. |
Countries
France
Outcome results
None listed