Phase 2a Study Evaluating the Arsenic Trioxide (ATO) in Systemic Lupus (SLE) (Protocol LUPSENIC) (LUPSENIC)

Phase 2a Study Evaluating the Arsenic Trioxide (ATO) in Systemic Lupus (SLE)

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.

Study Overview

• Status: Terminated
• Conditions: Systemic Lupus
• Intervention / Treatment: Drug: Arsenic trioxide

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Bordeaux, France
    • CHU de Bordeaux
  • Lille, France
    • CHRU de Lille
  • Marseille, France
    • CHU de Marseille
  • Nantes, France, 44093
    • Nantes University Hospital
  • Paris, France
    • AP-HP - la Pitié-Salpétrière
  • Strasbourg, France
    • CHRU de Strasbourg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Arsenic trioxide; 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).

Drug: Arsenic 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiac adverse events whatever grade and any adverse event of grade 3 or 4	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.	30 days after the last infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite response of SLE	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.	30 months
Anti-nuclear antibodies (ANA).	The modification of anti-nuclear antibodies (ANA).	30 months
Anti-native DNA	The modification of anti-native DNA.	30 months
C3 complement	The modification of C3 complement.	30 monhs
C4 complement	The modification of C4 complement.	30 months
Sedimentation rate	Analysis of Sedimentation rate.	30 months
Serum creatinine	Analysis of serum creatinine.	30 months
Proteinuria/creatinuria ratio	Analysis of proteinuria/creatinuria ratio.	30 months
Serum protein electrophoresis	Analysis of serum protein electrophoresis.	30 months
Quantitation of immunoglobulins	Analysis of quantitation of immunoglobulins.	30 months
Quality of life	Assessment of quality of life wih questionnaires SF36 and LupusQol.	30 months
Steroids	Reduction of the dose of steroids throughout the study.	30 months
Immunosuppressive treatments	Cessation of immunosuppressive treatments.	30 months
Response time	Response time in case of positive response.	30 months
Time to relapse	Time to relapse in case of positive response.	30 months
Blood test of arsenic	Pharmacokinetic study of arsenic plasma with analysis of potential correlations blood rates/ toxicity and response.	D1, D2, D3, D4, D8, D11, D15, D18, D22 and D25 (before and after each infusion)

Collaborators and Investigators

• Sponsor: Nantes University Hospital
• Collaborators: Medsenic Company
• Investigators: Principal Investigator: Mohamed HAMIDOU, Profesor, CHU de Nantes; Study Chair: Zahir AMOURA, Profesor, AP-HP - la Pitié-Salpétrière; Study Chair: Jean SIBILIA, Profesor, CHRU de Strasbourg; Study Chair: Jean-François VIALLARD, Profesor, University Hospital, Bordeaux; Study Chair: Nicolas SCHLEINITZ, Profesor, CHU de Marseille; Study Chair: Eric HACHULLA, Profesor, CHRU de Lille

Publications and helpful links

General Publications

• Hamidou M, Neel A, Poupon J, Amoura Z, Ebbo M, Sibilia J, Viallard JF, Gaborit B, Volteau C, Hardouin JB, Hachulla E, Rieger F. Safety and efficacy of low-dose intravenous arsenic trioxide in systemic lupus erythematosus: an open-label phase IIa trial (Lupsenic). Arthritis Res Ther. 2021 Mar 3;23(1):70. doi: 10.1186/s13075-021-02454-6.

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (ACTUAL): October 1, 2015
• Study Completion (ACTUAL): October 1, 2015

Study Registration Dates

• First Submitted: November 28, 2012
• First Submitted That Met QC Criteria: November 29, 2012
• First Posted (ESTIMATE): November 30, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): January 6, 2016
• Last Update Submitted That Met QC Criteria: January 5, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Arsenic trioxide; clinically; Systemic Lupus; biologically active
• Additional Relevant MeSH Terms: Antineoplastic Agents; Arsenic Trioxide
• Other Study ID Numbers: RC12_0021; 2012-002259-40 (EUDRACT_NUMBER)