Efficacy and Tolerance of Abacavir/Lamivudine Treatment in Patients With Systemic Lupus Erythematosus (PENCIL)

Randomized Pilot Trial to Evaluate the Efficacy and Tolerance of Abacavir/Lamivudine Treatment in Patients With Systemic Lupus Erythematosus (PENCIL)

Systemic lupus (SL) is a rare chronic autoimmune disease characterized by the production of autoantibodies directed against nuclear antigens, particularly native double-stranded deoxyribonucleic acid (DNA), and excessive production of antiviral cytokines: type I interferons, particularly interferon alpha (IFN-α). IFN-α production results from the excessive detection of nucleic acids (DNA or Ribonucleic Acid (RNA)) by endosomal or intracytoplasmic receptors that are capable of inducing interferon production. The precise mechanisms of cytoplasmic sensor activation remain unknown; however, recent work in the field of interferonopathies suggests a role for human endogenous retroviruses (HERVs). HERVs are remnants of ancient infections caused by exogenous retroviruses integrated into the genome during evolution and represent 8% of the human genome.Several studies have suggested a role for HERVs in the development and maintenance of an excessive immune response in lupus patients and other autoimmune diseases by affecting the type I interferons (I IFN) signalling pathway.

To date, none of the approved immunosuppressive drugs for Systemic Lupus Erythematosus (SLE) have been shown to be effective in the background treatment of SL or in preventing relapse. Consequently, there is an urgent need to identify new molecules and therapeutic avenues for disease-modifying therapies.

In this study, an innovative therapeutic strategy using a combination of nucleoside reverse transcriptase inhibitors (NRTIs), abacavir/lamivudine, is proposed to treat SLE. Thus, we propose a pilot Phase II, randomized, open-label study using NRTIs in patients with SL in remission or with low clinical activity, and evaluating a biological endpoint (IFN signature), which is a direct proxy for the drug's expected effect.

The main objective is to compare the addition of Abacavir/Lamivudine (Add-on) to standard care for 6 months, on the value of the interferon (IFN) transcriptomic signature of patients with systemic lupus with low activity as defined by the Lupus Low Disease Activity State (LLDAS).

Study Overview

• Status: Not yet recruiting
• Conditions: Systemic Lupus Erythematosus
• Intervention / Treatment: Biological: Blood sample; Drug: Treatment :Abacavir 600 mg/lamivudine 300 mg; Other: Lupus Impact Tracker questionnaire

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Alexandre BELOT; Phone Number: +33 04 27 85 61 26; Email: Alexandre.belot@chu-lyon.fr
• Study Contact Backup: Name: Samira PLASSART; Phone Number: +33 04 27 85 54 42; Email: Samira.plassart@chu-lyon.fr

Study Locations

• France
  • Bordeaux, France, 33076
    • Groupe Hospitalier Pellegrin-CHU de Bordeaux
    • Contact: Christophe RICHEZ, MD, PhD; Phone Number: +33 05 56 79 56 79; Email: christophe.richez@chu-bordeaux.fr
    • Principal Investigator: Christophe RICHEZ, MD, PhD
  • Bron, France, 69677
    • Hôpital Femme-Mère-Enfant (HCL)
    • Contact: Alexandre BELOT, MD, PhD; Phone Number: +33 04 27 85 61 26; Email: Alexandre.belot@chu-lyon.fr
    • Principal Investigator: Alexandre BELOT, MD, PhD
  • Clermont-Ferrand, France, 63003
    • CHU de Clermont-Ferrand - Hôpital Gabriel Montpied
    • Contact: Marc ANDRE, MD, PhD; Phone Number: +33 0473751440; Email: mandre@chu-clermontferrand.fr
    • Principal Investigator: Marc ANDRE, MD, PhD
  • Grenoble, France, 38043
    • CHU Nord de Grenoble - Albert Michallon
    • Contact: Laurence BOUILLET, MD, PhD; Phone Number: +33 04 76 76 76 40; Email: lbouillet@chu-grenoble.fr
    • Principal Investigator: Laurence BOUILLET, MD, PhD
  • Lille, France, 59037
    • Hôpital Claude Huriez
    • Contact: Éric HACHULLA, MD, PhD; Phone Number: +33 03 20 44 56 50; Email: eric.hachulla@chru-lille.fr
    • Principal Investigator: Éric HACHULLA, MD, PhD
  • Lyon, France, 69004
    • Hôpital de la Croix-Rousse (HCL)
    • Contact: Yvan JAMILLOUX, MD, PhD; Phone Number: +33 0426732636; Email: yvan.jamilloux@chu-lyon.fr
    • Principal Investigator: Yvan JAMILLOUX, MD, PhD
  • Lyon, France, 69437
    • Hôpital Edouard Herriot (HCL)
    • Contact: Thomas BARBA, MD; Phone Number: +33 0472119583; Email: thomas.barba@chu-lyon.fr
    • Principal Investigator: Thomas BARBA, MD
  • Paris, France, 75015
    • Hopital Necker-Enfants Malades
    • Contact: Brigitte BADER-MEUNIER, MD; Phone Number: +33 0144494332; Email: brigitte.bader-meunier@aphp.fr
    • Principal Investigator: Brigitte BADER-MEUNIER, MD
  • Paris, France, 75651
    • Hopital Pitie-Salpetriere
    • Principal Investigator: Zahir AMOURA, MD, PhD
    • Contact: Zahir AMOURA, MD, PhD; Phone Number: +33 01 42 17 80 01; Email: zahir.amoura@aphp.fr
  • Pierre-Bénite, France, 69310
    • Hôpital Lyon Sud (HCL)
    • Contact: Mael Richard, MD; Phone Number: +33 0478861352; Email: mael.richard@chu-lyon.fr
    • Principal Investigator: Mael Richard, MD
  • Saint-Priest-en-Jarez, France, 42270
    • CHU de Saint-Etienne - Hôpital Nord
    • Contact: Martin KILLIAN, MD, PhD; Phone Number: +33 04 77 82 91 79; Email: martin.killian@chu-st-etienne.fr
    • Principal Investigator: Martin KILLIAN, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient ≥12 years old (weighing more than 25 kg) and ≤ 65 years old
• Diagnosis of SL according to 2019 American College of rheumatology (ACR) / European Ligue against Rheumatism (EULAR) criteria (score >10)
• Patient with SL in remission or with low clinical activity according to LLDAS disease criteria
• For patients (including sexually active adolescents) of childbearing age, effective contraception (sexual abstinence, hormonal contraception, intrauterine device or hormone-releasing system, cap, diaphragm, sponge with spermicide, or condom) for the entire duration of treatment is required. Pregnancy tests will be performed according to the inclusion criteria.
• Patient affiliated to a social security scheme
• Free, informed and written consent signed by patient or parents/legal guardian

Exclusion Criteria:

• Patients with HLA-B*5701 status (risk of allergy or hypersensitivity to Abacavir)
• History of allergy or hypersensitivity to abacavir, lamivudine, or excipients (tablet core: microcrystalline cellulose, crospovidone, magnesium stearate, colloidal anhydrous silica, talc; film coating: hypromellose, titanium dioxide (E171), macrogol, polysorbate 80).
• Patients on anti-retroviral therapy
• Patients with chronic HIV, HBV or HCV infection
• Pregnant or breast-feeding woman
• Patient treated with Lamivudine and/or Abacavir
• Patient treated with a cytidine analog
• Patient on treatment containing Cladribine
• Patient on treatment containing a trimethoprim/sulfamethoxazole combination
• Patients with renal insufficiency (creatinine clearance < 50 ml/min)
• Patients with moderate or severe hepatic impairment (prothrombin level <50%)
• Patient participating in other interventional drug research

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Abacavir 600 mg/lamivudine 300 mg; Patients randomized to this group will take 1 tablet (600 mg lamivudine and 300 mg abacavir) once daily for 6 months in addition to their usual treatment.	Biological: Blood sample; blood test to assess : human leukocyte antigen (HLA)-B*5701 status to identify risk of allergy or hypersensitivity to abacavir (the study treatment); IFN-signature ans IFN-alpha dosage; human immunodeficiency virus (HIV), hepatitis B virus (HBV) and Hepatitis C virus (HCV) serologies; Human chorionic gonadotropin (βHCG); HERVs dosage A biological collection will also be created. The total volume of blood collected specifically for the research for the entire duration of the study is 62.5 millilitre (mL) maximum.; Drug: Treatment :Abacavir 600 mg/lamivudine 300 mg; Patients randomised to the experimental arm will be required to take 1 tablet (600 mg lamivudine and 300 mg abacavir) once daily for 6 months in addition to their usual treatment.; Other: Lupus Impact Tracker questionnaire; Patients will be asked to complete the Lupus Impact Tracker questionnaire at visit V1 (randomisation visit), visit 3 (at 6 months of treatment) and visit 4 (12 months after visit 1).
Active Comparator: Control group (standard of care); Patients randomized to this group will continue their usual treatment for lupus systemic.	Biological: Blood sample; blood test to assess : human leukocyte antigen (HLA)-B*5701 status to identify risk of allergy or hypersensitivity to abacavir (the study treatment); IFN-signature ans IFN-alpha dosage; human immunodeficiency virus (HIV), hepatitis B virus (HBV) and Hepatitis C virus (HCV) serologies; Human chorionic gonadotropin (βHCG); HERVs dosage A biological collection will also be created. The total volume of blood collected specifically for the research for the entire duration of the study is 62.5 millilitre (mL) maximum.; Other: Lupus Impact Tracker questionnaire; Patients will be asked to complete the Lupus Impact Tracker questionnaire at visit V1 (randomisation visit), visit 3 (at 6 months of treatment) and visit 4 (12 months after visit 1).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute variation in interferon signature (IFN)	Absolute change in interferon (IFN) signature will be assessed between the start of treatment (M0) and after 6 months of treatment (M6) in the total population (then in the pediatric population, then in the adult population)..	At M6 (after 6 months of treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
percentage of patients maintaining LLDAS criteria	The percentage of patients maintaining LLDAS criteria will be assessed at M6 and M12 in the 2 arms.	until 12 months after randomisation
number of relapses	number of relapses and time to relapse between M0 and M12 (collected continuously) will be assessed	until 12 months after randomisation
anti-native double-stranded DNA quantification	Evaluation of the effect of treatment on lupus biomarkers by quantifying anti-native double-stranded DNA	until 12 months after randomisation
anti-extractable nuclear antigens (anti-ENA) quantification	Evaluation of the effect of treatment on lupus biomarkers by quantifying anti-ENA	until 12 months after randomisation
interferon-α production quantification	Evaluation of the effect of treatment on lupus biomarkers by interferon-α production	until 12 months after randomisation
Number of successful patients	The number of patients in each arm achieving success will be assessed. Success is defined as a ≥50% reduction in IFN signature between M0 and M6.	until 6 months after randomisation
Cumulative dose of intravenous (IV) corticosteroids	The impact of treatment on corticosteroid intake in the "Intervention" arm and the "No intervention" arm at M control arm will be assessed by observing the cumulative dose of intravenous (IV) and oral corticosteroids.	until 12 months after randomisation
Lupus Impact Tracker questionnaire score	Quality of life will be assessed by comparing Lupus Impact Tracker™ questionnaire scores at M6 and M12 in the Intervention arm and control arm. The lupus impact tracker (LIT) is a 10-item patient reported outcome tool to measure the impact of systemic lupus erythematosus or its treatment on patients' daily lives. Each answer is marked from 0 to 4 points. The lower the Lupus Impact score, the less impact lupus is having on the life of patient.	until 12 months after randomisation
number of missed treatment	Adherence to treatment will be assessed by recording the number of doses missed and the reasons for missed doses.	until 6 months after randomisation
number of adverse event (AE)	To assess the safety and tolerability of the drug, the number of AE will be compared between the two randomisation arms.	until 12 months after randomisation
number of serious adverse event (SAE)	To assess the safety and tolerability of the drug, the number of SAE will be compared between the two randomisation arms.	until 12 months after randomisation
HERVs transcription quantification	The difference in HERVs copy number in the 2 arms will be assessed. A comparison between groups will be performed.	until 12 months after randomisation

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2024
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: April 4, 2024
• First Submitted That Met QC Criteria: April 4, 2024
• First Posted (Actual): April 10, 2024

Study Record Updates

• Last Update Posted (Actual): April 10, 2024
• Last Update Submitted That Met QC Criteria: April 4, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Systemic Lupus Erythematosus; abacavir; lamivudine; nucleoside reverse transcriptase inhibitors; Systemic lupus
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Connective Tissue Diseases; Lupus Erythematosus, Systemic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Lamivudine; Abacavir
• Other Study ID Numbers: 69HCL22_0878; 2023-508611-22-00 (Ctis)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No