Clinical trial NCT06356740: Efficacy and Tolerance of Abacavir/Lamivudine Treatment in Patients With Systemic Lupus Erythematosus
Official title: Randomized Pilot Trial to Evaluate the Efficacy and Tolerance of Abacavir/Lamivudine Treatment in Patients With Systemic Lupus Erythematosus (PENCIL)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Systemic Lupus Erythematosus
Keywords: Systemic lupus
Systemic Lupus Erythematosus
abacavir
lamivudine
nucleoside reverse transcriptase inhibitors
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2024-04-10
Enrollment: 70
Sex: ALL
Minimum age (years): 12
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open-label randomized, controlled study with 2 parallel arms (Add-on treatment versus standard of care treatment)
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: 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

Primary outcomes:
measure: Absolute variation in interferon signature (IFN)
timeFrame: At M6 (after 6 months of treatment)
Secondary outcomes:
measure: percentage of patients maintaining LLDAS criteria
timeFrame: until 12 months after randomisation
measure: number of relapses
timeFrame: until 12 months after randomisation
measure: anti-native double-stranded DNA quantification
timeFrame: until 12 months after randomisation
measure: anti-extractable nuclear antigens (anti-ENA) quantification
timeFrame: until 12 months after randomisation
measure: interferon-α production quantification
timeFrame: until 12 months after randomisation
measure: Number of successful patients
timeFrame: until 6 months after randomisation
measure: Cumulative dose of intravenous (IV) corticosteroids
timeFrame: until 12 months after randomisation
measure: Lupus Impact Tracker questionnaire score
timeFrame: until 12 months after randomisation
measure: number of missed treatment
timeFrame: until 6 months after randomisation
measure: number of adverse event (AE)
timeFrame: until 12 months after randomisation
measure: number of serious adverse event (SAE)
timeFrame: until 12 months after randomisation
measure: HERVs transcription quantification
timeFrame: until 12 months after randomisation
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Groupe Hospitalier Pellegrin-CHU de Bordeaux
city: Bron
country: France
facility: Hôpital Femme-Mère-Enfant (HCL)
city: Clermont-Ferrand
country: France
facility: CHU de Clermont-Ferrand - Hôpital Gabriel Montpied
city: Grenoble
country: France
facility: CHU Nord de Grenoble - Albert Michallon
city: Lille
country: France
facility: Hôpital Claude Huriez
city: Lyon
country: France
facility: Hôpital de la Croix-Rousse (HCL)
city: Lyon
country: France
facility: Hôpital Edouard Herriot (HCL)
city: Paris
country: France
facility: Hôpital Necker-Enfants malades
city: Paris
country: France
facility: Hôpital Pitié-Salpêtrière
city: Pierre-Bénite
country: France
facility: Hôpital Lyon Sud (HCL)
city: Saint-Priest-en-Jarez
country: France
facility: CHU de Saint-Etienne - Hôpital Nord
Study officials:
References: