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

Systemic Lupus Erythematosus Clinical Trial

— PENCIL  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06356740
• Other study ID #: 69HCL22_0878
• Secondary ID: 2023-508611-22-0
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: September 1, 2024
• Est. completion date: June 1, 2029

Study information

• Verified date: April 2024
• Source: Hospices Civils de Lyon
• Contact: Alexandre BELOT
• Phone: 04 27 85 61 26
• Email: Alexandre.belot[@]chu-lyon.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 70
• Est. completion date: June 1, 2029
• Est. primary completion date: November 1, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Lupus Erythematosus, Systemic
• Systemic Lupus Erythematosus

Intervention

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 (ßHCG) 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).

Locations

Country	Name	City	State
France	Groupe Hospitalier Pellegrin-CHU de Bordeaux	Bordeaux
France	Hôpital Femme-Mère-Enfant (HCL)	Bron
France	CHU de Clermont-Ferrand - Hôpital Gabriel Montpied	Clermont-Ferrand
France	CHU Nord de Grenoble - Albert Michallon	Grenoble
France	Hôpital Claude Huriez	Lille
France	Hôpital de la Croix-Rousse (HCL)	Lyon
France	Hôpital Edouard Herriot (HCL)	Lyon
France	Hôpital Necker-Enfants malades	Paris
France	Hôpital Pitié-Salpêtrière	Paris
France	Hôpital Lyon Sud (HCL)	Pierre-Bénite
France	CHU de Saint-Etienne - Hôpital Nord	Saint-Priest-en-Jarez

Sponsors (1)

Lead Sponsor	Collaborator
Hospices Civils de Lyon

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	number of relapses	number of relapses and time to relapse between M0 and M12 (collected continuously) will be assessed	until 12 months after randomisation
Secondary	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
Secondary	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
Secondary	interferon-a production quantification	Evaluation of the effect of treatment on lupus biomarkers by interferon-a production	until 12 months after randomisation
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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