Phase IIb Study of IFN-K in Systemic Lupus Erythematosus

Study Overview
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Brief Summary
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The safety and immunogenicity of the IFNα-Kinoid (IFN-K) have been evaluated in a phase I clinical study conducted in subjects with Systemic Lupus Erythematosus (SLE). Preliminary results showed acceptable safety profile and patients developped antibodies response. The principal aim of the present study is to confirm the neutralization of the interferon gene signature and the clinical efficacy of IFN-K in subjects with SLE. In addition, the immune responses and the safety elicited by IFN-K will also be evaluated.

Official Title
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A Phase IIb, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Neutralization of the Interferon Gene Signature and the Clinical Efficacy of IFNα-Kinoid in Adult Subjects With Systemic Lupus Erythematosus

Conditions
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Systemic Lupus Erythematosus

Intervention / Treatment
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* Biological: IFNα-Kinoid
* Other: Placebo
* Other: ISA 51 VG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has had a diagnosis of SLE according to current American College of Rheumatology (ACR) criteria (4 of 11 ACR criteria) Has SLEDAI-2K ≥ 6 Has at least 1 BILAG A and/or at least 2 BILAG B Has a positive IFN gene signature by reverse transcription quantitative polymerase chain reaction (RT-qPCR) Has anti-nuclear antibodies (ANA) ≥ 1:160 and/or anti-dsDNA antibodies ≥ 7.0 IU/mL Currently receiving at least one treatment for SLE Exclusion Criteria: Has active, severe lupus nephritis as defined either by the immediate need for cyclophosphamide treatment or by renal BILAG A Has active, severe, neuropsychiatric SLE, defined as neuropsychiatric BILAG A Has been treated with corticosteroids (CS) at a dose of >20 mg of prednisone equivalent/day for > 7 consecutive days Is currently receiving or has received pulse dose CS (≥ 250 mg prednisone equivalent/day) Has received potent immunosuppressive drugs Has received abatacept, sifalimumab, rontalizumab, anifrolumab, belimumab, tumor necrosis factor (TNF) antagonists or another registered or investigational biological therapy Has received anti-B-cell therapy (e.g., rituximab, epratuzumab) Has frequent recurrences of oral or genital herpes simplex lesions Is at high risk of significant infection and/or has any current signs or symptoms of infection at entry or has received intravenous antibiotics Has received any live vaccine Has used any investigational or non-registered product or any investigational or non-registered vaccine Is high-risk human papilloma virus (HPV) positive by rRT-qPCR on a cervical swab Has cytological abnormalities ≥ high grade squamous intraepithelial lesions (HSIL) on a cervical swab

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IFNα-Kinoid<br>IFNα-Kinoid (IFN-K) adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 μg at W0, W1, W4 and 1 administration of 120 μg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment. | Biological: IFNα-Kinoid<br> <br> Other: ISA 51 VG<br> <br> |
| Placebo Comparator: Placebo<br>Placebo normal saline (0.9% Sodium Chloride) adjuvanted with ISA 51 VG via intramuscular injection. 1 administration of 240 μg at week (W)0, W1, W4 and 1 administration of 120 μg at month 3 (W12) and month 6 (W24) in addition to standard of care treatment. | Other: Placebo<br> <br> Other: ISA 51 VG<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in IFN Gene Signature at W36 | The biological endpoint aimed at evaluating the neutralization of the IFN gene signature following treatment with IFN-K compared to placebo, as measured by the % change from baseline of the expression of IFN-induced genes. | Baseline and Last Available Value (LVA) between week 24 and week 36 | 
| Number of Participants Who Achieved a British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) With Superimposed CS Tapering at Week 36 | British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) responder was defined as a subject who had the following criteria at week 36: All BILAG A scores at baseline improve to B/C/D and all BILAG B scores improve to C/D at W36, and No BILAG worsening in other body systems: no new BILAG A or ≥ 2 new BILAG B scores at W36, and No worsening in SLEDAI-2K total score at W36 compared with baseline, and No deterioration in Physician Global Assessment (PGA) (< 10% worsening) on Visual Analog Scale (VAS) 100 mm at W36 compared with baseline, and No addition or increased dose level of anti-malarial drugs or immunosuppressive drugs or CS* between W24 and W36 (*≤5 mg prednisolone or equivalent /day at W24 and no increase until W36). | At Week 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Achieved a Systematic Lupus Erythematosus (SLE) Responder Index (SRI)-4 at Week 36 | SLE Responder Index (SRI); SRI-4 responder was defined as a subject who had the following criteria at week 36: reduction ≥4 points in SELENA-SLEDAI at week 36 compared with baseline, and no new BILAG A at week 36, and no more than 1 new BILAG B at week 36, and no deterioration in PGA (<10% worsening) on 100-mm VAS compared with baseline | W36 (9 months) | 
| Number of Participants Who Achieved a Lupus Low Disease Activity State (LLDAS) at Week 36 | Lupus low disease activity state (LLDAS) was conceptually defined as 'a state which, if sustained, is associated with a low likelihood of adverse outcome, considering disease activity and medication safety'. Subsequently defined using consensus methodology, LLDAS is attained if all the following items are met: SLEDAI-2K ≤4, with no activity in major organ systems (renal, central nervous system (CNS), cardiopulmonary, vasculitis, fever) and no hemolytic anemia or gastrointestinal activity No new features of lupus disease activity compared with the previous assessment SELENA-SLEDAI physician global assessment (PGA, scale 0-3) ≤1 Current prednisolone (or equivalent) dose ≤7.5 mg daily Well tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents, excluding investigational drugs | At Week 36 | 
| BILAG Global Score Change From Baseline to Last Available Value (LVA) Between Week 24 and Week 36 | British Isles Lupus Assessment Group (BILAG)-2004 index, it categorizes disease activity into 5 different levels from A to E, with Grade A representing very active disease and Grade E indicating no current or previous disease activity. Scoring was based on a total of 101 items, grouped into 9 organ/systems and the summation of the numerical values for the nine-system scores was given by the following formula: Numerical global score = A*12 + B*8 + C*1, where A, B and C represent the number of Grades A, B and C respectively at each assessment. Grades D and E are considered as 0 (Chee-Seng Yee et al, 2010). The minimum score is 0 with no predefined maximum. The higher scores mean a worse outcome. The BILAG global score change from baseline to Last Available Value (LVA) week 24 and week 36 were presented analyzed. | Last Available Value (LVA) between week 24 and week 36 | 
| SELENA-SLEDAI - Change From Baseline to Week 36 | Safety of Estrogens in Systemic Lupus Erythematosus National Assessment (SELENA)-SLEDAI, is a slightly modified version of the SLEDAI. This is a weighted index in which signs and symptoms, laboratory tests, and Physician's Global Assessment (PGA) for each of nine organ systems are given a weighted score and summed up if present at the time of the visit or in the preceding 10 days. The maximum theoretical score for the SELENA SLEDAI is 105 (all 24 descriptors present simultaneously) with 0 indicating inactive disease. | Baseline and Week 36 | 
| SLICC/ACR-DI Change From Baseline at Week 36 | Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index for systemic lupus erythematosus (SLICC/ACR-DI) captures permanent changes which have occurred in patients with SLE, regardless of causality. The questionnaire contains 41 items covering 12 different organ systems. The score of items ranges from 1 to 3 and the total score from 0 to 47. By definition score 0 corresponds to diagnostics and damage over time can only be stable or increase, theoretically to a maximum of 47 points. | Baseline and Week 36 | 
| CLASI Total Activity Change From Baseline at Week 36 | Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) was specifically developed to assess the cutaneous manifestations of SLE. It measures both disease activity and permanent damage (e.g. dyspigmentation and scarring) over the entire body surface. CLASI total activity score ranges from 0 to 70, with higher scores indicating more severe skin disease. | Baseline and Week 36 | 
| Number of Participants Who Achieved a Composite SRI-4 Including CS ≤7,5mg/Day at Week 36 | SRI (4) plus CS ≤ 7.5 mg/day responder was defined as a participant who had the following criteria at week 36: reduction ≥4 points in SELENA-SLEDAI at week 36 compared with baseline, and no new BILAG A at week 36, and no more than 1 new BILAG B at week 36, and no deterioration in PGA (<10% worsening) on 100-mm VAS compared with baseline plus CS ≤7.5mg equivalent prednisolone per day at week 36 | At Week 36 | 
| Number of Participants Who Achieved a Composite SRI-4 Including CS ≤5mg/Day at Week 36 | SRI-4 plus CS ≤ 5mg/day responder was defined as a participant who had the following criteria at Week 36: reduction ≥4 points in SELENA-SLEDAI at week 36 compared with baseline, and no new BILAG A at week 36, and no more than 1 new BILAG B at week 36, and no deterioration in PGA (<10% worsening) on 100-mm VAS compared with baseline plus corticosteroids (CS) ≤5mg equivalent prednisolone per day at week 36 | At Week 36 | 
| Number of Participants With Neutralizing Anti-IFN-alpha Antibodies at W36 | Individual serum antibody neutralizing capacity against recombinant IFN-alpha2b was measured by reporter gene assay using Interferon Sensitive Response Element (ISRE) reporter. | At week 36 | 
| Number of Participants With Treatment-related Adverse Events | Number of participants who reported any treatment-related adverse events until month 9 | 9 months |