E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Systemic Lupus Erythematosus |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10042945 |
E.1.2 | Term | Systemic lupus erythematosus |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary Objective:
The primary objective of the main study (at week 36) is to evaluate the neutralization of the IFN gene signature following treatment with IFN-K, as measured by the change from baseline of the expression of IFN-induced genes and to evaluate the efficacy of treatment with IFN-K using the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) response criteria.
The study will be considered as positive if a statistically significant better effect of IFN-K compared to placebo is observed on the neutralization of the IFN gene signature and if at least a trend favoring IFN-K is observed on the BICLA response. |
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives
The secondary objectives of this study are:
•To evaluate the efficacy of treatment with IFN-K using:
- The SLE Responder Index [(SRI)-4 and above]
- The SLE Disease Activity Index-2000 (SLEDAI-2K)
- The BILAG-2004 index
- The Safety of Estrogen in Lupus Erythematosus National Assessment-SLEDAI (SELENA-SLEDAI) Flare index
- The Systemic Lupus International Collaborating Clinics/American College of Rheumatology-Damage Index for Systemic Lupus Erythematosus (SLICC/ACR DI)
- The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) in patients with cutaneous lesions at baseline
•To evaluate the immune response induced by IFN-K
- Anti-IFNα antibody response
- Anti-Keyhole Limpet Hemocyanin (KLH) antibody response
- Anti-IFNα antibody neutralizing capacities
•To assess the safety of IFN-K emulsified with ISA 51 VG
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A patient meeting all of the following inclusion criteria at screening will be eligible for participation in the study:
1. Has had a diagnosis of SLE according to current ACR criteria (4 of 11 ACR criteria)
2. Has SLEDAI-2K ≥ 6
3. Has at least 1 BILAG A and/or at least 2 BILAG B
4. Has a positive IFN gene signature by RT-qPCR as assessed on a limited number of genes
5. Has anti-nuclear antibodies (ANA) ≥ 1:160 and/or anti-dsDNA antibodies ≥ 7.0 IU/mL
6. Be a male or female, aged between 18 and 65 years, inclusive, at the time of the screening visit
7. Agrees to receive influenza vaccination during each influenza season of the study period
8. Currently receiving at least one of the following treatment:
• Corticosteroids (CS) at a dose of ≤ 20 mg of prednisone equivalent/day
• Antimalarial drugs (hydroxychloroquine [HCQ] or chloroquine [CQ]); the patient must have been treated since at least 8 weeks and on stable dose for at least 4 weeks prior to first planned administration of the study product
• Methotrexate (MTX); the patient must have been treated and be on stable dose (≤ 20 mg/week) for at least 12 weeks prior to the first planned administration of the study product
• Azathioprine (AZA); the patient must have been treated and be on stable dose (≤ 2.5 mg/kg/day) for at least 12 weeks prior to the first planned administration of the study product
• Mycophenolate mofetil (MMF), the patient must have been treated and be on stable dose (≤ 2 g/day) for at least 12 weeks prior to the first planned administration of the study product
9. Study patient and his/her partner has to use effective method of contraception for the duration of the study including the Extended Follow-up Period.
Note: If of child-bearing potential, effective contraception methods include:
- Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least 6 weeks prior to the first planned administration of the study product. In case of oophorectomy alone, the reproductive status of the woman must be confirmed by follow up hormone level assessment.
- Male sterilization (at least 6 months prior to Screening).
- Combination of the following:
• Oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception or
• Placement of an intrauterine device (IUD) or intrauterine system (IUS)
• And barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, she is considered not of child bearing potential only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
10. Is able and willing to comply with the requirements of the study protocol (e.g., completion of the diary cards, return for follow-up visits), in the opinion of the Investigator
11. Has provided written informed consent |
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E.4 | Principal exclusion criteria |
A patient meeting any of the following exclusion criteria at study entry will not be eligible for the study:
1. Has active, severe lupus nephritis as defined either by the immediate need for cyclophosphamide treatment or by renal BILAG A
2. Has active, severe, neuropsychiatric SLE, defined as neuropsychiatric BILAG A
3. During the 4 months prior to the first planned administration of the study product, has been treated with corticosteroids (CS) at a dose of >20 mg of prednisone equivalent/day for > 7 consecutive days
4. Is currently receiving or has received pulse dose CS (≥ 250 mg prednisone equivalent/day) within 3 months prior to the first planned administration of the study product
5. Has received potent immunosuppressive drugs such as cyclophosphamide, cyclosporine A, oral tacrolimus within 3 months prior to the first planned administration of the study product
6. Has received abatacept, sifalimumab, rontalizumab, anifrolumab, belimumab, TNF antagonists or another registered or investigational biological therapy within 6 months prior to the first planned administration of the study product
7. Has received anti-B-cell therapy (e.g., rituximab, epratuzumab) within 12 months prior to the first planned administration of the study product
8. Has significant electrocardiogram (ECG) abnormalities that are clinically relevant and preclude study eligibility in the Investigator’s opinion
9. Has inflammatory joint or skin disease other than SLE that may interfere with study assessments
10. Has any laboratory abnormality that is clinically relevant and precludes study entry in the Investigator’s opinion
11. Has a history of malignant cancer, except the following treated cancers: cervical carcinoma in situ, basal cell carcinoma, or dermatological squamous cell carcinoma.
For US patients only: Has a history of malignant cancer, except the following treated cancer: basal cell carcinoma. Note: only patients with negative screening tests for malignancy according to The American Cancer Society guidelines (see Appendix 12), documented within the 12 months prior screening visit will be enrolled.
12. Has frequent recurrences of oral or genital herpes simplex lesions
(≥ 6 occurrences during the 12 months prior to first study product administration)
13. Has had an episode of shingles during the 12 months prior to the first planned administration of the study product
14. Has no IgG against herpes simplex virus (HSV-1 and HSV-2), varicella zoster virus (VZV), cytomegalovirus (CMV) or Epstein-Barr virus (EBV)
15. Is positive for HTLV 1-2 antibodies, HIV antibodies, Hepatitis C (HCV) antibodies, or Hepatitis B surface antigen (HBsAg)
16. Is at high risk of significant infection and/or has any current signs or symptoms of infection at entry or has received intravenous antibiotics within 2 months prior to the first planned administration of the study product
17. Has received any live vaccine within 3 months prior to the first planned administration of the study product (e.g. nasal flu vaccine, oral poliomyelitis vaccine, measles-mumps-rubella vaccine, yellow fever vaccine, Japanese encephalitis vaccine, dengue vaccine, rotavirus vaccine, varicella vaccine, zoster vaccine, Bacillus Calmette-Guérin [BCG] vaccine, oral typhoid vaccine)
18. Has used any investigational or non-registered product within 30 days or 5 half-lives, whichever is longer, or any investigational or non-registered vaccine within 30 days prior to the first planned administration of the study product
19. Has a history of chronic alcohol and/or drug abuse within 6 months prior to the first planned administration of the study product
20. Is breastfeeding, pregnant, or planning to become pregnant during the study period
21. Has known hypersensitivity to any component of the study product
22. Is high-risk human papilloma virus (HPV) positive by reverse transcription polymerase chain reaction (RT-qPCR) on a cervical swab at Screening or within 3 months prior to the first planned study product administration
23. Has cytological abnormalities ≥ HSIL on a cervical swab at Screening or within 3 months prior to the first planned study product administration |
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E.5 End points |
E.5.1 | Primary end point(s) |
Two co-primary endpoints will be evaluated in the trial:
• Change from baseline in the expression of IFN-induced genes at Week 36.
• Response to treatment with IFN-K as measured by the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) response 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 Week 36
and
- No BILAG worsening in other body systems: no new BILAG A or ≥ 2 new BILAG B scores at Week 36
and
- No worsening in SLEDAI-2K total score at Week 36 compared with baseline
and
- No deterioration in PGA (< 10% worsening) on VAS 100 mm at Week 36 compared with baseline
and
- No addition or increased dose level of anti-malarial drugs or immunosuppressive drugs or corticosteroids between Week
24 and Week 36 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Clinical secondary endpoints:
• Response to treatment with IFN-K, as measured by the SLE Responder Index (SRI)-4 response criteria at Week 36:
- Reduction ≥ 4 points in SELENA-SLEDAI
and
- No new BILAG A
and
- No more than 1 new BILAG B
and
- No deterioration in PGA (< 10% worsening) on VAS 100 mm compared with baseline
• Response to treatment with IFN-K, as measured by SLEDAI response, defined as a reduction of the SLEDAI-2K score of at least 4 points at Week 36 compared to baseline
• Response to treatment with IFN-K, as measured by BILAG grade changes by body system
• Response to treatment with IFN-K, as measured by incidence of SLE flare (SELENA SLEDAI flare index, BILAG flares)
• Response to treatment with IFN-K, as measured by SLICC/ACR-DI
• Response to treatment with IFN-K, as measured by Cutaneous LE Disease Area and Severity Index (CLASI)
Immunogenicity secondary endpoints:
At timepoints specified on the flow chart, Geometric Mean Titers (GMT) and seroconversion rates for:
• Anti-IFNα binding antibody titers
• Anti-IFNα neutralizing antibody titers
• Anti-KLH binding antibody titers
Safety endpoints:
• Occurrence, intensity and relationship of any solicited local and systemic AEs during a 7-day follow-up period (i.e. day of study product administration and 6 subsequent days) after each IFN-K or placebo dose
• Occurrence, intensity and relationship of unsolicited local and systemic AEs occurring throughout the study period
• Occurrence and relationship of all SAEs occurring throughout the study period
• Occurrence and intensity of solicited injection site reactions 1 hour post study product administration
• Occurrence and intensity of solicited systemic reactions 1 hour post study product administration
• Hematological and biochemical levels within or outside the normal ranges and percent change from baseline at each visit
• Occurrence, intensity and relationship of any abnormality in physical examination, vital signs, 12-lead ECG, clinical laboratory evaluations
• Rate and severity of viral infections
Exploratory Endpoints:
• Evaluation of clinical response by assessing disease activity using: PGA scores, Number of SLE flares, Time to first SLE flare in patients, 28-Tender and Swollen Joint Counts, Joint Pain VAS and incidence of patient requiring change in lupus therapy (intensification and/or addition of drugs)
• Quality of life using:
- Changes in the SF-36 score: Physical Component Summary (PCS) and Mental Component Summary (MCS) scores
- FACIT fatigue score
• Evaluation of biological response by assessing :
- Changes in the levels of auto-antibodies (anti-dsDNA, anti-Smith antigen [anti-Sm], anti-RNP, anti-SSA/Ro, anti-SSB/La, anti-cardiolipin, and anti-β2-glycoprotein I antibodies)
- Changes in the levels of biomarkers (C3, C4, CH50)
- Neutralizing Anti-IFNα antibodies towards IFNα subtypes
- Anti-IFNα and anti-KLH antibody isotyping
- IFNβ cross neutralization
- Anti-hemagglutinin antibody response |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 39 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Belgium |
Bulgaria |
Chile |
Colombia |
Croatia |
France |
Georgia |
Germany |
Italy |
Korea, Republic of |
Mexico |
Moldova, Republic of |
Peru |
Philippines |
Poland |
Russian Federation |
Serbia |
Spain |
Switzerland |
Taiwan |
Thailand |
Tunisia |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 7 |