| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Systemic Lupus Erythematosus |
| Systemischer Lupus Erythematodes (SLE) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Systemic Lupus Erythematosus |
| Systemischer Lupus Erythematodes (SLE) |
|
| 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 | 21.1 |
| 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 |
|
| 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 |
The primary objective of this study is to evaluate whether treatment with eight weekly subcutaneous injections of daratumumab is associated with a reduction of pathogenic serum anti-dsDNA antibodies in patients with moderate to severe SLE.
Primary objective of the LTE observational period ist to evaluate of the long-term safety of daratumumab, previously administered in the core study period, for the treatment of SLE; |
|
| E.2.2 | Secondary objectives of the trial |
1. Assessment of safety and tolerability
2. Evaluating the effect of daratumumab on SLE serology
3. Investigating the effect of daratumumab on SLE clinical endpoints and glucocorticoid sparing
4. Analyzing health-related quality of life
5. Objectives of the LTE observational period are
a) to evaluate the long-term efficacy of daratumumab
b) to investigate the long-term serologic changes of anti-dsDNA antibodies and other autoantibodies present at baseline of the core study, and total
immunoglobulin levels in serum;
c) to assess the long-term health outcome measures
d) to investigate the damage accrual according to SLICC Damage Index (SDI)
Additional objectives:
1. Investigate pharmacodynamic markers
3. Additional objectives of the LTE observational period is to investigate pharmacodynamic markers from week 36 to week 84
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. diagnosis of SLE according to the 2019 EULAR/ACR Systemic Lupus Erythematosus classification criteria.
2. age between 18 and 60 years, inclusive, at consent.
3. have a body mass index (BMI) between 18 and 32 kg/m² (BMI = weight/height2), inclusive, and a body weight of no less than 35 kg.
4. demonstrate moderate to severe disease based on SLEDAI-2K score ≥ 6 observed at screening
5. SLEDAI-2K ≥ 4 for clinical features (i.e. SLEDAI excluding laboratory results) at screening
6. have a positive anti-double stranded desoxyribonucleic acid (anti-dsDNA) test, as measured by enzyme-linked immunosorbent assay (ELISA) test.
7. Failure or lack of tolerability of at least 2 previous state-of-the-art immunosuppressive drugs/immunomodulatory drugs including antimalarials (does not account for glucocorticoids).
8. if using oral corticosteroids, must be receiving this medication for at least 4 weeks and on a stable dose equivalent to an average dose of <20 mg of prednisone daily for at least 4 weeks prior to the first dose of study agent.
9. if using immunosuppressive drugs within the past 6 months, must not have exceeded the following dose levels: methotrexate 25 mg/week, azathioprine 2mg/kg/day, mycophenolate mofetil (MMF) 3g/day, or mycophenolic acid (MPA) 1440mg/day.
10. if using immunosuppressive drugs, must be using not more than 1 immunosuppressive drug (does not account for antimalarials and glucocorticoids) and not have used any additional immunosuppressive drug within the past 3 months prior to the first dose of study agent.
Inclusion criteria for entering the long-term observational period:
1. Participation in the DARALUP core-study
2. Written consent to the long-term extension of the observational period
3. If the patient is of childbearing potential, she agrees to: comply with effective contraceptive measures, has been using adequate contraception since the last menses, will use adequate contraception
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|
| E.4 | Principal exclusion criteria |
- has any unstable or progressive manifestation of SLE (lupus cerebritis, optic neuritis, transverse myelitis, psychosis, uncontrolled seizures, systemic vasculitis, end-stage renal disease, rapidly progressive Class III or IV glomerulonephritis, isolated Class V lupus nephritis [i.e. without coexistent Class I, II, III, or IV nephritis], Class VI lupus nephritis, pulmonary hemorrhage, myocarditis) that is likely to warrant escalation in therapy beyond permitted background medications. Subjects requiring renal hemodialysis or peritoneal dialysis are also excluded.
- has or has had a history of any clinically significant medical illness, or medical disorders the investigator considers significant should exclude the participant, including (but not limited to), hematological disease, immune deficiency states, respiratory disease, cardiovascular disease (including poor peripheral venous access), hepatic or gastrointestinal (GI) disease, neurological or psychiatric disease, ophthalmological disorders, neoplastic disease, renal or urinary tract diseases, or dermatological disease.
- has or has had a serious infection (e.g. sepsis, pneumonia, or pyelonephritis), or been hospitalized or received IV antibiotics for a serious infection during the 3 months prior to consent.
- had major surgery, (e.g. requiring general anesthesia) within 3 months before screening.
- has or has had an acute illness, including a common cold, within 2 weeks prior to first study treatment or has had a major illness or hospitalization within 3 months prior to consent.
- has other inflammatory diseases that might confound the evaluations of efficacy, including but not limited to rheumatoid arthritis (RA), psoriatic arthritis.
- has received, is known to have received, or is suspected to have an intolerance or hypersensitivity (including delayed-type hypersensitivity) to any monoclonal antibodies or antibody fragments, is known to have allergies or clinically significant reactions to human proteins, monoclonal antibodies, or antibody fragments, or to any components of the formulation used in this study, including daratumumab.
- has received any live virus or bacterial vaccinations within 12 weeks prior to first study treatment or is expected to receive any live virus or bacterial vaccinations during the study or up to 20 weeks after last study treatment.
- has received B cell depleting therapy within 12 months prior to first administration of the study agent (e.g. rituximab, ocrelizumab or obinutuzumab),
- has received a therapy that inhibits B-cell activating factor (BAFF) (i.e. belimumab) within 3 months prior to first administration of the study agent.
- has received prior experimental immunosuppressive biologic therapy for lupus (other than that described as allowed), less than 5 half-lives or 6 months, whichever is longer prior to first administration of the study agent.
- has used oral or IV cyclophosphamide within 2 months prior to first administration of the study agent.
- has ever been exposed to daratumumab or any anti-CD38 antibodies (e.g. TAK-079, MOR202, isatuximab).
- has a history of, or ongoing, chronic or recurrent infection/diagnosed latent infection, including but not limited to, chronic renal infection, chronic chest infection (e.g. bronchiectasis), sinusitis, recurrent urinary tract infection (e.g. recurrent pyelonephritis), an open, draining, or infected skin wound, or an ulcer.
- has or has had a serious infection (e.g. sepsis, pneumonia or pyelonephritis) or has been hospitalized or received IV antibiotics for a serious infection during the 3 months prior to consent.
- Ongoing infection (requiring antibiotic treatment or fever > 38°C), including known HIV, active or chronic hepatitis B or hepatitis C.
- has experienced a recent single dermatomal herpes zoster eruption within the past 6 months, or has a history of disseminated forms of zoster within the past 2 years prior to screening.
- has a history of hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) positive, or other clinically active liver disease, or tests positive for HBsAg or anti-HCV at Screening.
- has a history of human immunodeficiency virus (HIV) antibody positive, or tests positive for HIV at Screening.
- have had an opportunistic infection (e.g. pneumocystis, aspergillosis, mycobacterium avium complex).
- has a history of malignancy within 5 years before consent (squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or a malignancy which is considered cured with minimal risk of recurrence).
- has a known history of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy of unusual size or location, or history of monoclonal gammopathy of undetermined significance.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the significant reduction in serum anti-dsDNA antibody titers after 8 repeated weekly injections of daratumumab at Week 12, i.e. 4 weeks after the last daratumumab injection, compared to baseline. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Safety, will be investigated by reporting the proportion of participants with treatment emergent adverse events (TEAE) by severity and SAEs through EOS.
2. To investigate the effect of daratumumab on serologic changes, the following secondary endpoints are defined:
• Change from baseline in serum levels of immunoglobulins (IgM, IgG and IgA), antinuclear antibodies (ANA) and extractable antinuclear antibodies (ENA), such as anti-Smith, anti-Ro (SSA), anti-La (SSB), anti-ribonucleoprotein (RNP) and anti-phospholipid antibodies, rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA) (if present) by visit
• Change from baseline in serum complement factors for C3 and C4 by visit
• Change from Baseline in levels of protective vaccine-induced serum antibody titers for Tetanus toxoid, Diphtheria and Measles by visit
3. To evaluate whether daratumumab treatment is associated with clinical efficacy and glucocorticoid sparing, the following secondary outcome measures will be performed:
• Proportion of subjects with a SLE responder index of 4 (SRI-4), SRI-4 being defined as (1) a ≥ 4-point reduction in SELENA-SLEDAI score as compared to baseline, and (2) no new BILAG A score or ≤ 1 new BILAG B score, and (3) no deterioration from baseline in the physician´s global assessment by ≥ 0.3 points, at Week 12 (4 weeks after the last daratumumab injection).
• Proportion of subjects with a SLE responder index of 4 (SRI-4), SRI-4 being defined as (1) a ≥ 4-point reduction in SELENA-SLEDAI score as compared to baseline, and (2) no new BILAG A score or ≤ 1 new BILAG B score, and (3) no deterioration from baseline in the physician´s global assessment by ≥ 0.3 points, by visit
• Proportion of subjects that meet the Lupus Low Disease Activity State (LLDAS) response criteria by visit
• Change from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores by visit
• Change from baseline in physician global assessment (PGA), a scale ranging from 0-3, by visit
• Change from baseline in CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index), CDAI (Clinical Disease Activity Index) and proteinuria (urinary protein/creatinine ratio, UPCR) by visit
• Time to first flare (SELENA-SLEDAI flare index, SFI), SFI flare rates (mild/moderate or severe) were defined by the modified SELENA–SLEDAI SFI (the modified SFI excludes severe flares that were triggered only by an increase in the SELENA–SLEDAI score to >12)
• The daily prednisolone (or equivalent) dosage, by visit between Week 12 and Week 36
4. To evaluate whether daratumumab treatment is associated with improvement of health-related quality of life, the following outcome measures will be performed:
• Change from baseline in Health-related quality of life (HR-QoL), measured by SF-36 score
• Change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score.
• Change from screening in the number of organs with damage according to the SLICC Damage Index (SDI) measured at the final visit at Week 84
ADDITIONAL ENDPOINTS
1. Immunologic changes (pharmacodynamics) following daratumumab treatment will be evaluated as follows:
• Change from baseline in number and phenotype of peripheral blood plasmacytoid dendritic cells (pDC), natural killer (NK) cells, CD4+ and CD8+ T cells, CD19+ B cells and CD19+CD20negCD27high plasmablasts, by visit. Immunophenotyping will be performed by multicolor flow cytometry including expression analysis of CD38 on immune cell subsets by using an anti-CD38 multitope antibody that binds to an epitope distinct from the epitope bound by daratumumab.
• Change from baseline in interferon type I activity, by visit, Type I interferon activity is a hallmark of SLE; it will be measured by analyzing its surrogate parameter SIGLEC-1 (CD169) on monocytes by flow cytometry.
• Change from baseline in gene expression profile and antigen receptor repertoire on peripheral blood T and B cells. Time frame: week 9 (one week after the last daratumumab injection). Transcriptomic profiling will be performed using single-cell RNA sequencing (scRNA-Seq) combined with T cell receptor (TCR) and B cell receptor (BCR) analysis in peripheral blood CD4+ and CD8+ T cell and CD19+ B cell subsets.
2. Pharmacokinetics
• Daratumumab concentrations will be analyzed after the end of the study from cryopreserved serum samples, which had been obtained at Week 9 (one week after the last daratumumab injection), provided that the primary endpoint will be achieved. Time frame: Week 9 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
secondary endpoint will be evaluated at week 0, 2, 4, 8, 12, 16, 20, 24, 28, 32 and week 36.
Safety will be evaluated from inclusion up to week 36. |
|
| 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 | Yes |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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