E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025140 |
E.1.2 | Term | Lupus nephritis |
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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 The primary objective of this trial is to evaluate the efficacy of atacicept compared to placebo in subjects with active LN who are receiving corticosteroids and sequential therapy with cyclophosphamide (CY) and azathioprine (AZA).
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E.2.2 | Secondary objectives of the trial |
SECONDARY The secondary objective of this trial is to evaluate the safety and tolerability profile of atacicept in subjects with active LN who are receiving corticosteroids and sequential therapy with CY and AZA. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Diagnosis of SLE satisfying at least 4 out of the 11 American College of Rheumatology (ACR) criteria 2. Positive test results for ANA (HEp-2 ANA ≥1:80) and/or anti-dsDNA (≥30 IU/mL) at screening. 3. Renal biopsy performed at or within 3 months before screening with histological findings consistent with International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III or IV (A or A/C) LN (results must be available during screening). 4. Active LN as defined by proteinuria (urine protein:creatinine ratio >1.0 mg/mg) and haematuria (>5 RBCs/hpf). These results must be available during screening. All causes of haematuria other than active LN must be excluded according to the local standard of care. 5. Male or female of ≥18 years of age. 6. Written informed consent, given before any trial-related procedure. Subjects must have read and understood the informed consent form, must fully understand the requirements of the trial, and must be willing to comply with all trial visits and assessments. 7. Female subjects must have avoided pregnancy for at least 4 weeks before the screening visit, and must be willing to avoid pregnancy for the duration of the trial (until 24 weeks after the last dose of trial medication) by using an adequate method of contraception. This requirement does not apply to surgically sterile subjects or to subjects who are postmenopausal for at least 2 years. Adequate contraception is defined as two barrier methods, or one barrier method with a spermicide, or an intrauterine device or a female hormonal contraceptive. 8. Women of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test at Study Day 1 before dosing. For the purpose of this trial, women of childbearing potential are defined as all female subjects after puberty unless they are post-menopausal for at least 2 years or surgically sterile.
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E.4 | Principal exclusion criteria |
1. Significant renal disease unrelated to SLE (e.g., diabetes mellitus or renovascular disease, whether or not associated with antiphospholipid syndrome). 2. Estimated GFR ≤30 mL/min per 1.73 m2 (as calculated by the modified MDRD equation) at screening, unless it is documented that all GFR values from the 12 weeks before screening are >30 mL/min per 1.73 m2. 3. Active central nervous system SLE deemed to be severe or progressive and/or associated with significant cognitive impairment leading to inability to provide informed consent and/or comply with the protocol. 4. Comorbidities requiring systemic corticosteroid therapy (such as asthma or inflammatory bowel disease) and/or preventing engagement in trial conduct. 5. Any treatment with CY within the last 12 months before the screening visit. 6. Known intolerance/toxicity to CY, AZA, or to both ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB). 7. Treatment with MMF, azathioprine or methotrexate within 2 weeks before screening. 8. Treatment with IV steroids within 2 weeks before screening. 9. Treatment with oral steroids at a dose >0.5 mg/kg/day of prednisolone (or equivalent) within 30 days before screening. 10. Any prior treatment with abatacept, rituximab, belimumab or other B-cell modulating agents. 11. Treatment with other investigational agents within the last 12 months 12. Any condition, including laboratory findings and findings in the medical history or in the screening assessments, that, in the opinion of the Investigator, constitutes a risk or a contraindication for participation in the trial or that could interfere with the trial’s objectives, conduct, or evaluation. 13. Active gastroduodenal ulcers. 14. History of or planned renal transplant. 15. Known active clinically significant infection, or any major episode of infection requiring hospitalisation or treatment with parenteral anti-infectives within 4 weeks of screening or completion of oral anti-infectives within 2 weeks before screening. 16. Positive HIV, hepatitis C, or hepatitis B (HBsAg) serology. 17. Active tuberculosis. 18. Latent tuberculosis, diagnosed according to local guidelines, unless this has been treated or is currently being treated according to the local standard of care. 19. Diagnosis or family history of Creutzfeldt-Jakob disease (CJD). 20. History or presence of uncontrolled or New York Heart Association (NYHA) class 3 or 4 congestive heart failure. [NYHA class 3: Cardiac disease resulting in marked limitation of physical activity. Subjects are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnoea, or anginal pain. NYHA class 4: Cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.] 21. History of cancer, except adequately treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix. 22. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 x upper limit of normal (ULN) or total bilirubin >1.5 x ULN unless attributable to active SLE. 23. Clinically significant abnormality in any haematological test (for example, haemoglobin <5.5 mmol/L [9 g/dL], WBC <2.5 x 109/L [2500/mm3], platelets <75 x 109/L [75,000/mm3]) unless attributable to active SLE. 24. Serum IgG below 4 g/L, unless attributable by the investigator to proteinuria. 25. Clinically significant abnormality on chest X-ray performed within 3 months before screening (if allowed by local guidelines and regulations) or on electrocardiogram (ECG) performed at screening that is considered by the Investigator to constitute a risk or a contraindication for participation in the trial. 26. Hypersensitivity to any of the components of the formulated atacicept. 27. Immunisation with live vaccines or Ig treatment within one month before screening. 28. Planned major surgery during the trial period (including trial follow-up). 29. History of alcohol or drug abuse in the last 6 months before screening. 30. Breastfeeding or pregnancy. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the proportion of subjects with confirmed CR(ACR) at Week 52.
Definition: Complete Response as per ACR guidelines (CR(ACR)): - Normalisation of renal function based on calculated GFR within 10% of the normal value of 90 mL/min/1.73 m2, and - Improvement in proteinuria, defined as a urine protein:creatinine ratio of <0.2 mg/mg, and - Improvement in haematuria, defined as urine sediment of <or=5 red blood cells (RBCs)/high powered field (hpf) and no RBC casts.
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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) | Yes |
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.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
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 | Information not present in EudraCT |
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 |
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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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For administrative and safety reporting purposes, the end of the trial will be defined as the date of the final clinical database lock. This provides for a single and conservative definition across all trial sites. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 7 |