E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Systemic Lupus Erythematosus (SLE) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10042945 |
E.1.2 | Term | Systemic lupus erythematosus |
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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 |
To evaluate the efficacy of belimumab in subjects with SLE.
To evaluate the safety and tolerability of belimumab in subjects with SLE.
To evaluate the impact of belimumab on quality of life in subjects with SLE.
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E.2.2 | Secondary objectives of the trial | |
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The Pharmacogenetic Research is contained in Appendix 12 of the Protocol (22 August 2006, protocol amendment 01)
Objectives: To establish the relationship between genetic variants and the pharmacokinetics of belimumab.
To establish the relationship between genetic variants and the safety and tolerability of belimumab.
To establish the relationship between genetic variants and the efficacy of belimumab. |
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E.3 | Principal inclusion criteria |
1. Are at least 18 years of age. 2. Have a clinical diagnosis of SLE according to the American College of Rheumatology (ACR) criteria. 3. Have active SLE disease defined as a SELENA SLEDAI score of greater than or equal to 6 at screening. 4. Have unequivocally positive anti-nuclear antibody (ANA) test results from 2 independent time points as follows: • Positive test results from 2 independent time points within the study screening period. Screening results must be based on the study’s central laboratory results. A positive ANA test is defined as an ANA titer of greater than or equal to 1:80 and/or a positive anti-dsDNA (greater than or equal to 30 IU/mL) serum antibody. OR • One positive historical test result and 1 positive test result during the screening period. Historical documentation of a positive test of ANA (eg, ANA by HEp-2 titer or ELISA) or anti-dsDNA (eg, anti-dsDNA by Farr assay or ELISA) must include the date and type of the test, the name of the testing laboratory, numerical reference range, and a key that explains values provided as positive vs negative OR negative, equivocal/borderline positive). 5. Are on a stable SLE treatment regimen consisting of any of the following medications (alone or in combination) for a period of at least 30 days prior to Day 0 (ie, day of 1st dose of study agent) • Corticosteroids (prednisone or prednisone equivalent, up to 40 mg/day): - For subjects on SLE combination therapy, their stable steroid dose must be fixed within the range of 0 to 40 mg/day (prednisone or prednisone equivalent). For subjects whose only SLE treatment is steroids, their stable steroid dose must be fixed within the range of 7.5 to 40 mg/day (prednisone or prednisone equivalent). For those subjects on alternating day doses of steroids, use the average of 2 daily doses to calculate the average daily steroid dose. • Other immunosuppressive or immunomodulatory agents including methotrexate, azathioprine, leflunomide, mycophenolate (including mycophenolate mofetil, mycophenolate mofetil hydrochloride, and mycophenolate sodium) calcineurin inhibitors (eg, tacrolimus, cyclosporine), sirolimus, oral cyclophosphamide, 6-mercaptopurine or thalidomide. • Anti-malarials (eg, hydroxychloroquine, chloroquine, quinacrine). • Non-steroidal anti-inflammatory drugs. •Pre-existing SLE medications must be stable for at least 30 days prior to Day 0. • Corticosteroids may be added as new medication or their doses adjusted only up to 30 days prior to Day 0. • New SLE therapy other than corticosteroids must not be added within 60 days of Day 0. 6. Subjects on angiotensin pathway antihypertensives (eg, ACE inhibitors, angiotensin receptor blockers [ARBs]) must be on a stable regimen for a period of at least 30 days prior to Day 0. 7. Subjects on HMG CoA reductase inhibitors (“statins”, such as simvastatin, rosuvastatin, atorvastatin, lovastatin, pravastatin, fluvastatin) must be on a stable regimen for a period of at least 30 days prior to Day 0. 8. A female subject is eligible to enter the study if she is: • Not pregnant or nursing; • Of non-childbearing potential (ie, women who had a hysterectomy, are postmenopausal which is defined as 1 year without menses, have both ovaries surgically removed or have current documented tubal ligation); or • Of childbearing potential (ie, women with functional ovaries and no documented impairment of oviductal or uterine function that would cause sterility). This category includes women with oligomenorrhoea [even severe], women who are perimenopausal or have just begun to menstruate. These women must have a negative serum pregnancy test at screening, and agree to 1 of the following: Complete abstinence from intercourse from 2 weeks prior to administration of the 1st dose of study agent until 8 weeks after the last dose of study agent; or Consistent and correct use of 1 of the following acceptable methods of birth control for 1 month prior to the start of the study agent and 8 weeks after the last dose of study agent: • Implants of levonorgestrel; •Injectable progesterone; • Any intrauterine device (IUD) with a documented failure rate of less than 1% per year; • Oral contraceptives (either combined or progesterone only); • Double barrier method: Condom, cervical cap or diaphragm with spermicidal agent; •Transdermal contraceptive patch; • Male partner who is sterile prior to the female subject’s entry into the study and is the sole sexual partner for the female subject. 9. A male subject is eligible to enter the study if he agrees to use effective contraception throughout the study and for 3 months after the last dose of study agent. 10. Have the ability to understand the requirements of the study, provide written informed consent (including consent for the use and disclosure of research-related health information) and comply with the study protocol procedures (including required study visits).
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E.4 | Principal exclusion criteria |
. Have received treatment with any B cell targeted therapy (eg rituximab, other anti-CD20 agents, anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], BLyS-receptor fusion protein [BR3], TACI-Fc or belimumab) at any time 2. Have received any of the following within 364 days of Day 0: Abatacept; A biologic investigational agent other than B cell targeted therapy (eg abetimus sodium, anti-CD40L antibody [BG9588/ IDEC-131])(Investigational agent applies to any drug not approved for sale in the country in which it is being used) 3. Have required 3 or more courses of systemic corticosteroids for concomitant conditions (eg asthma, atopic dermatitis) within 364 days of Day 0 (Topical/inhaled steroids permitted) 4. Have received intravenous (IV) cyclophosphamide within 180 days of Day 0 5. Have received any of the following within 90 days of Day 0: Anti-TNF therapy; Interleukin-1 receptor antagonist (anakinra); Intravenous immunoglobulin (IVIG); High dose prednisone (>100 mg/day); Plasmapheresis 6. Have received any of the following within 60 days of Day 0: A non-biologic investigational agent Any new immunosuppressive/immunomodulatory agent, anti-malarial, NSAID, HMG CoA reductase inhibitor (eg statin) or angiotensin pathway antihypertensive (eg ACE inhibitor, angiotensin receptor blocker). (Inc Criteria 5, 6 & 7) Note: New inhaled steroids and new topical immunosuppressive agents (eg eye drops, topical creams) are allowed.Any NSAID use for <1 week is allowed Any steroid injection (intramuscular, intraarticular or intravenous) 7. Have received any of the following within 30 days of Day 0: A live vaccine; Change in dose of a corticosteroid, other; immunosuppressive/immunomodulatory agent, antimalarial, NSAID, HMG CoA reductase inhibitor (statin) or angiotensin pathway antihypertensive (eg ACE inhibitor, angiotensin receptor blocker) (Inc Criteria 5, 6 & 7) 8. Have severe lupus kidney disease (defined by proteinuria >6g/24 hour or equivalent using spot urine protein to creatinine ratio, or serum creatinine >2.5mg/dL), have active nephritis, or have required hemodialysis or high-dose prednisone (>100 mg/day) within 90 days of Day 0 9. Have active central nervous system (CNS) lupus (including seizures, psychosis, organic brain syndrome, cerebrovascular accident [CVA], cerebritis or CNS vasculitis) requiring therapeutic intervention within 60 days of Day 0 10. Have a history of a major organ transplant or hematopoietic stem cell/marrow transplant 11. Have clinical evidence of significant unstable or uncontrolled acute or chronic diseases not due to SLE (ie cardiovascular, pulmonary, hematologic, gastrointestinal, hepatic, renal, neurological, malignancy or infectious diseases) which in the opinion of the PI could confound the results of the study or put the subject at risk 12. Have a planned surgical procedure or a history of any other medical disease (eg cardiopulmonary), lab abnormality or condition that in the opinion of the PI makes the subject unsuitable for the study 13. Have a history of malignant neoplasm within the last 5 years except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the cervix 14. Have required management of acute or chronic infections as follows: Currently on any suppressive therapy for a chronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria) Hospitalization for treatment of infection within 60 days of Day 0 Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti-parasitic agents) within 60 days of Day 0 15. Have current drug/alcohol abuse or dependence or history of drug/alcohol abuse or dependence within 364 days prior to Day 0 (Appendix 2) 16. Have a historically positive test or test positive at screening for HIV antibody, hepatitis B surface antigen or hepatitis C antibody. 17. Have an IgA deficiency (IgA level <10mg/dL). 18. Have a Grade 3 or greater lab abnormality based on the protocol toxicity scale in Appendix 13 the following are allowed: Stable Grade 3 prothrombin time (PT) secondary to warfarin treatment Stable Grade 3 partial thromboplastin time (PTT) due to lupus anticoagulant and not related to liver disease or anti-coagulant therapy Stable Grade 3/4 proteinuria (≤6 g/24 hour equivalent by spot urine protein to creatinine ratio allowed) Stable Grade 3 hypoalbuminemia due to lupus nephritis and not related to liver disease or malnutrition Stable Grade 3 gamma glutamyl transaminitis transferase (GGT) elevation) due to lupus hepatitis, and not related to alcoholic liver disease, uncontrolled diabetes or viral hepatitis. If present, any abnormalities in the ALT and or AST must be ≤ Grade 2. Stable Grade 3 neutropenia or stable Grade 3 WBC count. 19. Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is response rate at Week 52. • A response is defined as: • Greater than or equal to a 4 point reduction from baseline in SELENA SLEDAI score, AND • No worsening (increase of < 0.30 points from baseline) in Physician’s Global Assessment (PGA), AND • No new BILAG A organ domain score or 2 new BILAG B organ domain scores compared with baseline at the time of assessment (ie, at Week 52).
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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 | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | No |
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
| 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial months | 3 |