E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Systemic lupus erythematosus patients with a history of renal disease |
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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 | 10042945 |
E.1.2 | Term | Systemic lupus erythematosus |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this event-driven trial is to determine whether abetimus sodium is more effective than placebo in delaying the time to renal flare in SLE patients with a history of SLE renal disease. The safety and efficacy of abetimus sodium in SLE patients will be evaluated at weekly doses of 300 mg and 900 mg over the treatment period. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the trial are to determine whether treatment with abetimus sodium is more effective than placebo - in reducing proteinuria - in delaying time to major SLE flare |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Each patient must meet all the following criteria in order to participate in this trial:
2.1.1 Males or females aged between 12 and 70 years, inclusive; as required by local or national requirements, enrollment is limited to males or females aged between 18 and 70 years inclusive. 2.1.2 Female patients must be non-pregnant and non-lactating and have a negative urine pregnancy test result prior to enrollment in the study. Female patients of childbearing potential (including perimenopausal women who have had a menstrual period within 1 year) must be using appropriate birth control (defined as a method which results in a failure rate of less than 1% per year, when used consistently and correctly, for example oral contraceptives, contraceptive patch, implants, injectables, some intrauterine contraceptive devices [IUDs], or sexual abstinence) during the entire duration of the study. Males enrolled in the trial must have no plans to father a child during the course of the trial and agree to use adequate birth control methods. 2.1.3 Diagnosis of SLE for purposes of this trial utilizes the 1996 Revised Criteria for the Classification of SLE as defined by the American College of Rheumatology (ACR) where a diagnosis of SLE is established when >= 4 of the 11 criteria are met. 2.1.4 The patient must have had at least one documented episode of active SLE renal disease within 4 years prior to randomization as defined by at least one of the following 4 criteria: a. Renal biopsy showing active lesions of SLE, Morphologic Classification of Lupus Nephritis defined by the World Health Organization (WHO) Class III, IV or V or b. Increase in serum creatinine: - by greater than 0.3 mg/dL if previous value was less than 2.0 mg/dL - by greater than 0.4 mg/dL if previous value was 2.0 mg/dL to 5.0 mg/dL - AND either hematuria OR a C3, C4 or CH50 below lower limits of normal or at least 25% lower than a previous value. Patients with hereditary C4 deficiency cannot qualify on the C4 or CH50 criterion alone. or c. Increase in proteinuria (measured by 24 hour urine protein or predicted 24 hour urine protein using either protein osmolality ratio or protein creatinine ratio): - to greater than 1000 mg/24 hour if the previous value was < 200 mg/24 hour - to greater than 2000 mg/24 hour if the previous value was >= 200 mg/24 hour and <= 1000 mg/24 hour - to greater than 2 times the previous value if that value was > 1000 mg/24 hour or d. Use of cyclophosphamide to treat lupus nephritis that is documented in clinical or hospital records. 2.1.5 Elevated anti-dsDNA antibody concentration at pre-screening Visit 0 (>= 10 IU/mL) as measured by the Farr Assay at the regional central laboratory. 2.1.6 Ability to communicate meaningfully with the investigational staff, competence to give written informed consent, and ability to comply with the entire study procedure. 2.1.7 Duly executed, written, informed consent obtained from the patient, next of kin, or other legal representative. If required by local or national requirements, duly executed, written, informed consent obtained from the patient. Patients who are incarcerated in penal institutions or are committed to mental institutions may not consent to participate in this trial. |
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E.4 | Principal exclusion criteria |
Any of the following will exclude a patient from this trial:
2.2.1 Active SLE renal disease within the 3 months prior to Visit 3 as evidenced by: Increase in serum creatinine: - of greater than 0.3 mg/dL if previous value was less than 2.0 mg/dL - of greater than 0.4 mg/dL if previous value was 2.0 mg/dL to 5.0 mg/dL - AND either hematuria OR a C3, C4 or CH50 below lower limits of normal or at least 25% lower than a previous value or Reproducible increase in proteinuria (measured by 24 hour urine protein or predicted 24 hour urine protein using either protein/osmolality ratio or protein/creatinine ratio): - to greater than 1000 mg/24 hour if the previous value was < 200 mg/24 hour - to greater than 2000 mg/24 hour if the previous value was >= 200 mg/24 hour and <= 1000 mg/24 hour - to greater than 2 times the previous value if that value was > 1000 mg/24 hour or Any other evidence of active renal disease. 2.2.2 An increase in the anti-dsDNA antibody concentration of more than 50% with an incremental increase of at least 50 IU/mL in antidsDNA antibody concentration by Farr Assay between the samples taken at Visit 0 and Visit 1 during the screening period. 2.2.3 Use of the following therapeutics: - Prednisone > 20 mg/day within 1 month prior to Visit 1 - Any use of the following therapies or therapeutics within 2 months prior to randomization or 1 month prior to Visit 1: - alkylating agents (e.g., cyclophosphamide) - TNF inhibitors (e.g., etanercept, infliximab) - cyclosporine - plasmapheresis - intravenous immunoglobulin - prosorba column - Use of mycophenolate mofetil that exceeds 1000 mg/day 1 month prior to Visit 1 - Any use of azathioprine that exceeds 100 mg/day within 1 month prior to Visit 1 - Any use of methotrexate that exceeds 10 mg/week within 1 month prior to Visit 1 - Any use of leflunomide that exceeds 10 mg/day within 1 month prior to Visit 1 - Any use of rituximab within 5 months prior to Visit 1 - Previous or concurrent medications and/or other therapies or devices that in the judgment of the Investigator are likely to confound the evaluation of the safety or efficacy of abetimus. Examples include: - Immunosuppressants or immunomodulatory drugs other than those therapies specifically noted above to include new immunomodulatory agents that may become commercially available during the course of the study - Drugs that have the potential to induce SLE (e.g.,isoniazid, phenytoin, hydralazine, procainamide, etc.) - Radiation therapy within the last year. - If the Investigator has any question concerning a particular medication, he/she should discuss this with the Medical Monitor prior to randomization. - Patient has received any investigational new drug or device within 30 days prior to screening or 5 half-lives of the agent (whichever is longer), or any investigational new drug with a long-term effect. (e.g., ocrelizumab, tacrolimus). - Prior participation in study LJP 394-90-14. 2.2.4 Exclusionary laboratory values: - leukocyte count < 2,000 cells/mm3 - platelet count < 50,000 cells/mm3 - hemoglobin < 8.5 gm/dL - serum hepatic transaminases >= 3X the upper limit of normal - serum creatinine > 3.5 mg/dL within the 2 months prior to randomization 2.2.5 Malignant disease or immunodeficiency syndrome within 5 years, except patients with basal cell or squamous cell carcinoma of the skin with complete excision and clean borders. 2.2.6 Evidence of current abuse of drugs or alcohol. 2.2.7 History of poor procedural compliance in previous investigational studies. 2.2.8 History of serious cardiac disease or functional classification New York Heart Association Class III or IV. 2.2.9 Patient has previously undergone organ transplantation. 2.2.10 Other medical conditions that are considered by the Investigator to preclude adequate evaluation of drug safety or efficacy including but not limited to: - diabetic nephropathy - uncontrolled hypertension - history of patient being HIV positive - hereditary bleeding disorders including Hemophilia A, Hemophilia B, von Willebrand’s disease and other rarer Conditions - severe acquired bleeding disorders (e.g. severe liver disease, vitamin K deficiency, etc) 2.2.11 Patient has known hypersensitivity to the class of medications under study or any of the constituents of abetimus. 2.2.12 In the opinion of the Investigator, any other acute or chronic disease, which may influence the outcome of the study, should be discussed with the Medical Monitor prior to randomization. |
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E.5 End points |
E.5.1 | Primary end point(s) |
4.10.1 Primary Efficacy Endpoint The primary efficacy endpoint, time to renal flare, will be based on laboratory data from the central laboratory and confirmed by supporting data as stipulated in [protocol] Section 4.10.2. For renal flare, laboratory data leading to the primary endpoint will be considered valid for defining the endpoint only after causes other than increased activity of SLE renal disease have been excluded and the Principal Investigator, with concurrence of the Medical Monitor, has attributed the changes in laboratory values to an SLE-related renal flare. An independent Renal Events Committee will review renal flare data to adjudicate the attribution of renal flares to SLE prior to the data from the trial being unblinded. Once a patient’s renal flare has been adjudicated by the Renal Events Committee, as meeting the renal flare endpoint, patients should be encouraged to continue treatment and their participation in the study for purposes of evaluating the secondary endpoint but will be censored for any future renal event.† Patients experiencing a renal flare may be treated with prednisone, cyclophosphamide, and/or other immunosuppressive agents as needed. When 128 renal flares have been adjudicated as meeting the definition of the study endpoint, the study is considered completed and all patients will conclude their treatment period and will follow the 30, 60, 90-day Safety Follow up Procedures […].
4.10.2. [...] A renal flare endpoint will have been reached if one or the other of the following criteria, or both, are met following a renal flare signal as outlined in the protocol. Either: A reproducible increase in serum creatinine of > 20% OR at least 0.3 mg/dL, whichever is greater. This endpoint cannot be met using this criterion unless this increase is documented by two consecutive tests from two different days and each consecutive test continues to meet the endpoint increase in serum creatinine and each of the consecutive tests is accompanied by the presence of clinically significant proteinuria (> 1000 mg/24 h) and/or red cell casts. Or: A reproducible increase in 24-hr urine protein: • to greater than 1000 mg/24 hr if the screening value was < 200 mg/24 hr • to greater than 2000 mg/24 hr if the screening value was ≥ 200 mg/24 hr and ≤ 1000 mg/24 hr • to greater than 2 times the screening value if that value was > 1000 mg/24 hr AND the documentation of increased urinary protein is reproducible and is based on specimens from 2 different days. This will require at least two 24-hr urine collections.
Safety and tolerability Endpoints: Adverse experiences, laboratory parameters, reasons for premature study termination, and cause(s) of death will be collected and assessed as measures of safety and tolerability. All patients who receive at least one dose of study drug will be included in analyses of safety and tolerability. |
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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 | Yes |
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) | 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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 48 |
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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All clinical trial patients must be followed at 30, 60, and 90 days following the last dose of the study drug in order to report SAEs occuring within that timeframe. Follow up of all SAEs will be continued until the overall clinical outcome has been ascertained, the event has resolved or stabilized, or the event has been diagnosed as chronic. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |