| 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 |
|
| 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 |
|
| 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 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 and 900 mg
over the intended 52-week exposure period.
|
|
| 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 all major SLE flares |
|
| 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 between 12 and 70 years old, inclusive.
2.1.2 Female patients must be non-pregnant and non-lactating and have a negative serum pregnancy test result prior to enrollment in the study. Female patients of childbearing potential (including peri-menopausal women who have had a menstrual period within 1 year) must be using appropriate birth control (defined as a method which results in a low 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 utilize 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 (refer to Section 8.2 of protocol).
2.1.4 At least one documented episode of active SLE renal disease within 4 years prior to randomization at study Visit 3 as defined by at least one of the following:
- 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 (refer to Section 8.3 of protocol)
- 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.
-Increase in proteinuria:
• to greater than 1000 mg/24 hr if the previous value was < 200 mg/24 hr
• to greater than 2000 mg/24 hr if the previous value was ≥ 200 mg/24 hr and ≤ 1000 mg/24 hr
• to greater than 2 times the previous value if that value was > 1000 mg/24 hr
- 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. |
|
| E.4 | Principal exclusion criteria |
Any of the following will exclude a patient from this trial:
2.2.1 Active SLE renal disease in the 3 months prior to Visit 3 as evidenced by:
- 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.
- Reproducible increase in proteinuria:
• to greater than 1000 mg/24 hr if the previous value was < 200 mg/24 hr
• to greater than 2000 mg/24 hr if the previous value was ≥ 200 mg/24 hr and ≤ 1000 mg/24 hr
• to greater than 2 times the previous value if that value was > 1000 mg/24 hr
2.2.2 An increase in the anti-dsDNA antibody concentration of more than 50% with an incremental increase of at least 50 units in anti-dsDNA 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
- Any 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 other therapies or devices that in the judgment of the Investigator are likely to confound the evaluation of the safety or efficacy of abetimus sodium. 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 1 year.
- If the Investigator has any question concerning a particular medication, he/she should discuss this with the Medical Monitor prior to enrollment.
- 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.
- 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, excepting 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, including but not limited to diabetic nephropathy, uncontrolled hypertension, history of patient being HIV positive, that are considered by the Investigator to preclude adequate evaluation of drug safety or efficacy.
2.2.11 Patient has known hypersensitivity to the class of medications under study or any of the constituents of abetimus.
2.2.12 Patients who have any other acute or chronic disease which in the opinion of the Investigator may influence the outcome of the study should be discussed with the Medical Monitor prior to enrollment |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
4.13.1. The primary efficacy endpoint, time to first renal flare, will be based on laboratory data from the central laboratory and confirmed by supporting data as stipulated in section 4.13.2. and other relevant sections.
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.
Patients reaching a renal flare endpoint are encouraged to stay in the study and receive weekly administration of study drug until they complete the one-year evaluation period. Patients experiencing a renal flare may be treated with prednisone, cyclophosphamide, and//or other immunosuppressive agents as needed.
4.13.2. .... 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.
4.13.3 Subsequent Flares
A subsequent flare (second flare, third flare, etc.) will be considered to have occured if the first flare has resolved, i.e., the parameters responsible for the first flare have returned to baseline and remain at baseline for at least 3 months. The primary endpoint, time to renal flare, will be based exclusively on the occurence of the first on-study renal flare.
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.
|
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| 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 |
|
| 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
|
| 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. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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