| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients With Systemic Lupus Erythematosus (SLE) |
|
| E.1.1.1 | Medical condition in easily understood language |
| In SLE, the body identifies its own proteins as invaders and attacks itself leading to inflammation. Antibodies are made that recognize normal tissues as foreign resulting in tissue damage. |
|
| 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 | 14.0 |
| 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 the efficacy of a 200 mcg dose of CEP 33457 compared with placebo in patients with active systemic lupus erythematosus (SLE) as assessed by the proportion of patients achieving a combined clinical response using the SLE responder index (SRI) at week 24. An SRI response is defined as a reduction from baseline in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) score of at least 4 points, no worsening in Physician’s Global Assessment (PhGA) (with worsening defined as an increase in PhGA of more than 0.30 point from baseline), no new British Isles Lupus Assessment Group A (BILAG A) body system score, and no more than 1 new BILAG B body system score from baseline. |
|
| E.2.2 | Secondary objectives of the trial |
•efficacy objectives
―SRI response
―reduction of at least 4 points in the SLEDAI 2K total score
―disease activity (BILAG 2004 disease activity index)
―status of disease (PhGA and Patient’s Global Assessment scales)
―health related QoL (SF 36 and the Lupus QoL Questionnaires)
―arthritis (28 joint count examination for pain and tenderness)
―cutaneous manifestations of disease (CLASI)
―biologic markers of disease activity (eg serology B [autoantibodies, complement components, immunoglobulins, interleukins]) and immunophenotyping)
―incidence of disease flares (ie SELENA Flare Index and SLEDAI 2K score>15)
―occurrence of SLE induced organ damage (eg SLICC/ACR Damage Index and AEs)
―change in steroid dose
―QoL
•safety objectives
―AEs
―clinical laboratory (serum chemistry, hematology and urinalysis)
―vital signs (blood pressure, pulse, temperature, and body weight)
―12 lead ECG
―physical examination
―concomitant medication |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients are included in the study if all of the following criteria are met:
(a) The patient is a man or woman between 18 and 70 years of age with an established diagnosis of SLE as defined by ACR Classification Revised Criteria. The diagnosis is fulfilled provided that at least 4 criteria are met.
(b) The patient has a positive test for ANA at screening (titer must be at least 1:80 [by human epithelial cell tumor line (HEp 2) ANA assay]) and/or a positive test for anti dsDNA Ab at screening (value must be 30 IU/mL or more by ELISA).
(c) Written informed consent is obtained.
(d) Women must be surgically sterile, 2 years postmenopausal, or, if of childbearing potential, using a medically accepted method of contraception, and must agree to continued use of this method for the duration of the study and for 30 days after discontinuation of study drug treatment. Acceptable methods of contraception include barrier method with spermicide, abstinence, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, and injected) in conjunction with a barrier method.
(e) The patient has a clinical SLEDAI 2K score of at least 6 points during screening. A clinical SLEDAI 2K score is the calculated score without inclusion of the points that may be contributed by having a positive titer for anti dsDNA Ab or decreased serum complement levels.
(f) The patient does not have an “A” score on the BILAG 2004 scale.
(g) If the patient is using oral corticosteroids, the weekly cumulative dose must not exceed 80 mg of prednisone equivalent; the weekly dose must be stable over the 4 weeks preceding the 1st dose of study drug.
(h) If the patient is using antimalarials, methotrexate, leflunomide, mycophenolate mofetil, or azathioprine, the start date must be at least 3 months prior to the 1st dose of study drug, and the daily dose must be stable over the 4 weeks preceding the 1st dose of study drug.
(i) If the patient is not currently using corticosteroids, antimalarials, methotrexate, mycophenolate mofetil, or azathioprine, the last dose (in case of previous use) must be at least 4 weeks prior to the 1st dose of study drug. For leflunomide, the stop date must be at least 8 weeks before the 1st dose of study drug, unless an adequate cholestyramine washout has been completed.
(j) The patient must be willing and able to comply with study restrictions, to remain at the study center for the required duration during each study visit, and to return to the study center for the final assessment as specified in this protocol. |
|
| E.4 | Principal exclusion criteria |
Patients are excluded from participating in this study if 1 or more of the following criteria are met:
(a) The patient has been treated with intramuscular or iv pulse steroids (ie, 250 to 1000 mg iv total daily dose of methylprednisolone) within 4 weeks of the 1st dose of study drug. The use of intra articular steroids may be allowed after consultation with the medical expert.
(b) The patient has received tacrolimus, cyclosporine A, or intravenous immunoglobulins (IVIG) within 3 months of the 1st dose of study drug.
(c) The patient has received cyclophosphamide within 12 months prior to the 1st dose of study drug.
(d) The patient has been treated for SLE with agents such as fusion proteins, therapeutic proteins, or monoclonal antibodies or antibody fragments, within 12 months of the 1st dose of study drug.
(e) The patient has received B cell depleting agents such as rituximab and has not yet normalized the B cell count (ie, CD20+ B cell count is less than 200 and the absolute lymphocyte count [ALC] is less than 1500/µL).
(f) The patient has New York Heart Association (NYHA) Class III or IV congestive heart failure.
(g) The patient has severe active lupus nephritis or cerebritis.
(h1) The patient has an estimated glomerular filtration rate (eGFR) of
less than 30 mL/min/1.73 m2 (via Modification of Diet in Renal Disease
[MDRD] equation).
(i) The patient has an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value greater than 2 times the upper limit of normal (ULN) or a total bilirubin level greater than 1.5 times the ULN.
(j) The patient has a planned immunization with a live or live attenuated vaccine within 3 months prior to administration of the 1st dose of study drug and for 3 months after administration of the last dose of study drug.
(k1) The patient has any clinically significant abnormalities on the 12-
lead ECG that are not related to SLE, as determined by the investigator.
Patients with stable ECG changes without evidence of active
cardiovascular disease may participate at the discretion of the
investigator and medical monitor.
(l) The patient has an ongoing active systemic infection requiring treatment or a history of severe infection, such as hepatitis or pneumonia, in the 3 months prior to administration of the 1st dose of study drug. Less severe infections in the 3 months prior to administration of the 1st dose of study drug are permitted at the discretion of the investigator and medical monitor.
(m1) The patient has any concomitant medical condition unrelated to
SLE that may
interfere with his or her safety or with evaluation of the study drug, as
determined by the investigator.
(n) The patient has a history of a medical condition other than SLE that
has required treatment with steroids in excess of 80 mg of prednisone
equivalent/week within 6 months of the 1st dose of study drug.
(o) The patient has a positive test result for HBsAg or HCV Ab.
(p) The patient has a known positive history of antibodies to human
immunodeficiency virus (HIV) or HIV disease.
(q) The patient has a history of alcohol or substance dependence or
abuse (with the exception of nicotine), according to the Diagnostic and
Statistical Manual of Mental Disorders of the American Psychiatric
Association, Fourth Edition, Text Revision (DSM IV TR), within 3 months
of the screening visit or has current substance abuse.
(r) The patient has a history of severe allergic reactions to or
hypersensitivity to any component of the study drug or placebo.
(s2) The patient has undergone or is undergoing treatment with another
investigational drug for the treatment of lupus within 6 months prior to
the 1st dose of study drug or has received any other investigational drug
for any other condition within 30 days prior to the 1st dose of study
drug.
(t) The patient has previously participated in a Cephalon or ImmuPharma sponsored clinical study with CEP 33457.
(u) The patient is a pregnant or lactating woman. (Any women becoming pregnant during the study will be withdrawn from the study.)
(v) The patient is unlikely to comply with the study protocol or is unsuitable for any other reason, as judged by the investigator or medical monitor. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy variable for this study is the proportion of patients achieving a combined clinical response using the SRI at week 24. An SRI response is defined as a reduction from baseline in the SLEDAI 2K score of at least 4 points; no worsening in PhGA (with worsening defined as an increase in PhGA of more than 0.30 point from baseline); no new BILAG A body system score, and no more than 1 new BILAG B body system score from baseline. The combined clinical response is intended to demonstrate an improvement in overall disease activity without worsening of disease in any organ system as determined by the investigator’s quantitative and qualitative assessments.
The SLEDAI 2K is a validated objective measure that assesses disease activity within the last 28 days before completion of the index. It is a global index and includes 24 weighted clinical and laboratory variables. The total score (sum of all 24 scores) ranges from 0 to 105. A SLEDAI 2K score of 6 to 10 is indicative of moderate disease activity, and improvement is defined as a reduction of greater than 3 points. The SLEDAI 2K was chosen because it is an accepted scale for assessing disease activity, has been shown to be reliable and sensitive to change, and is easy for clinicians to use. The SLEDAI-2K should be administered at each visit throughout the study by the same physician assessor trained and qualified to use this scale.
The PhGA will be completed by the physician using a 3 inch visual analog scale (VAS) labeled from 0=none to 3=severe. This scale was chosen because it measures a domain of disease activity that may not be fully assessed in the other measures of disease activity. A change of greater than 0.3 point on the VAS indicates worsening. The PhGA should be administered at each visit throughout the study by the same physician assessor trained and qualified to use this scale.
The BILAG 2004 is a validated objective and subjective global measure of the disease activity of SLE based upon the physician intention to treat and refers to disease activity within the last month prior to completion of the index. It includes 97 clinical and laboratory items to evaluate SLE disease activity in 9 organ systems; each organ system is assigned a score displayed as a grade from A to E, as follows: A=very active disease; B=patient needs increase in treatment for moderately active disease; C=stable or mild disease; D=previous organ involvement but no current disease activity; and E=no current disease activity and the organ system has never been involved. The BILAG 2004 was chosen because it is a reliable scale for evaluating SLE disease activity on the basis of the physician’s intent to treat. The individual organ domain scores are evaluations of disease activity in individual organ systems that may be improving, worsening, or stable, and they provide information that is comparable and complementary to the SLEDAI 2K score. The BILAG 2004 should be administered at each visit throughout the study by the same physician assessor trained and qualified to use this scale. It includes 97 clinical and laboratory items to evaluate SLE disease activity in 9 organ systems. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy variables and endpoints for this study are as follows:
• proportion of patients achieving an SRI response at each visit during the treatment period
• proportion of patients achieving a reduction of at least 4 points in the SLEDAI-2K total score at each visit during the treatment period
• proportion of patients achieving a clinical SLEDAI-2K response at each visit during the treatment period, where the clinical response is defined as a reduction of at least 4 points in the SLEDAI-2K clinical score
• proportion of patients achieving a BILAG-2004 response at each visit during the treatment period (no new A body system score and no more than 1 new BILAG B body system score from baseline)
• proportion of patients achieving a BILAG-2004 clinical response at each visit during the treatment
period (an improvement in at least 1 category from a B score to a C or D score, with no worsening in any other category)
• proportion of patients showing no worsening on a global assessment scale at each visit (physician and patient) during the treatment period
• absolute and relative changes in the SF-36 at week 12 and the final
assessment (week 24 or early termination) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 |
|
| 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 | 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 40 |
| 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 | No |
| 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 |
| Belgium |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Poland |
| Portugal |
| Spain |
| Ukraine |
| United States |
|
| 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
|
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
