| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| SYSTEMIC LUPUS ERYTHEMATOSUS |
|
| E.1.1.1 | Medical condition in easily understood language |
| Heterogeneous, inflammatory, multisystem autoimmune disease in which antinuclear antibodies occur. "Lupus erythematosus" describes the typical rash of SLE. |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025134 |
| E.1.2 | Term | Lupus erythematosus |
| E.1.2 | System Organ Class | 100000004859 |
|
| 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 clinical efficacy of three doses of CC-220 (0.45 mg once per day [QD], 0.3 mg QD or 0.15 mg QD) compared to placebo, for the treatment of active systemic lupus erythematosus (SLE) using the SLE Responder Index at Week 24, defined as:
- Reduction from baseline of ≥ 4 points in the SLEDAI 2K and
- No new one or more British Isles Lupus Assessment Group (BILAG) A or new* 2 or more BILAG B items compared to baseline using BILAG 2004 Index and
- No worsening from baseline defined by an increase of < 0.30 points from baseline on a Physician's Global Assessment (PGA) visual analog scale (VAS) from 0-3
*new excludes A to B |
|
| E.2.2 | Secondary objectives of the trial |
Week 24
- To evaluate additional measures of clinical disease activity of CC-220 (0.45 mg once per day [QD], 0.3 mg QD or 0.15 mg QD) compared to placebo for the treatment of subjects with active SLE
- To assess the reduction in steroid use
- To evaluate the safety and tolerability of 0.45 mg QD, 0.3 mg QD, and 0.15 mg QD of CC-220 compared to placebo in subjects with active SLE
Week 52
-To evaluate additional measures of clinical disease activity and maintenance of effect of CC-220 (0.45 mg once per day [QD], 0.3 mg QD or 0.15 mg QD) for the treatment of subjects with active SLE
- To assess the reduction in steroid use
- To evaluate the longer term safety and tolerability of 0.45 mg QD, 0.3 mg QD, and 0.15 mg QD of CC-220 in subjects with active SLE |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Male or female 18 years of age or older at the time of signing the informed consent.
•Understand and voluntarily sign informed consent forms (ICFs) prior to the initiation of any study specific assessments/procedures.
•Able and willing to adhere to the visit schedule and other protocol requirements.
Disease Specific
•Have a diagnosis of SLE for at least 6 months prior to the Screening Visit and fulfill the 1997 update of the 1982 American College of Rheumatology (ACR) Classification Criteria for SLE at the Screening Visit.
•At the Screening Visit a SLEDAI 2K score of ≥ 6 points, at least four points of which are a "clinical" SLEDAI 2K score. The “clinical” score is the SLEDAI 2K assessment score without the inclusion of points attributable to any urine or blood laboratory results including immunologic measures. Neurologic descriptors of the SLEDAI 2K (items 1-7) are not counted towards the SLEDAI study entry criteria.
•At the Baseline Visit, a clinical SLEDAI 2K score of ≥ 4 points.
•Positive antibodies associated with SLE, which must include at least one of the following within the Screening Phase:
Positive antinuclear antibody (ANA) test at the central laboratory with a titer of 1:80 or greater, associated with a diagnosis of SLE,
Anti-dsDNA antibodies elevated to above normal as per the central laboratory,
Anti-Smith (anti-Sm) antibody elevated to above normal as per the central laboratory.
Pregnancy
All male and female subjects should be counseled about pregnancy precautions and risks of fetal exposure as described in the Pregnancy Prevention Plan (provided separately).
•Females of childbearing potential (FCBP) must:
- Have two negative pregnancy tests as verified by the Investigator prior to starting study therapy, one within 10 to 14 days prior to the first dose of CC-220 and again within 24 hours before taking the first dose of CC-220. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact.
- Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use two forms of reliable contraception simultaneously. One must be a highly effective method and one additional effective (barrier) method, and both must be practiced without interruption, 28 days prior to starting investigational product, during the study therapy (including dose interruptions), and for 28 days after discontinuation of study therapy.
- Male subjects must: Practice true abstinence or agree to use a barrier contraception (male latex condom or non-latex condom NOT made out of natural [animal] membrane [for example, polyurethane]) during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 90 days following investigational product discontinuation, even if he has undergone a successful vasectomy.
•Male subjects must agree not to donate semen or sperm during therapy and for at least 90 days following the discontinuation of IP.
•All subjects must:
- Understand that the IP could have potential teratogenic risk.
- Agree to abstain from donating blood while taking IP and for 28 days following discontinuation of the IP.
- Agree not to share IP with another person.
- Other than the subject, FCBP and males able to father a child should not handle the IP or touch the capsules unless gloves are worn.
- Be counseled about pregnancy precautions and risks of fetal exposure as described in the Pregnancy Prevention Plan.
Concomitant Medications
•If taking steroids, subjects must be on oral corticosteroids (OCS) for at least 4 weeks prior to the Screening Visit, and maintained on a stable dose of ≤ 20 mg/d of prednisone or equivalent for at least 2 weeks prior to the Baseline Visit.
•If taking hydroxychloroquine, quinacrine, chloroquine, methotrexate, leflunomide, sulfasalazine, mycophenolate mofetil, mycophenolic acid, azathioprine, 6-mercaptopurine, tacrolimus or cyclosporine, subjects must have been treated for 12 weeks prior to and be on a stable dose for at least 4 weeks prior to Baseline. NOTE: For subjects not taking, or are on unstable doses of antimalarials, methotrexate, sulfasalazine, leflunomide, tacrolimus, cyclosporine A, azathioprine, 6-mercaptopurine or mycophenalate, the last dose (in case of previous use) must be at least 8 weeks prior to the Baseline Visit.
•Subjects taking daily doses of NSAIDs must be on a stable dose two weeks prior to the Screening Visit. Subjects taking NSAIDs or analgesics on an as needed basis must hold them 72 hours prior to the Baseline Visit. |
|
| E.4 | Principal exclusion criteria |
1.The subject has received:
a.Cyclophosphamide within 3 months of the Baseline Visit. Previous use of Melphalan or other alkylating agents is prohibited.
b.Etanercept within 4 weeks prior to the Baseline Visit.
c.Belimumab within 3 months prior to the Baseline Visit.
d.B-cell depleting or modulating agents, such as rituximab or anti-CD22 therapy, within one year prior to the Baseline Visit.
e.Any other biologic or non-biologic immunosuppressive agent within 2 months of 5 pharmacokinetic half-lives (whichever is longer) prior to the Baseline Visit.
2.The subject has been treated with intra-articular, intralesional, subcutaneous, intradermal, intramuscular or IV pulse corticosteroids 6 weeks prior to the Baseline Visit.
3.The subject has received high potency topical corticosteroids within two weeks of the Screening Visit (only Class 6 or 7 are permitted).
4.The subject has undergone plasmapheresis within 3 months of the Baseline Visit.
5.The subject has received IV immunoglobulin within 3 months of the Baseline Visit.
6.The subject has received strong inhibitors or inducers of CYP3A4/5 including grapefruit, St. John’s Wort or related products within two weeks prior to the Baseline Visit.
7.The subject has a planned or received immunization with a live or live attenuated vaccine within 2 months prior to the Baseline Visit and for 2 months after administration of the last dose of IP.
Disease Severity
8.The subject has severe lupus nephritis defined as: estimated glomerular filtration rate (eGFR) of < 45 mL/1.73 m2 or proteinuria > 2000 mg/day if stable for the past 3 months, or proteinuria > 500 mg/day if unstable. Proteinuria will be based upon spot urine testing.
9.The subject has active, severe or unstable neuropsychiatric lupus disease (e.g., poorly controlled seizure disorder, acute confusional state, myelitis, stroke or stroke syndrome, cerebellar ataxia or dementia related to SLE, psychosis, organic brain syndrome, cerebrovascular accident [CVA], cerebritis or CNS vasculitis), within 6 months of the Screening Visit.
Concomitant Disease
10.The subject has QTcF of > 450 milliseconds.
11.The subject has a history of hepatitis B and/or hepatitis C.
12.The subject has a confirmed positive test for Hepatitis B or Hepatitis C during the Screening Phase. Subjects with isolated positive hepatitis B surface antibody are not excluded.
13.The subject has a history of congenital and/or acquired immunodeficiencies (eg, common variable immunodeficiency, human immunodeficiency virus [HIV], etc).
14.The subject has active or history of recurrent bacterial, viral, fungal, mycobacterial or other infections, or any major episode of infection requiring hospitalization or treatment with intravenous or oral antibiotics within 4 weeks of the Screening Visit and at any time during the Screening Phase, up through the first dose of IP.
15.The subject has a history of latent or active TB, unless there is medical record documentation of successful completion of a standard course of treatment per local guidelines.
16.The subject has an abnormal chest radiograph with evidence of active infection or possible malignancy. Alternatively, PA or PA/lateral radiographs that were taken within the 3 months (or longer periods based on local health authority requirements) prior to the Screening Visit will be accepted for evaluation for participation in the study.
17.The subject has malignancy or history of malignancy, except for:
•treated (eg, cured) basal cell or squamous cell in situ skin carcinomas
•treated (eg, cured) cervical intraepithelial neoplasia or carcinoma in situ of the cervix with no evidence of recurrence within 5 years of the Screening Visit.
18.The subject has a diagnosis or history consistent with Antiphospholipid Syndrome.
19.History of arterial or venous thrombosis, unless on appropriate anticoagulation for at least 6 months prior to Baseline Visit & throughout the study
20.The subject has a history or current diagnosis of peripheral neuropathy (sensory or motor) ≥ Grade 2.
21.The subject has a presence of active uveitis or any other ophthalmological finding that in the opinion of the Investigator is clinically significant.
22.The subject has dermatomyositis, polymyositis, scleroderma, rheumatoid arthritis or other non-SLE driven inflammatory joint or skin disease or overlap syndromes as the primary disease.
23.Laboratory criteria:
•Neutrophil count < 1.0 x 109/L
•White blood cell (WBC) count ≤ 2500 /µL (≤ 2.5 X 109/L) or > 20,000/µL (> 20 X 109/L)
•Lymphocyte count ≤ 500/mm3 or 0.5 x 109/L
•Platelet count ≤ 75 x 109/L and > 550 x 109/L
•Hemoglobin < 8g/dL or > 18 g/dL
•Serum creatinine > 1.8 mg/dL (> 159.12 µmol/L)
•Total bilirubin > 2 x ULN
•Aspartate transaminase (AST [serum glutamic oxaloacetic transaminase, SGOT]) > 2 x upper limit of normal (ULN)
•Alanine transaminase (ALT [serum glutamic pyruvic transaminase, SGPT]) > 2 x upper limit of normal (ULN) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
SRI(4)
SLEDAI 2K
CLASI
BILAG
Joint Counts
PGA
Fatigue
BILAG
Corticosteroid Reduction
Flare
SLE Damage |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
SRI(4): Week 52
SLEDAI 2K: Week 24 and Week 52
CLASI: Week 24 and Week 52
BILAG: Week 24 and Week 52
Joint Counts: Week 24 and Week 52
PGA: Week 24 and Week 52
Fatigue: Week 24 and Week 52
BILAG: Week 24 and Week 52
Corticosteroid Reduction: Week 24 and Week 52
Flare: All visits
SLE Damage: Week 52 |
|
| 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 | 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) | 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 | 4 |
| 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 | 43 |
| 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 |
| Argentina |
| Belgium |
| Brazil |
| Canada |
| Colombia |
| Germany |
| Hungary |
| Italy |
| Mexico |
| Poland |
| Russian Federation |
| Serbia |
| Spain |
| 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
|
| The End of Trial is defined as either the date of the last visit of the last subject to complete the post-treatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as pre-specified in the protocol, whichever is the later date. |
|
| 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 | 2 |
| 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 | 2 |
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