| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Systemic Lupus Erythematosus
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 21.1 |
| 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 |
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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 |
The primary objective is to evaluate the efficacy of ustekinumab in subjects with active systemic lupus erythematosus (SLE) who have not adequately responded to one or more standard-of-care treatments.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to evaluate the following in subjects with active SLE despite receiving one or more standard-of-care treatments:
1. Reduction in SLE flares
2. Improvement in global and organ-specific (mucocutaneous, musculoskeletal, etc) measures of SLE disease activity
3. Glucocorticoid sparing |
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| 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 |
Cutaneous Disease Photography Substudy:
In order to correlate CLASI assessment findings with images of cutaneous lupus, a cutaneous disease photography substudy will be performed at selected sites on a subset of subjects with cutaneous lupus present at baseline.
Pharmacogenomic (DNA) Evaluations:
DNA samples will be analyzed for identification of genetic factors to better understand the molecular effects of ustekinumab and/or SLE, and to evaluate markers that can predict clinical response. Genetic (DNA) research may consist of the analysis of 1 or more candidate genes or analysis of the entire genome (as appropriate) in relation to ustekinumab and/or SLE. |
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| E.3 | Principal inclusion criteria |
• Between 16 (unless restricted by local requirements) and 75 years of age, inclusive.
• Diagnosis of SLE made or confirmed by a physician experienced in the treatment of SLE.
• Documented medical history (ie, met at least 1 of the bulleted criteria below) that subject met the SLICC classification criteria for SLE at least 3 months prior to first dose of study agent:
- Met a total of at least 4 SLICC criteria including at least 1 clinical and at least 1 immunologic.
- Had a diagnosis of lupus nephritis, confirmed by renal biopsy and at least 1 of the following autoantibodies: ANA or anti-dsDNA.
• At least 1 well-documented unequivocally positive test in medical history and detected during screening, for at least 1 of the following autoantibodies: ANA, anti-dsDNA, and/or anti-Smith.
• Have at least 1 BILAG A and/or 2 BILAG B domain scores observed during screening.
• Have a CLASI activity score of at least 4 or at least 4 joints with pain and signs of inflammation at screening or at Week 0, or both.
• Demonstrate active disease based on SLEDAI-2K score ≥6 observed during screening. Must also have SLEDAI-2K ≥4 for clinical features (ie, SLEDAI-2K score excluding headache, and laboratory abnormalities) present at Week 0 prior to randomization.
• Must be receiving one or more of the following protocol-permitted, systemic standard-of-care treatments:
a) Oral glucocorticoids (average daily dose ≤20 mg of prednisone or equivalent) for ≥6 weeks and at a stable dose ≥4 weeks prior to first dose of study agent.
- If currently not using oral glucocorticoids, must not have received them for ≥6 weeks prior to the first dose of study agent.
b) Antimalarials for ≥12 weeks and at a stable dose for ≥6 weeks prior to first dose of study agent
c) If using one or more of the following immunomodulatory drugs, must be receiving for ≥12 weeks and be on a stable dose for ≥6 weeks prior to first dose of study agent:
-MMF ≤2 g/day
-MPA ≤1.5 g/day
-AZA /6-MP ≤2 mg/kg/day; up to 100 mg/day for subjects weighing ≤50 kg
-Oral MTX ≤25 mg/Week or SC or intramuscular (IM) MTX ≤20 mg/Week with concomitant folic acid or folinic acid.
If the subject is using concomitantly 2 or more of the immunomodulatory drugs listed above (MMF, MPA, AZA, 6-MP, MTX), the suitability of the subject to participate in the study must be discussed with the medical monitor and/or sponsor before the subject is randomized.
• Before randomization, a woman must be either:
a. Not of childbearing potential, or
b. Of childbearing potential:
-Practicing a highly effective method of contraception
-Agrees to remain on a highly effective method of contraception throughout the study and for at least 16 weeks after the last dose of study agent.
• A woman of childbearing potential must have a negative urine pregnancy tests
• beta-hCG obtained during screening and at Week 0 before the first dose of study agent.
• A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 4 months after receiving the last dose of study agent.
• A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control.
• A man who is sexually active with a woman who is pregnant must use a condom and all men must not donate sperm during the study and for 20 weeks after receiving the last dose of study agent.
• Subjects must have laboratory test results within the following parameters at
screening:
- Hemoglobin ≥8.0 g/dL (SI: ≥ 80 g/L)
- Lymphocytes ≥0.5 x 103 /microL (SI: ≥0.5 GI/L)
- Neutrophils ≥1.0 x 103 / microL (SI: ≥1.0 GI/L)
- Platelets ≥75 x 103 /microL (SI: ≥ 75 GI/L)
- Serum creatinine ≤1.8 mg/dL (SI: ≥ 159 micromol/L)
- AST and ALT<or= 3 x ULN
If any other labs are grade 3 or above, this must be discussed with the medical monitor.
For rest of Inclusion criteria and/or more details on the above, please refer to the study protocol. |
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| E.4 | Principal exclusion criteria |
•Has any unstable or progressive manifestation of SLE that is likely to warrant escalation in therapy beyond permitted background medications. Subjects requiring renal hemodialysis or peritoneal dialysis are also excluded •Has other inflammatory disease that might confound the evaluations of efficacy, including but not limited to rheumatoid arthritis (RA), PsA, RA/lupus overlap, psoriasis, Crohn's disease, or active Lyme disease •Is pregnant, nursing, or planning a pregnancy or planning to father a child while enrolled in the study or within 4 months after receiving the last administration of study agent •Has received systemic immunomodulatory agents other than those described in inclusion criteria within 3 months prior to the first dose of study agent •Has used oral cyclophosphamide within 90 days or IV cyclophosphamide within 180 days of starting screening •Exclusions for treatment with B-cell targeted therapies*: a.Treatment with a single B-cell targeted therapy within 3 months prior to first dose of study agent. b.Treatment with >1 previous B-cell targeted therapy within 6 months prior to first dose of study agent. c.Treatment with B-cell depleting therapy within 12 months prior to first dose of study agent, or have evidence of continued B-cell depletion following such therapy *If a subject has received one or more B-cell targeted therapies, the length of time required before administering the first dose of study agent should be whichever is the longest applicable washout period. •Has ever received ustekinumab •Has received prior immunomodulatory biologic therapy not described in Section 8.1.7 of protocol less than 5 half-lives or 3 months, whichever is longer, prior to first dose of the study agent. •Has received ACTH administered by injection within 1 month prior to the first administration of study agent •Has received topical cream/ointment preparations of cyclosporine A, high-potency topical glucocorticoids, or other topical immunomodulatory agents within 4 weeks prior to the first administration of study agent •Is currently receiving venom immunotherapy •Subjects likely to require multiple courses of systemic steroids for reasons other than SLE •Has received epidural, IV, IM, intra-articular (IA), intrabursal, or intralesional admin of glucocorticoids within 6 weeks prior to the first administration of study agent •BCG vaccination within 12 months of screening •Live virus or live bacterial vaccination within 16 weeks prior to the first administration of study agent •History of active granulomatous infection, including histoplasmosis, or coccidioidomycosis •Chest radiograph within 3 months prior to the first dose that shows an abnormality suggestive of a malignancy or current active infection, including TB •A nontuberculous mycobacterial infection or opportunistic infection •A history of, or ongoing, chronic or recurrent infectious disease •History of HIV antibody positive, or tests positive for HIV at screening •Hepatitis B infection. Subjects must undergo screening for hepatitis B virus •Seropositive for antibodies to hepatitis C virus (HCV), unless has 2 negative HCV RNA test results 6 months apart prior to screening and has a third negative HCV RNA test result at screening •Has experienced a recent single dermatomal herpes zoster eruption within the past 4 months. Has ever had multi-dermatomal herpes zoster or CNS zoster infection
•Within 2 months prior to first administration of study agent, has had a serious infection, or has been hospitalized for an infection, or has been treated with IV antibiotics for an infection. Less serious infections need not be considered exclusionary at the discretion of the Investigator •History or suspected occurrence of drug-induced lupus •Has inherited complement deficiency or combined variable immunodeficiency •Urinary protein level of >4g/day or protein/creatinine ratio estimating >4g/day equivalent proteinuria •History of catastrophic antiphospholipid syndrome •Has a known hypersensitivity to human immunoglobulin proteins •Any major illness/condition or evidence of an unstable clinical condition, disease of any organ system, or active acute or chronic infection/infectious illness •Has had major surgery within 1 month before screening, or will not have fully recovered from surgery, or has major surgery planned during the time the subject is expected to participate in the study or within 1 month after the last dose of study agent administration Has a transplanted organ •Uses semipermanently attached wigs that would interfere with scoring of cutaneous disease •Has or has had a substance abuse (drug or alcohol) problem within the previous 3 years •Presence or history of malignancy within 5 years before screening. Note cervical carcinoma and skin cancer exceptions per protocol for malignancy exclusion
(...) For rest of criteria or more details, please see the protocol |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the proportion of subjects achieving an SRI-4 composite response at Week 52.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1. Time to flare based on the proportion of subjects with a flare occurring at any time after the baseline visit through Week 52, with flare defined as either 1 or more new BILAG A or 2 or more new BILAG B domain scores
2. The proportion of subjects with an SRI-4 composite response at Week 24
3. The proportion of subjects achieving at least a 50% improvement in the number of joints with pain and signs of inflammation at Week 52 in subjects with at least 4 affected joints at baseline
4. The Proportion of subjects receiving glucocorticoids at baseline who achieve reduction in glucocorticoid dose by Week 40 and sustain that reduction through Week 52.
5. The proportion of subjects achieving at least a 50% improvement in the CLASI Activity Score at Week 52 in subjects with a CLASI Activity Score of 4 or greater at baseline
6. The proportion of subjects receiving glucocorticoids at baseline who achieve reduction on glucocorticoid dose by Week 40, sustain that reduction through Week 52, and achieve an SRI-4 composite resopnse at Week 52 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Week 52
2.Week 24
3.Week 52
4.Week 52
5.Week 52
6.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 | No |
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | Yes |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| 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 |
| Bulgaria |
| Canada |
| China |
| Colombia |
| Germany |
| Hungary |
| Japan |
| Korea, Republic of |
| Lithuania |
| Poland |
| Portugal |
| Russian Federation |
| Serbia |
| South Africa |
| Spain |
| Taiwan |
| Thailand |
| Ukraine |
| United States |
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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 | 5 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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