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A Phase 2b Dose Ranging Study to Evaluate the Efficacy and Safety of Rozibafusp Alfa (AMG 570) in Subjects With Active Systemic Lupus Erythematosus (SLE) With Inadequate Response to Standard of Care (SOC) Therapy

Efficacy and Safety of AMG 570 in Subjects With Active Systemic Lupus Erythematosus (SLE)

244

Sex: Women (228 [93.4%]) and men (16 [6.6%]) Age: Mean (SD): 43.5 (10.9) years. Race: White (201 [82.4%]), Asian 19 [7.8%]), Black (17 [7.0%]), other (4 [1.6%]), and American Indian or Alaska Native (3 [1.2%]). Ethnicity: Not Hispanic/Latino (175 [71.7%]), Hispanic/Latino (68 [27.9%]), and unknown (1 [0.4%]).

A total of 244 subjects (rozibafusp alfa: 182 and placebo: 62) were randomized in the study. A total of 154 subjects (63.1%) completed the study. Ninety subjects (36.9%) discontinued the study. The reasons for study discontinuation reported for >= 5% of subjects were decision by sponsor (53 [21.7%]) and withdrawal of consent from study (33 [13.5%]).

A total of 141 subjects (77.9%) in the overall rozibafusp alfa group and 42 subjects (67.7%) in the placebo group had at least 1 adverse event. The adverse events by preferred term reported for >= 10% of subjects (overall rozibafusp alfa vs placebo) were COVID-19 (19.3% vs 8.1%), urinary tract infection (14.4% vs 9.7%), and upper respiratory tract infection (11.0% vs 12.9%).

SRI-4 Response at Week 52: Twenty-nine of 51 subjects (56.9%), 21 of 35 subjects (60.0%), and 35 of 48 subjects (72.9%) in the 70, 280, and 420 mg rozibafusp alfa dose groups, respectively, and 26 of 43 subjects (60.5%) in the placebo group who had the opportunity to complete the week 52 visit had SRI-4 response.

SRI-4 Response at Week 24: Thirty of 58 subjects (51.7%), 20 of 36 subjects (55.6%), and 46 of 66 subjects (69.7%) in the 70, 280, and 420 mg rozibafusp alfa dose groups, respectively, and 33 of 54 subjects (61.1%) in the placebo group who had the opportunity to complete the week 24 visit had SRI-4 response. BICLA Response at Week 24: Nineteen of 58 subjects (32.8%), 18 of 36 subjects (50.0%), and 35 of 66 subjects (53.0%) in the 70, 280, and 420 mg rozibafusp alfa dose groups, respectively, and 24 of 54 subjects (44.4%) in the placebo group who had the opportunity to complete the week 24 visit had BICLA response. LLDAS Response at Week 52: Eighteen of 51 subjects (35.3%), 6 of 35 subjects (17.1%), and 21 of 48 subjects (43.8%) in the 70, 280, and 420 mg rozibafusp alfa dose groups, respectively, and 12 of 43 subjects (27.9%) in the placebo group who had the opportunity to complete the week 52 visit had LLDAS response. BICLA Response at Week 52: Twenty of 51 subjects (39.2%), 15 of 35 subjects (42.9%), and 29 of 48 subjects (60.4%) in the 70, 280, and 420 mg rozibafusp alfa dose groups, respectively, and 21 of 43 subjects (48.8%) in the placebo group who had the opportunity to complete the week 52 visit had BICLA response. SRI-4 Response at Week 52 With Reduction in the Dose of Oral Corticosteroids: One of 16 subjects (6.3%), 2 of 19 subjects (10.5%), and 8 of 25 subjects (32.0%) in the 70, 280, and 420 mg rozibafusp alfa dose groups, respectively, and 5 of 27 subjects (18.5%) in the placebo group who had the opportunity to complete the week 52 visit. Annualized Flare Rate: Annualized moderate and severe flare rate (as measured by SELENA-SLEDAI flare index) over 52 weeks was 0.52, 0.46, and 0.34 in the 70, 280, and 420 mg rozibafusp alfa dose groups, respectively, and 0.34 in the placebo group. Annualized severe flare rate (as measured by SELENA-SLEDAI flare index) over 52 weeks was 0.24, 0.30, and 0.16 in the 70, 280, and 420 mg rozibafusp alfa dose groups, respectively, and 0.21 in the placebo group. Annualized flare rate (as measured by BILAG score designation of "worse" or "new" resulting in a B score in >= 2 organs or an A score in >= 1 organ) over 52 weeks was 0.22, 0.30, and 0.31 in the 70, 280, and 420 mg rozibafusp alfa dose groups, respectively, and 0.13 in the placebo group. Improvement in Tender and Swollen Joints Count (Limited to Hands and Wrists) in Subjects With >= 6 Tender and Swollen Joints at Baseline: Fifty-five of 94 subjects (58.5%), 64 of 87 subjects (73.6%), 61 of 80 subjects (76.3%), and 56 of 71 subjects (78.9%) in the overall rozibafusp alfa group, and 20 of 34 subjects (58.8%), 23 of 32 subjects (71.9%), 26 of 31 subjects (83.9%), and 19 of 26 subjects (73.1%) in the placebo group had >= 50% improvement in tender and swollen joints count at week 12, 24, 36, and 52, respectively,. Improvement in CLASI Activity Score in Subjects With a Baseline CLASI Activity Score >= 8: Eleven of 38 subjects (28.9%), 12 of 33 subjects (36.4%), 14 of 30 subjects (46.7%), and 14 of 28 subjects (50.0%) in the overall rozibafusp alfa group and 3 of 13 subjects (23.1%), 3 of 10 subjects (30.0%), 1 of 9 subjects (11.1%), and 0 of 8 subjects in the placebo group had >= 50% improvement in CLASI activity score at week 12, 24, 36, and 52, respectively.

- Treatment with rozibafusp alfa did not result in improvement of any of the efficacy endpoints over placebo in patients with active SLE with inadequate response to SOC. Placebo rates were higher than assumed for the primary endpoint. - The safety profile observed for subjects treated with rozibafusp alfa in this study was consistent with the known profile of rozibafusp alfa. No new safety risks were identified. No apparent dose trend of adverse events was observed.

Yes

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

Kimura Takeshi

Amgen K.K.

Midtown Tower 9-7-1 Akasaka, Minato-ku, Tokyo

clinicaltrials_japan@amgen.com

Local Contact

Amgen K.K.

Midtown Tower 9-7-1 Akasaka, Minato-ku, Tokyo

+81-80-7217-8592

clinicaltrials_japan@amgen.com

completed

Feb. 19, 2020

Interventional

Allocation: Randomized Masking: None (Open Label) Intervention Model: Parallel Assignment This is a Bayesian adaptive phase 2b, multi-center, double-blind, randomized, placebo-controlled, 52-week, dose-ranging study in subjects with active SLE and inadequate response to SOC therapies including oral corticosteroids (OCS), immunosuppressants and immunomodulators.

treatment purpose

2

Inclusion Criteria Screening Visit:
1. Subject has provided informed consent prior to initiation of any study-specific activities/procedures.
2. Age >= 18 years to <= 75 years at screening visit.
3. Fulfills classification criteria for SLE according to the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for SLE (Aringer et al, 2019), with antinuclear antibody >= 1:80 by immunofluorescence on Hep-2 cells being present at screening.
4. Hybrid SLEDAI score >= 6 points with a "Clinical" hSLEDAI score >= 4 points. The "Clinical" hSLEDAI is the hSLEDAI assessment score without the inclusion of points attributable to laboratory results, including urine or immunologic parameters.
Additional protocol-specific rules are applied at screening and throughout the study, as follows:
- Arthritis: Arthritis (at least 3 tender and swollen joints) must involve joints in the hands or wrists for the hSLEDAI scoring.
- Alopecia: Subjects should have hair loss without scarring; should neither have alopecia areata nor androgenic alopecia; and should have a CLASI activity score for alopecia >= 2.
- Oral ulcers: Ulcers location and appearance must be documented by the investigator.
- Scleritis and Episcleritis: the presence of stable SLE-related scleritis and episcleritis must be documented by an ophthalmologist and other causes excluded.
- Renal: subjects with urine protein/creatinine ratio < 3000 mg/g (or equivalent method) in a clear catch spot urine sample can enroll and be scored in the hSLEDAI, provided the subject has a clinical hSLEDAI >= 4 and did not receive induction treatment for nephritis within the last year.
- Pleurisy and Pericarditis: symptoms of pleurisy and pericarditis must be accompanied by objective findings to be scored in the hSLEDAI.
5. Unless there is a documented intolerance, subjects must be taking:
- Only 1 of the following SLE treatments: anti-malarial (hydroxychloroquine, chloroquine, or quinacrine), azathioprine, methotrexate, leflunomide, mycophenolate mofetil/acid mycophenolic, or dapsone.
OR
- 2 of the above-mentioned SLE treatments in which 1 must be anti-malarial (hydroxychloroquine, chloroquine, or quinacrine).
- Treatment should be taken for >= 12 weeks prior to screening and must be a stable dose for >= 8 weeks prior to screening.
6. For subjects taking OCS, dose must be <= 20 mg/day of prednisone or OCS equivalent, and the dose must be stable at baseline visit for >= 2 weeks prior to screening visit.

Exclusion Criteria Screening Visit
Subjects are excluded from the study if any of the following criteria apply:
Disease Related:
1. Urine protein creatinine ratio >= 3000 mg/g (or equivalent) at screening or induction therapy for lupus nephritis within 1 year prior to screening visit.
2. Active CNS lupus within 1 year prior to screening including, but not limited to, aseptic meningitis, ataxia, CNS vasculitis, cranial neuropathy, demyelinating syndrome, optic neuritis, psychosis, seizures, or transverse myelitis.

Both

Systemic Lupus Erythematosus (SLE)

investigational material(s)
Generic name etc : Rozibafusp Alfa
INN of investigational material : Rozibafusp Alfa
Therapeutic category code : 339 Other agents relating to blood and body fluids
Dosage and Administration for Investigational material : Rozibafusp Alfa 70 mg, 280 mg, or 420 mg will be administered subcutaneously every 2 weeks

control material(s)
Generic name etc :
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : Placebo will be administered subcutaneously once every 2 weeks.

1. Number of Participants With a SLE Responder Index (SRI-4) Response at Week 52 [Time Frame: Week 52]
SRI-4 response at Week 52 is defined as a >= 4-point decrease in the hybrid Systemic Lupus Erythematosus Disease Activity Index (hSLEDAI) score, and no new British Isles Lupus Assessment Group (BILAG) 2004 A score, no greater than 1 new BILAG B domain scores compared with baseline, and a less than 0.3-point deterioration from baseline in Physician Global Assessment (PGA) (scale 0 to3), and no use of more than protocol allowed therapies.

1. Number of Participants With a SRI-4 Response at Week 24 [Time Frame: Week 24]
2. Number of Participants Who Achieved a BILAG Based Combined Lupus Assessment (BICLA) Response at Week 24 [Time Frame: Week24]
3. Number of Participants Who Achieved a Lupus Low Disease Activity State (LLDAS) Response at Week 52 [Time Frame: Week 52]
4. Number of Participants Who Achieved a BICLA Response at Week 52 [Time Frame: Week 52]
5. Number of Participants Achieving a SRI-4 Response With a Reduction of Oral Corticosteroids (OCS) to <= 7.5 mg/Day by Week 44 and Sustained Through Week 52 In Participants With a Baseline OCS Dose >= 10 mg/Day [Time Frame: Up to Week 52]
6. Annualized Moderate and Severe Flare Rate Over 52 Weeks as Measured by Safety of Estrogens in Systemic Lupus Erythematosus National Assessment [SELENA] -Systemic Lupus Erythematosus Disease Activity Index [SLEDAI] Flare Index (SFI) [Time Frame: Up to Week 52]
7. Annualized Severe Flare Rate Over 52 Weeks as Measured by SFI [Time Frame: Up to Week 52]
8. Annualized Flares Rate Over 52 Weeks as Measured by BILAG Score Designation of "Worse" or "New" Resulting in a B-Score In >= 2 Organs or an A-Score in >= 1 Organ [Time Frame: Up to Week 52]
9. Number of Participants With >= 6 Tender and Swollen Joints in Hands and Wrists at Baseline Achieving >= 50% Improvement From Baseline at Weeks 12, 24, 36, and 52 [Time Frame: Week 12, 24, 36, and 52]
10. Number of Participants With a Cutaneous Lupus Erythematosus Area and Severity Index (CLASI) Activity Score >= 8 at Baseline Achieving >= 50% Improvement From Baseline at Weeks 12, 24, 36, and 52 [Time Frame: Week 12, 24, 36, and 52]
11. Change From Baseline in Patient-Reported Outcome Measurement Information System Fatigue Short Form 7a Instrument (PROMIS-Fatigue SF7a) Score at Weeks 12, 24, 36, 44, and 52 [Time Frame: Week 12, 24, 36, 44, and 52]
12. Change From Baseline in the Short Form 36 Version 2 (SF-36v2) Health Survey Physical Component Score at Weeks 12, 24, 36, 44 and 52 [Time Frame: Week 12, 24, 36, 44, and 52]
13.Change From Baseline in the SF-36v2 Health Survey Mental Component Score at Weeks 12, 24, 36, 44 and 52 [Time Frame: Week 12, 24,36, 44, and 52]
14. Change From Baseline in the SF-36v2 Health Survey Physical Functioning Domain Score at Weeks 12, 24, 36, 44 and 52 [Time Frame: Week 12, 24, 36, 44, and 52]
15. Change From Baseline in the SF-36v2 Health Survey Physical Role Domain Score at Weeks 12, 24, 36, 44 and 52 [Time Frame: Week 12,24, 36, 44, and 52]
16. Change From Baseline in the SF-36v2 Health Survey Bodily Pain Domain Score at Weeks 12, 24, 36, 44 and 52 [Time Frame: Week 12, 24,36, 44, and 52]
17. Change From Baseline in the SF-36v2 Health Survey General Health Domain Score at Weeks 12, 24, 36, 44 and 52 [Time Frame: Week 12,24, 36, 44, and 52]
18. Change From Baseline in the SF-36v2 Health Survey Vitality Domain Score at Weeks 12, 24, 36, 44 and 52 [Time Frame: Week 12, 24, 36,44, and 52]
19. Change From Baseline in the SF-36v2 Health Survey Social Role Functioning Domain Score at Weeks 12, 24, 36, 44 and 52 [Time Frame: Week 12, 24, 36, 44, and 52]
20. Change From Baseline in the SF-36v2 Health Survey Emotional Role Domain Score at Weeks 12, 24, 36, 44 and 52 [Time Frame: Week 12,24, 36, 44, and 52]
21. Change From Baseline in the SF-36v2 Health Survey Mental Health Domain Score at Weeks 12, 24, 36, 44 and 52 [Time Frame: Week 12,24, 36, 44, and 52]
22. Change From Baseline in Lupus Quality of Life Questionnaire (LupusQoL) Score at Weeks 12, 24, 36, 44, and 52 [Time Frame: Week 12, 24,36, 44, and 52]
23. Change From Baseline in Patient Global Assessment Score (PtGA) at Weeks 12, 24, 36, 44, and 52 [Time Frame: Week 12, 24, 36, 44, and52]
24. Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) [Time Frame: Up to approximately 68 weeks]
25. Serum Concentration of Rozibafusp Alfa [Time Frame: Week 1, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 36, Week 44, Week 52, Week 56, Week 60, Week 64, and Week 68]
26. Terminal Half-life of Rozibafusp Alfa [Time Frame: Up to Week 68]

Sept. 04, 2019