Efficacy and Safety of Anifrolumab Compared to Placebo in Adult Subjects With Active Systemic Lupus Erythematosus

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02446899
• Collaborator: PRA Health Sciences (Industry)
• Enrollment: 373
• Locations: 113
• Arms: 2
• Actual Duration (Months): 38.6
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of an intravenous treatment regimen of anifrolumab versus placebo in adult participants with moderately to severely active, autoantibody-positive systemic lupus erythematosus (SLE).

Condition or Disease	Intervention/Treatment	Phase
Active Systemic Lupus Erythematosus	Biological: Anifrolumab; Drug: Placebo	Phase 3

Detailed Description

This is a Phase 3, multicentre, multinational, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of an intravenous treatment regimen of anifrolumab versus placebo in participants with moderately to severely active, autoantibody-positive systemic lupus erythematosus (SLE) while receiving standard of care (SOC) treatment. Participants must be taking either 1 or any combination of the following: oral corticosteroids (OCS), antimalarial, and/or immunosuppressants. The study will be performed in adult participants aged 18 to 70 years of age.

Approximately 360 participants receiving SOC treatment will be randomised in a 1:1 ratio to receive a fixed intravenous dose of anifrolumab 300 mg or placebo every 4 weeks for a total of 13 doses (Week 0 to Week 48), with the primary endpoint evaluated at the Week 52 visit. Investigational product will be administered as an intravenous infusion (IV) via an infusion pump over a minimum of 30 minutes, every 4 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 373 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 3 Study Evaluating the Efficacy and Safety of Anifrolumab in Adult Subjects With Active Systemic Lupus Erythematosus
• Actual Study Start Date: Jul 9, 2015
• Actual Primary Completion Date: Sep 27, 2018
• Actual Study Completion Date: Sep 27, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Anifrolumab Anifrolumab 300 mg intravenous infusion (IV) administered every 4 weeks for a total of 13 doses.	Biological: Anifrolumab; Intravenous infusion (IV)
Placebo Comparator: Placebo Placebo intravenous infusion (IV) administered every 4 weeks for a total of 13 doses.	Drug: Placebo; Intravenous infusion (IV)

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Achieved the British Isles Lupus Assessment Group Based Composite Lupus Assessment (BICLA) Response at Week 52 [Baseline; Week 52]

   Composite endpoint BICLA was defined by meeting all of the following criteria: Reduction of all baseline British Isles Lupus Assessment Group (BILAG)-2004 A to B/C/D and baseline BILAG-2004 B to C/D, and no BILAG-2004 worsening in other organ systems, as defined by ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B No worsening from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), where worsening is defined as an increase from baseline of >0 points in SLEDAI-2K No worsening from baseline in participants' lupus disease activity, where worsening is defined by an increase ≥0.30 points on a 3-point Physician's Global Assessment (PGA) visual analogue scale (VAS) No discontinuation of investigational product No use of restricted medications beyond the protocol allowed threshold before assessment

Secondary Outcome Measures

1. Number of Participants Who Achieved the British Isles Lupus Assessment Group Based Composite Lupus Assessment (BICLA) Response at Week 52 in the IFN Test-High Sub-group [Baseline; Week 52]

   Defined by meeting all of the following criteria: Reduction of all baseline British Isles Lupus Assessment Group (BILAG)-2004 A to B/C/D and baseline BILAG-2004 B to C/D, and no BILAG-2004 worsening in other organ systems, as defined by ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B No worsening from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), where worsening is defined as an increase from baseline to >0 points in SLEDAI-2K No worsening from baseline in participants' lupus disease activity, where worsening is defined by an increase ≥0.30 points on a 3-point Physician's Global Assessment (PGA) visual analogue scale (VAS) No discontinuation of investigational product No use of restricted medications beyond the protocol allowed threshold before assessment

2. Number of Participants Who Achieved and Maintained an Oral Corticosteroids (OCS) Dose of ≤7.5 mg/Day at Week 52 in the Sub-Group of Participants With Baseline OCS ≥10 mg/Day [Week 40; Week 52]

   Maintained OCS reduction was defined by meeting all of the following criteria: Achieve an OCS dose of ≤7.5 mg/day prednisone or equivalent by Week 40 Maintain an OCS dose ≤7.5 mg/day prednisone or equivalent from Week 40 to Week 52 No discontinuation of investigational product No use of restricted medications beyond the protocol allowed threshold before assessment

3. Number of Participants With a ≥50% Reduction in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Score at Week 12 in The Sub-Group of Participants With Baseline CLASI Activity Score of ≥10 [Baseline; Week 12]

   50% reduction in CLASI activity score compared to baseline was defined by meeting all of the following criteria: Achieve ≥50% reduction of CLASI activity score at Week 12 compared to baseline No discontinuation of investigational product No use of restricted medications beyond the protocol allowed threshold before assessment

4. Number of Participants With ≥50% Reduction in Joint Counts at Week 52 in The Sub-group of Participants With ≥6 Swollen and ≥6 Tender Joints at Baseline [Baseline; Week 52]

   50% reduction in the number of swollen and tender joints compared to baseline was defined by meeting all of the following criteria: Achieve ≥50% reduction from baseline in the number of swollen and tender joints, separately No discontinuation of investigational product No use of restricted medications beyond the protocol allowed threshold before assessment

5. Annualised Flare Rate Through 52 Weeks [Baseline to Week 52]

   A flare was defined as either 1 or more new British Isle Lupus Assessment Group (BILAG-2004) A or 2 or more new BILAG-2004 B items compared to the previous visit. The occurrence of a new flare was checked for each available visit versus the previous available visit up to Week 52. If no new flares occurred, the number of flares was set to 0. Otherwise all flares were counted leading to the maximum number of flares of 13. The annualized flare rate was calculated as the number of flares divided by the flare exposure time in days multiplied with 365.25 (1 year). The flare exposure time is the time up to Week 52 (date of BILAG-2004 assessment at Week 52) or up to the date of last available BILAG-2004 assessment.

6. Number of Participants With One or More Adverse Events (AEs) [Baseline to end of study (Maximum of 60 weeks)]

   An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. AEs were collected throughout the duration of the study, from baseline until end of follow-up (a maximum of 12 weeks post last dose [Week 48]), or until Week 52 for participants who enrolled onto the long term extension (LTE). The reported value is inclusive of serious and non-serious AEs.

7. Number of Participants With One or More Adverse Events of Special Interest (AESIs) [Baseline to end of study (Maximum of 60 weeks)]

   An AESI is an adverse event (AE) of scientific and medical concern specific to understanding biologics. An AESI may be serious or non-serious. AESI are serious infections, including non-opportunistic serious infections, opportunistic infections, anaphylaxis, malignancy, herpes zoster, tuberculosis (TB) (including latent TB), influenza, vasculitis (non-systemic lupus erythematosus [SLE]), and major adverse cardiovascular events (MACE) (including stroke, myocardial infarction [MI], or cardiovascular death). AESIs were collected throughout the study, from baseline until end of follow-up (a maximum of 12 weeks post last dose [Week 48]), or until Week 52 for participants who enrolled onto the long term extension (LTE).

8. Number of Participants With a Potentially Clinically Important Change From Baseline in Vital Sign Measurements [Baseline to end of study (Maximum of 60 weeks)]

   Vital sign measurements included oral temperature, blood pressure (BP), pulse rate, and respiratory rate. Vital signs were collected throughout the duration of the study, from baseline until end of follow-up (a maximum of 12 weeks post last dose [Week 48]), or until Week 52 for participants who enrolled onto the long term extension (LTE).

9. Number of Participants With a Potentially Clinically Important Change From Baseline in Clinical Laboratory Tests [Baseline to end of study (Maximum of 60 weeks)]

   Clinical laboratory tests were analyzed in a central clinical laboratory and included hematology, serum chemistry and urinalysis tests. Laboratory values were collected throughout the duration of the study, from baseline until end of follow-up (a maximum of 12 weeks post last dose [Week 48]), or until Week 52 for participants who enrolled onto the long term extension (LTE).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Aged 18 through 70 years at the time of screening

2. Diagnosis of paediatric or adult SLE with a diagnosis of SLE according to the ACR 1982 revised criteria ≥24 weeks prior to signing the Informed Consent form (ICF)

3. Currently receiving at least 1 of the following:

4. Where prednisone is the single standard of care medication (ie, the subject is not concurrently receiving any medication listed in inclusion criterion 3(c)), a dose of oral prednisone ≥7.5 mg/day but ≤40 mg/day (or prednisone equivalent) for a minimum of 8 weeks prior to Day 1. In addition, the dose of oral prednisone or prednisone equivalent the subject is taking must be stable for a minimum of 2 weeks prior to randomisation

5. Where prednisone is not the single standard of care medication (ie, the subject is concurrently receiving at least one medication listed in inclusion criterion 3(c), a dose of oral prednisone (≤40 mg/day) (or prednisone equivalent) for a minimum of 2 weeks prior to signing of the ICF. In addition, the dose of oral prednisone or prednisone equivalent the subject is taking must be stable for a minimum of 2 weeks prior to randomisation.

6. Any of the following medications administered for a minimum of 12 weeks prior to signing the informed consent, and at a stable dose for a minimum of 8 weeks prior to signing the informed consent and through Day 1:

(i) Azathioprine ≤200 mg/day (ii) Antimalarial (eg, chloroquine, hydroxychloroquine, quinacrine) (iii) Mycophenolate mofetil ≤2 g/day or mycophenolic acid ≤1.44 g/day (iv) Oral, subcutaneous (SC), or intramuscular methotrexate ≤25 mg/week (v) Mizoribine ≤150 mg/day

1. Fulfils at least 4 of the 11 ACR modified 1982 classification criteria for SLE, at least 1 of which must be:

2. Positive antinuclear antibody (ANA) test at screening by immunofluorescent assay (IFA) at the central laboratory with titre ≥1:80; OR

3. Anti-dsDNA antibodies at screening elevated to above normal (including indeterminate), as per the central laboratory; OR

4. Anti-Smith (anti-Sm) antibody at screening elevated to above normal as per the central laboratory

5. At Screening, Disease Activity Adjudication Group confirmation of:

SLEDAI-2K Criteria: SLEDAI-2K score ≥6 points and "Clinical" SLEDAI-2K score ≥4 points. The "Clinical" SLEDAI-2K is the SLEDAI-2K assessment score without the inclusion of points attributable to any urine or laboratory results including immunologic measures.

1. Must not have active or latent TB on either chest radiograph or by quantiferon gold test

2. Day 1 "Clinical" SLEDAI-2K score ≥4 points

3. OCS dose stable for at least 2 weeks prior to randomisation

4. Stable SLE SOC treatment at the time of randomisation

5. Women of child-bearing potential must have a negative serum β-hCG test at and negative urine pregnancy test at randomisation prior to administration of investigational product

Exclusion Criteria:

1. Receipt of any investigational product (small molecule or biologic agent) within 4 weeks or 5 half-lives prior to signing of the ICF, whichever is greater

2. Receipt of any of the following:

(a) Intra-articular, intramuscular or IV glucocorticosteroids within 6 weeks prior to Day 1

1. History of, or current diagnosis of, a clinically significant non SLE-related vasculitis syndrome.

2. Active severe or unstable neuropsychiatric SLE

3. Active severe SLE-driven renal disease

4. Diagnosis (within 1 year of signing the ICF) of mixed connective tissue disease or any history of overlap syndromes of SLE or SSc.

5. History of, or current, inflammatory joint or skin disease other than SLE

6. History of any non-SLE disease that has required treatment with oral or parenteral corticosteroids for more than 2 weeks within the last 24 weeks prior to signing the ICF

7. 26.27. Known history of a primary immunodeficiency, splenectomy, or any underlying condition that predisposes the subject to infection, or a positive result for human immunodeficiency virus (HIV) infection confirmed by central laboratory at screening. Subjects refusing HIV testing during the screening period will not be eligible for study participation

8. Confirmed positive test for hepatitis B or hepatitis C

9. Any severe herpes infection at any time prior to Week 0 (Day 1)

10. Opportunistic infection requiring hospitalisation or intravenous antimicrobial treatment within 3 years prior to randomization

11. History of cancer, apart from:

12. Squamous or basal cell carcinoma of the skin that has been successfully treated

13. Cervical cancer in situ that has been successfully treated

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Covina	California	United States	91723
2	Research Site	Hemet	California	United States	92543-4403
3	Research Site	Los Angeles	California	United States	90095
4	Research Site	San Leandro	California	United States	94578
5	Research Site	Torrance	California	United States	90509
6	Research Site	Upland	California	United States	91786
7	Research Site	Denver	Colorado	United States	80230
8	Research Site	Bridgeport	Connecticut	United States	06606
9	Research Site	Bridgeport	Connecticut	United States	6606
10	Research Site	Brandon	Florida	United States	33511
11	Research Site	Orlando	Florida	United States	32804
12	Research Site	Palm Harbor	Florida	United States	34684
13	Research Site	Tamarac	Florida	United States	33321
14	Research Site	Tampa	Florida	United States	33614
15	Research Site	Atlanta	Georgia	United States	30303
16	Research Site	Boston	Massachusetts	United States	02118
17	Research Site	Ann Arbor	Michigan	United States	48109
18	Research Site	Lincoln	Nebraska	United States	68516
19	Research Site	Las Cruces	New Mexico	United States	88011
20	Research Site	Brooklyn	New York	United States	11201
21	Research Site	New York	New York	United States	10016
22	Research Site	New York	New York	United States	10021
23	Research Site	New York	New York	United States	10032
24	Research Site	Greenville	North Carolina	United States	27834
25	Research Site	Oklahoma City	Oklahoma	United States	73104
26	Research Site	Duncansville	Pennsylvania	United States	16635
27	Research Site	Pittsburgh	Pennsylvania	United States	15213
28	Research Site	Memphis	Tennessee	United States	38163
29	Research Site	Dallas	Texas	United States	75231
30	Research Site	Houston	Texas	United States	77004
31	Research Site	Houston	Texas	United States	77034
32	Research Site	Stafford	Texas	United States	77477
33	Research Site	Arlington	Virginia	United States	22205
34	Research Site	Seattle	Washington	United States	98122
35	Research Site	Spokane	Washington	United States	99204
36	Research Site	Buenos Aires		Argentina	C1015ABO
37	Research Site	Mendoza		Argentina	5500
38	Research Site	Quilmes		Argentina	1878
39	Research Site	Bruxelles		Belgium	1070
40	Research Site	Leuven		Belgium	3000
41	Research Site	Liege		Belgium	B-4000
42	Research Site	Merksem		Belgium	B-2170
43	Research Site	Goiania		Brazil	74110-120
44	Research Site	Juiz de Fora		Brazil	36010 570
45	Research Site	Sao Paulo		Brazil	04032-060
46	Research Site	Sao Paulo		Brazil	05403-9000
47	Research Site	Sao Paulo		Brazil	05652-900
48	Research Site	Plovdiv		Bulgaria	4002
49	Research Site	Plovdiv		Bulgaria	4003
50	Research Site	Hamilton	Ontario	Canada	L8S 4K1
51	Research Site	Rimouski	Quebec	Canada	G5L 5T1
52	Research Site	Bordeaux		France	33000
53	Research Site	Lille		France	59037
54	Research Site	Montpellier CEDEX 5		France	34295
55	Research Site	Paris		France	75651
56	Research Site	Paris		France	75679
57	Research Site	Pessac		France	33604
58	Research Site	Toulouse		France	31000
59	Research Site	Berlin		Germany	D-10117
60	Research Site	Hamburg		Germany	20246
61	Research Site	Jena		Germany	07747
62	Research Site	Mainz		Germany	55131
63	Research Site	München		Germany	80336
64	Research Site	Chiba-shi		Japan	260-8712
65	Research Site	Chuo-ku		Japan	104-8560
66	Research Site	Fukuoka-shi		Japan	810-8539
67	Research Site	Fukuoka-shi		Japan	810-8563
68	Research Site	Hiroshima-shi		Japan	730-8619
69	Research Site	Kitakyushu-shi		Japan	807-8555
70	Research Site	Kurashiki-shi		Japan	710-8522
71	Research Site	Meguro-ku		Japan	152-8902
72	Research Site	Meguro-ku		Japan	153-8515
73	Research Site	Nagasaki-shi		Japan	852-8501
74	Research Site	Nagoya-shi		Japan	460-0001
75	Research Site	Omura-shi		Japan	856-8562
76	Research Site	Sapporo-shi		Japan	060-8638
77	Research Site	Sasebo-shi		Japan	857-1195
78	Research Site	Sendai-shi		Japan	980-8574
79	Research Site	Shinjuku-ku		Japan	160-8582
80	Research Site	Tsukuba		Japan	305-8577
81	Research Site	Jeju-si		Korea, Republic of	690-767
82	Research Site	Seoul		Korea, Republic of	05030
83	Research Site	Seoul		Korea, Republic of	06591
84	Research Site	Seoul		Korea, Republic of	133792
85	Research Site	Suwon-si		Korea, Republic of	16499
86	Research Site	Kaunas		Lithuania	LT-50009
87	Research Site	Klaipeda		Lithuania	LT-92288
88	Research Site	Chihuahua		Mexico	31000
89	Research Site	Leon		Mexico	37000
90	Research Site	Mexico D.F.		Mexico	014080
91	Research Site	Mexico		Mexico	06700
92	Research Site	Morelia		Mexico	58070
93	Research Site	Mérida		Mexico	97000
94	Research Site	San Luis Potosí		Mexico	78213
95	Research Site	Kemerovo		Russian Federation	650066
96	Research Site	Petrozavodsk		Russian Federation	185019
97	Research Site	Smolensk		Russian Federation	214015
98	Research Site	Tolyatti		Russian Federation	445039
99	Research Site	Vladimir		Russian Federation	600023
100	Research Site	Yaroslavl		Russian Federation	150003
101	Research Site	Cape Town		South Africa	7500
102	Research Site	Johannesburg		South Africa	2188
103	Research Site	Johannesburg		South Africa	2193
104	Research Site	Stellenbosch		South Africa	7600
105	Research Site	Barcelona		Spain	08035
106	Research Site	Getafe		Spain	28905
107	Research Site	Las Palmas de Gran Canaria		Spain	35010
108	Research Site	Madrid		Spain	28046
109	Research Site	Madrid		Spain	28702
110	Research Site	Mérida		Spain	06800
111	Research Site	Santiago de Compostela		Spain	15706
112	Research Site	Servilla		Spain	41014
113	Research Site	Vigo		Spain	36200

Sponsors and Collaborators

• AstraZeneca
• PRA Health Sciences

Investigators

• Study Director: Lilia Pineda, MD, Medical Science Director

Study Documents (Full-Text)

• Study Protocol - May 23, 2019
• Statistical Analysis Plan - Jul 26, 2019

More Information

Additional Information:

• Redacted CSP
• Redacted SAP

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02446899
• Other Study ID Numbers: D3461C00004
• First Posted: May 18, 2015
• Last Update Posted: Apr 21, 2020
• Last Verified: Apr 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by AstraZeneca: Active Systemic Lupus Erythematosus
• Additional relevant MeSH terms: Lupus Erythematosus, Systemic

Study Results

Participant Flow

Recruitment Details	Participants took part in the trial at 119 sites in 15 countries worldwide.
Pre-assignment Detail	8 participants were assigned study drug, but due to non-compliance were analyzed separately (not included in the participant flow). 3 additional participants were assigned study drug & included in the participant flow, but did not receive study drug due to an adverse event (1 Anifrolumab 300mg) & failure to meet randomization criteria (2 Placebo).

Arm/Group Title	Anifrolumab 300 mg	Placebo
Arm/Group Description	Anifrolumab (300 mg) administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).	Matching placebo administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).
Period Title: Overall Study
STARTED	181	184
Received Study Drug	180	182
COMPLETED	156	136
NOT COMPLETED	25	48

Baseline Characteristics

Arm/Group Title	Anifrolumab 300 mg	Placebo	Total
Arm/Group Description	Anifrolumab (300 mg) administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).	Matching placebo administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).	Total of all reporting groups
Overall Participants	180	182	362
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	175 97.2%	181 99.5%	356 98.3%
>=65 years	5 2.8%	1 0.5%	6 1.7%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	43.1 (11.95)	41.1 (11.47)	42.1 (11.74)
Sex: Female, Male (Count of Participants)
Female	168 93.3%	170 93.4%	338 93.4%
Male	12 6.7%	12 6.6%	24 6.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	54 30%	54 29.7%	108 29.8%
Not Hispanic or Latino	118 65.6%	120 65.9%	238 65.7%
Unknown or Not Reported	8 4.4%	8 4.4%	16 4.4%
Race/Ethnicity, Customized (Count of Participants)
White	110 61.1%	107 58.8%	217 59.9%
Black or African American	17 9.4%	25 13.7%	42 11.6%
Asian	30 16.7%	30 16.5%	60 16.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
American Indian or Alaska Native	4 2.2%	1 0.5%	5 1.4%
Other	11 6.1%	11 6%	22 6.1%
Missing	8 4.4%	8 4.4%	16 4.4%
Geographic region (Count of Participants)
Asia Pacific	27 15%	26 14.3%	53 14.6%
Europe	51 28.3%	46 25.3%	97 26.8%
Latin America	35 19.4%	32 17.6%	67 18.5%
United States/Canada	64 35.6%	68 37.4%	132 36.5%
Rest of World (South Africa)	3 1.7%	10 5.5%	13 3.6%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Achieved the British Isles Lupus Assessment Group Based Composite Lupus Assessment (BICLA) Response at Week 52
Description	Composite endpoint BICLA was defined by meeting all of the following criteria: Reduction of all baseline British Isles Lupus Assessment Group (BILAG)-2004 A to B/C/D and baseline BILAG-2004 B to C/D, and no BILAG-2004 worsening in other organ systems, as defined by ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B No worsening from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), where worsening is defined as an increase from baseline of >0 points in SLEDAI-2K No worsening from baseline in participants' lupus disease activity, where worsening is defined by an increase ≥0.30 points on a 3-point Physician's Global Assessment (PGA) visual analogue scale (VAS) No discontinuation of investigational product No use of restricted medications beyond the protocol allowed threshold before assessment
Time Frame	Baseline; Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set: All participants who were randomized and received at least one dose of study drug.

Arm/Group Title	Anifrolumab 300 mg	Placebo
Arm/Group Description	Anifrolumab (300 mg) administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).	Matching placebo administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).
Measure Participants	180	182
Count of Participants [Participants]	86 47.8%	57 31.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anifrolumab 300 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	The difference in estimates and associated 95% CI are weighted and are calculated using a stratified Cochran-Mantel-Haenszel (CMH) approach, with stratification factors (SLEDAI-2K score at screening [<10 points vs >= 10 points], Week 0 OCS dose [<10 mg/day vs >=10 mg/day prednisone or equivalent] and type I IFN gene signature test result at screening [high vs low]).
Statistical Test of Hypothesis	p-Value	0.0013
	Comments	Nominal p-value.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	16.3
	Confidence Interval	(2-Sided) 95%; 6.3 to 26.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants Who Achieved the British Isles Lupus Assessment Group Based Composite Lupus Assessment (BICLA) Response at Week 52 in the IFN Test-High Sub-group
Description	Defined by meeting all of the following criteria: Reduction of all baseline British Isles Lupus Assessment Group (BILAG)-2004 A to B/C/D and baseline BILAG-2004 B to C/D, and no BILAG-2004 worsening in other organ systems, as defined by ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B No worsening from baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), where worsening is defined as an increase from baseline to >0 points in SLEDAI-2K No worsening from baseline in participants' lupus disease activity, where worsening is defined by an increase ≥0.30 points on a 3-point Physician's Global Assessment (PGA) visual analogue scale (VAS) No discontinuation of investigational product No use of restricted medications beyond the protocol allowed threshold before assessment
Time Frame	Baseline; Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set: All participants who were randomized and received at least one dose of study drug, with a high interferon (IFN) test result at baseline.

Arm/Group Title	Anifrolumab 300 mg	Placebo
Arm/Group Description	Anifrolumab (300 mg) administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).	Matching placebo administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).
Measure Participants	150	151
Count of Participants [Participants]	72 40%	46 25.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anifrolumab 300 mg, Placebo
	Comments	The difference in estimates and associated 95% CI are weighted and are calculated using a stratified Cochran-Mantel-Haenszel (CMH) approach, with stratification factors (SLEDAI-2K score at screening [<10 points vs >= 10 points], Week 0 OCS dose [<10 mg/day vs >=10 mg/day prednisone or equivalent] and type I IFN gene signature test result at screening [high vs low]).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0022
	Comments	Adjusted p-value.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	17.3
	Confidence Interval	(2-Sided) 95%; 6.5 to 28.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Participants Who Achieved and Maintained an Oral Corticosteroids (OCS) Dose of ≤7.5 mg/Day at Week 52 in the Sub-Group of Participants With Baseline OCS ≥10 mg/Day
Description	Maintained OCS reduction was defined by meeting all of the following criteria: Achieve an OCS dose of ≤7.5 mg/day prednisone or equivalent by Week 40 Maintain an OCS dose ≤7.5 mg/day prednisone or equivalent from Week 40 to Week 52 No discontinuation of investigational product No use of restricted medications beyond the protocol allowed threshold before assessment
Time Frame	Week 40; Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set: All participants who were randomized and received at least one dose of study drug, who had a baseline OCS dose of ≥10 mg/day.

Arm/Group Title	Anifrolumab 300 mg	Placebo
Arm/Group Description	Anifrolumab (300 mg) administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).	Matching placebo administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).
Measure Participants	87	83
Count of Participants [Participants]	45 25%	25 13.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anifrolumab 300 mg, Placebo
	Comments	The difference in estimates and associated 95% CI are weighted and are calculated using a stratified Cochran-Mantel-Haenszel (CMH) approach, with stratification factors (SLEDAI-2K score at screening [<10 points vs >= 10 points], Week 0 OCS dose [<10 mg/day vs >=10 mg/day prednisone or equivalent] and type I IFN gene signature test result at screening [high vs low]).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0135
	Comments	Adjusted p-value.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	21.2
	Confidence Interval	(2-Sided) 95%; 6.8 to 35.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of Participants With a ≥50% Reduction in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity Score at Week 12 in The Sub-Group of Participants With Baseline CLASI Activity Score of ≥10
Description	50% reduction in CLASI activity score compared to baseline was defined by meeting all of the following criteria: Achieve ≥50% reduction of CLASI activity score at Week 12 compared to baseline No discontinuation of investigational product No use of restricted medications beyond the protocol allowed threshold before assessment
Time Frame	Baseline; Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set: All participants who were randomized and received at least one dose of study drug, and who had a CLASI activity score of ≥10 at baseline.

Arm/Group Title	Anifrolumab 300 mg	Placebo
Arm/Group Description	Anifrolumab (300 mg) administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).	Matching placebo administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).
Measure Participants	49	40
Count of Participants [Participants]	24 13.3%	10 5.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anifrolumab 300 mg, Placebo
	Comments	The difference in estimates and associated 95% CI are weighted and are calculated using a stratified Cochran-Mantel-Haenszel (CMH) approach, with stratification factors (SLEDAI-2K score at screening [<10 points vs >= 10 points], Week 0 OCS dose [<10 mg/day vs >=10 mg/day prednisone or equivalent] and type I IFN gene signature test result at screening [high vs low]).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0392
	Comments	Adjusted p-value.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	24.0
	Confidence Interval	(2-Sided) 95%; 4.3 to 43.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Number of Participants With ≥50% Reduction in Joint Counts at Week 52 in The Sub-group of Participants With ≥6 Swollen and ≥6 Tender Joints at Baseline
Description	50% reduction in the number of swollen and tender joints compared to baseline was defined by meeting all of the following criteria: Achieve ≥50% reduction from baseline in the number of swollen and tender joints, separately No discontinuation of investigational product No use of restricted medications beyond the protocol allowed threshold before assessment
Time Frame	Baseline; Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set: All participants who were randomized and received at least one dose of study drug, and who had ≥6 swollen and ≥6 tender joints at baseline.

Arm/Group Title	Anifrolumab 300 mg	Placebo
Arm/Group Description	Anifrolumab (300 mg) administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).	Matching placebo administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).
Measure Participants	71	90
Count of Participants [Participants]	30 16.7%	34 18.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anifrolumab 300 mg, Placebo
	Comments	The difference in estimates and associated 95% CI are weighted and are calculated using a stratified Cochran-Mantel-Haenszel (CMH) approach, with stratification factors (SLEDAI-2K score at screening [<10 points vs >= 10 points], Week 0 OCS dose [<10 mg/day vs >=10 mg/day prednisone or equivalent] and type I IFN gene signature test result at screening [high vs low]).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5469
	Comments	Adjusted p-value
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.7
	Confidence Interval	(2-Sided) 95%; -10.6 to 20.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Annualised Flare Rate Through 52 Weeks
Description	A flare was defined as either 1 or more new British Isle Lupus Assessment Group (BILAG-2004) A or 2 or more new BILAG-2004 B items compared to the previous visit. The occurrence of a new flare was checked for each available visit versus the previous available visit up to Week 52. If no new flares occurred, the number of flares was set to 0. Otherwise all flares were counted leading to the maximum number of flares of 13. The annualized flare rate was calculated as the number of flares divided by the flare exposure time in days multiplied with 365.25 (1 year). The flare exposure time is the time up to Week 52 (date of BILAG-2004 assessment at Week 52) or up to the date of last available BILAG-2004 assessment.
Time Frame	Baseline to Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set: All participants who were randomized and received at least one dose of study drug.

Arm/Group Title	Anifrolumab 300 mg	Placebo
Arm/Group Description	Anifrolumab (300 mg) administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).	Matching placebo administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).
Measure Participants	180	182
Number (95% Confidence Interval) [Annualized flare rate ratio]	0.43	0.64

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anifrolumab 300 mg, Placebo
	Comments	Analysed using a negative binomial regression model. The response variable in the model is the number of flares over the 52-week treatment period. The model includes covariates of treatment group, and the stratification factors (SLEDAI-2K score at screening [<10 points vs >=10 points], Week 0 OCS dose [<10 mg/day vs >=10 mg/day prednisone or equivalent] and type I IFN gene signature test result at screening [high vs low]). The logarithm of the follow-up time is used as an offset variable.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0809
	Comments	Adjusted p-value.
	Method	Negative binomial regression
	Comments
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.48 to 0.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Number of Participants With One or More Adverse Events (AEs)
Description	An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. AEs were collected throughout the duration of the study, from baseline until end of follow-up (a maximum of 12 weeks post last dose [Week 48]), or until Week 52 for participants who enrolled onto the long term extension (LTE). The reported value is inclusive of serious and non-serious AEs.
Time Frame	Baseline to end of study (Maximum of 60 weeks)

Outcome Measure Data

Analysis Population Description

Full Analysis Set: All participants who were randomized and received at least one dose of study drug.

Arm/Group Title	Anifrolumab 300 mg	Placebo
Arm/Group Description	Anifrolumab (300 mg) administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).	Matching placebo administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).
Measure Participants	180	182
Count of Participants [Participants]	162 90%	154 84.6%

8. Secondary Outcome

Title	Number of Participants With One or More Adverse Events of Special Interest (AESIs)
Description	An AESI is an adverse event (AE) of scientific and medical concern specific to understanding biologics. An AESI may be serious or non-serious. AESI are serious infections, including non-opportunistic serious infections, opportunistic infections, anaphylaxis, malignancy, herpes zoster, tuberculosis (TB) (including latent TB), influenza, vasculitis (non-systemic lupus erythematosus [SLE]), and major adverse cardiovascular events (MACE) (including stroke, myocardial infarction [MI], or cardiovascular death). AESIs were collected throughout the study, from baseline until end of follow-up (a maximum of 12 weeks post last dose [Week 48]), or until Week 52 for participants who enrolled onto the long term extension (LTE).
Time Frame	Baseline to end of study (Maximum of 60 weeks)

Outcome Measure Data

Analysis Population Description

Full Analysis Set: All participants who were randomized and received at least one dose of study drug.

Arm/Group Title	Anifrolumab 300 mg	Placebo
Arm/Group Description	Anifrolumab (300 mg) administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).	Matching placebo administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).
Measure Participants	180	182
Count of Participants [Participants]	29 16.1%	20 11%

9. Secondary Outcome

Title	Number of Participants With a Potentially Clinically Important Change From Baseline in Vital Sign Measurements
Description	Vital sign measurements included oral temperature, blood pressure (BP), pulse rate, and respiratory rate. Vital signs were collected throughout the duration of the study, from baseline until end of follow-up (a maximum of 12 weeks post last dose [Week 48]), or until Week 52 for participants who enrolled onto the long term extension (LTE).
Time Frame	Baseline to end of study (Maximum of 60 weeks)

Outcome Measure Data

Analysis Population Description

Full Analysis Set: All participants who were randomized and received at least one dose of study drug.

Arm/Group Title	Anifrolumab 300 mg	Placebo
Arm/Group Description	Anifrolumab (300 mg) administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).	Matching placebo administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).
Measure Participants	180	182
Count of Participants [Participants]	45 25%	45 24.7%

10. Secondary Outcome

Title	Number of Participants With a Potentially Clinically Important Change From Baseline in Clinical Laboratory Tests
Description	Clinical laboratory tests were analyzed in a central clinical laboratory and included hematology, serum chemistry and urinalysis tests. Laboratory values were collected throughout the duration of the study, from baseline until end of follow-up (a maximum of 12 weeks post last dose [Week 48]), or until Week 52 for participants who enrolled onto the long term extension (LTE).
Time Frame	Baseline to end of study (Maximum of 60 weeks)

Outcome Measure Data

Analysis Population Description

Full Analysis Set: All participants who were randomized and received at least one dose of study drug.

Arm/Group Title	Anifrolumab 300 mg	Placebo
Arm/Group Description	Anifrolumab (300 mg) administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).	Matching placebo administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).
Measure Participants	180	182
Count of Participants [Participants]	72 40%	87 47.8%

Adverse Events

Time Frame	Day 1 to end of study (Maximum of 60 weeks)
Adverse Event Reporting Description	AEs were either spontaneously reported by the participant or reported in response to open questions, revealed by observation, or were changes from baseline/deterioration in tests and vital signs that met serious adverse event (SAE) criteria or led to study drug discontinuation. A treatment-emergent adverse event (TEAE) is defined as an AE with an onset that occurs after receiving study drug. Full analysis set: All participants who had received at least one dose of study drug.
Arm/Group Title	Anifrolumab 300 mg		Placebo
Arm/Group Description	Anifrolumab (300 mg) administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).		Matching placebo administered via an intravenous infusion (IV) every 4 weeks for up to 48 weeks (13 doses).
All Cause Mortality
	Anifrolumab 300 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/180 (0.6%)		0/182 (0%)
Serious Adverse Events
	Anifrolumab 300 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/180 (8.9%)		34/182 (18.7%)
Blood and lymphatic system disorders
Anaemia	0/180 (0%)	0	1/182 (0.5%)	1
Cardiac disorders
Acute coronary syndrome	1/180 (0.6%)	1	0/182 (0%)	0
Atrial flutter	0/180 (0%)	0	1/182 (0.5%)	1
Cardiac failure congestive	0/180 (0%)	0	1/182 (0.5%)	1
Gastrointestinal disorders
Chilaiditi's syndrome	1/180 (0.6%)	1	0/182 (0%)	0
Haematemesis	0/180 (0%)	0	1/182 (0.5%)	1
Intra-abdominal haematoma	0/180 (0%)	0	1/182 (0.5%)	1
Oesophageal stenosis	0/180 (0%)	0	1/182 (0.5%)	1
General disorders
Influenza like illness	0/180 (0%)	0	1/182 (0.5%)	1
Hepatobiliary disorders
Cholecystitis	0/180 (0%)	0	1/182 (0.5%)	1
Immune system disorders
Hypersensitivity	1/180 (0.6%)	1	0/182 (0%)	0
Infections and infestations
Abscess	0/180 (0%)	0	1/182 (0.5%)	1
Appendicitis	1/180 (0.6%)	1	0/182 (0%)	0
Diverticulitis	1/180 (0.6%)	2	0/182 (0%)	0
Gastroenteritis	0/180 (0%)	0	1/182 (0.5%)	1
Gastroenteritis viral	2/180 (1.1%)	2	0/182 (0%)	0
Herpes zoster	1/180 (0.6%)	1	0/182 (0%)	0
Influenza	0/180 (0%)	0	1/182 (0.5%)	1
Periodontitis	0/180 (0%)	0	1/182 (0.5%)	1
Pneumonia	3/180 (1.7%)	3	7/182 (3.8%)	7
Sepsis	0/180 (0%)	0	1/182 (0.5%)	1
Sialoadenitis	0/180 (0%)	0	1/182 (0.5%)	1
Upper respiratory tract infection	0/180 (0%)	0	1/182 (0.5%)	1
Injury, poisoning and procedural complications
Ankle fracture	0/180 (0%)	0	1/182 (0.5%)	1
Fall	1/180 (0.6%)	1	0/182 (0%)	0
Radius fracture	0/180 (0%)	0	2/182 (1.1%)	2
Traumatic fracture	1/180 (0.6%)	1	0/182 (0%)	0
Investigations
Blood creatinine increased	1/180 (0.6%)	1	0/182 (0%)	0
International normalised ratio increased	0/180 (0%)	0	1/182 (0.5%)	1
Liver function test increased	0/180 (0%)	0	1/182 (0.5%)	1
Musculoskeletal and connective tissue disorders
Osteonecrosis	1/180 (0.6%)	1	1/182 (0.5%)	1
Systemic lupus erythematosus	1/180 (0.6%)	1	6/182 (3.3%)	6
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lip squamous cell carcinoma	1/180 (0.6%)	1	0/182 (0%)	0
Uterine cancer	0/180 (0%)	0	1/182 (0.5%)	1
Nervous system disorders
Hypoaesthesia	1/180 (0.6%)	1	0/182 (0%)	0
Psychiatric disorders
Panic attack	0/180 (0%)	0	1/182 (0.5%)	1
Psychotic disorder	0/180 (0%)	0	1/182 (0.5%)	1
Renal and urinary disorders
Acute kidney injury	0/180 (0%)	0	1/182 (0.5%)	1
Lupus nephritis	0/180 (0%)	0	1/182 (0.5%)	1
Nephrolithiasis	1/180 (0.6%)	1	0/182 (0%)	0
Reproductive system and breast disorders
Cervical dysplasia	1/180 (0.6%)	1	0/182 (0%)	0
Vaginal ulceration	0/180 (0%)	0	1/182 (0.5%)	1
Respiratory, thoracic and mediastinal disorders
Asthma	0/180 (0%)	0	1/182 (0.5%)	1
Pulmonary alveolar haemorrhage	0/180 (0%)	0	1/182 (0.5%)	1
Skin and subcutaneous tissue disorders
Angioedema	1/180 (0.6%)	1	0/182 (0%)	0
Drug eruption	0/180 (0%)	0	1/182 (0.5%)	1
Vascular disorders
Haematoma	0/180 (0%)	0	1/182 (0.5%)	1
Hypotension	0/180 (0%)	0	1/182 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Anifrolumab 300 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	125/180 (69.4%)		99/182 (54.4%)
Gastrointestinal disorders
Nausea	7/180 (3.9%)	7	10/182 (5.5%)	11
Infections and infestations
Bronchitis	23/180 (12.8%)	31	8/182 (4.4%)	8
Herpes zoster	12/180 (6.7%)	12	3/182 (1.6%)	3
Nasopharyngitis	28/180 (15.6%)	42	23/182 (12.6%)	31
Sinusitis	13/180 (7.2%)	21	9/182 (4.9%)	10
Upper respiratory tract infection	42/180 (23.3%)	57	19/182 (10.4%)	24
Urinary tract infection	21/180 (11.7%)	27	26/182 (14.3%)	40
Injury, poisoning and procedural complications
Infusion related reaction	25/180 (13.9%)	42	14/182 (7.7%)	27
Musculoskeletal and connective tissue disorders
Arthralgia	10/180 (5.6%)	11	6/182 (3.3%)	6
Back pain	11/180 (6.1%)	12	3/182 (1.6%)	3
Nervous system disorders
Headache	11/180 (6.1%)	13	18/182 (9.9%)	23
Respiratory, thoracic and mediastinal disorders
Cough	10/180 (5.6%)	11	7/182 (3.8%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.