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Clinical Trial Results:
A Phase 2 Study to Investigate the Safety and Efficacy of Elsubrutinib and Upadacitinib Given Alone or in Combination (ABBV-599 Combination) in Subjects With Moderately to Severely Active Systemic Lupus Erythematosus

Summary
EudraCT number	2019-000638-20
Trial protocol	DE ES HU NL BG IT
Global end of trial date	14 Jul 2022

Results information
Results version number	v1(current)
This version publication date	13 Jul 2023
First version publication date	13 Jul 2023
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

M19-130

ISRCTN number

US NCT number

NCT03978520

WHO universal trial number (UTN)

Sponsor organisation name

AbbVie Deutschland GmbH & Co. KG

Sponsor organisation address

AbbVie House, Vanwall Business Park, Vanwall Road,, Maidenhead, Berkshire, United Kingdom, SL6-4UB

Public contact

Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com

Scientific contact

Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

14 Jul 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

14 Jul 2022

Was the trial ended prematurely?

Main objective of the trial

The main objective of this study was to evaluate the safety and efficacy of elsubrutinib, upadacitinib (UPA), and ABBV-599 (elsubrutinib/upadacitinib) High Dose and Low Dose combinations vs placebo for the treatment of signs and symptoms of Systemic Lupus Erythematosus (SLE) in participants with moderately to severely active SLE and to define doses for further development.

Protection of trial subjects

Subjects or their legally authorized representative (if required per local regulations) must have understood and personally, voluntarily signed and dated an informed consent, approved by an independent ethics committee (IEC)/institutional review board (IRB), prior to the initiation of any screening or study-specific procedures. In Japan, subjects under 20 years of age must have voluntarily signed and dated an informed consent, in addition to their parent or legal guardian. Legally authorized representation did not apply in the case of Germany and France, and protected persons such as minors, adults under guardianship, pregnant women, persons deprived of their liberty and persons incapable or unable to express their consent were not included in the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

25 Jul 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 39

Country: Number of subjects enrolled

Australia: 13

Country: Number of subjects enrolled

Bulgaria: 6

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

China: 20

Country: Number of subjects enrolled

Colombia: 19

Country: Number of subjects enrolled

Germany: 4

Country: Number of subjects enrolled

Hungary: 12

Country: Number of subjects enrolled

Italy: 2

Country: Number of subjects enrolled

Japan: 22

Country: Number of subjects enrolled

Korea, Republic of: 5

Country: Number of subjects enrolled

Mexico: 24

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

New Zealand: 3

Country: Number of subjects enrolled

Poland: 11

Country: Number of subjects enrolled

Puerto Rico: 19

Country: Number of subjects enrolled

Spain: 16

Country: Number of subjects enrolled

Taiwan: 20

Country: Number of subjects enrolled

United Kingdom: 7

Country: Number of subjects enrolled

United States: 96

Worldwide total number of subjects

341

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

337

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Screening details

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Elsubrutinib placebo/upadacitinib placebo

Arm description

Placebo capsule for elsubrutinib once a day by mouth for up to 48 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for up to 48 weeks

Arm type

Placebo

Investigational medicinal product name

Placebo for elsubrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Capsule; Oral

Investigational medicinal product name

Placebo for upadacitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Film-coated tablet; Oral

ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)

Arm description

60 mg elsubrutinib capsule once a day by mouth for up to 48 weeks; 30 mg upadacitinib film-coated tablet once a day by mouth for up to 48 weeks

Arm type

Experimental

Investigational medicinal product name

Elsubrutinib

Investigational medicinal product code

Other name

ABBV-105

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Capsule; Oral

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

RINVOQ

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Film-coated tablet; Oral

Elsubrutinib Placebo/Upadacitinib 30 mg

Arm description

Placebo capsule for elsubrutinib once a day by mouth for up to 48 weeks; 30 mg upadacitinib film-coated tablet once a day by mouth for up to 48 weeks

Arm type

Experimental

Investigational medicinal product name

Placebo for elsubrutinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Capsule; Oral

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

RINVOQ

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Film-coated tablet; Oral

ABBV-599 Low Dose (Elsubrutinib 60 mg/Upadacitinib 15 mg)

Arm description

60 mg elsubrutinib capsule once a day by mouth for up to 24 weeks; 15 mg upadacitinib film-coated tablet once a day by mouth for up to 24 weeks

Arm type

Experimental

Investigational medicinal product name

Elsubrutinib

Investigational medicinal product code

Other name

ABBV-105

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Capsule; Oral

Investigational medicinal product name

Upadacitinib

Investigational medicinal product code

Other name

RINVOQ

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Film-coated tablet; Oral

Elsubrutinib 60 mg/Upadacitinib Placebo

Arm description

60 mg elsubrutinib capsule once a day by mouth for up to 24 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for up to 24 weeks

Arm type

Experimental

Investigational medicinal product name

Elsubrutinib

Investigational medicinal product code

Other name

ABBV-105

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Capsule; Oral

Investigational medicinal product name

Placebo for upadacitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Film-coated tablet; Oral

Number of subjects in period 1	Elsubrutinib placebo/upadacitinib placebo	ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)	Elsubrutinib Placebo/Upadacitinib 30 mg	ABBV-599 Low Dose (Elsubrutinib 60 mg/Upadacitinib 15 mg)	Elsubrutinib 60 mg/Upadacitinib Placebo
Started	75	68	62	69	67
Completed	52	52	51	24	29
Not completed	23	16	11	45	38
Adverse event, non-fatal	2	5	3	5	6
Other, not specified	9	4	1	1	2
Sponsor decision: interim analysis data review	-	-	-	33	24
Lost to follow-up	2	2	2	-	1
COVID-19 infection	-	1	-	-	-
Withdrawal by subject	10	4	5	6	5

Baseline characteristics

Top of page

Reporting group title

Elsubrutinib placebo/upadacitinib placebo

Reporting group description

Placebo capsule for elsubrutinib once a day by mouth for up to 48 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for up to 48 weeks

Reporting group title

ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)

Reporting group description

60 mg elsubrutinib capsule once a day by mouth for up to 48 weeks; 30 mg upadacitinib film-coated tablet once a day by mouth for up to 48 weeks

Reporting group title

Elsubrutinib Placebo/Upadacitinib 30 mg

Reporting group description

Placebo capsule for elsubrutinib once a day by mouth for up to 48 weeks; 30 mg upadacitinib film-coated tablet once a day by mouth for up to 48 weeks

Reporting group title

ABBV-599 Low Dose (Elsubrutinib 60 mg/Upadacitinib 15 mg)

Reporting group description

60 mg elsubrutinib capsule once a day by mouth for up to 24 weeks; 15 mg upadacitinib film-coated tablet once a day by mouth for up to 24 weeks

Reporting group title

Elsubrutinib 60 mg/Upadacitinib Placebo

Reporting group description

60 mg elsubrutinib capsule once a day by mouth for up to 24 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for up to 24 weeks

Reporting group values	Elsubrutinib placebo/upadacitinib placebo	ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)	Elsubrutinib Placebo/Upadacitinib 30 mg	ABBV-599 Low Dose (Elsubrutinib 60 mg/Upadacitinib 15 mg)	Elsubrutinib 60 mg/Upadacitinib Placebo	Total
Number of subjects	75	68	62	69	67	341
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	41.7 ± 12.05	42.7 ± 11.27	42.5 ± 11.89	41.4 ± 11.85	42.0 ± 11.84	-
Gender categorical
Units: Subjects
Female	75	62	57	63	62	319
Male	0	6	5	6	5	22
Race
Units: Subjects
American Indian or Alaska Native	3	3	0	1	4	11
Asian	23	14	13	13	9	72
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0
Black or African American	4	4	9	8	6	31
White	43	45	34	45	44	211
More than one race	2	2	6	2	4	16
Unknown or Not Reported	0	0	0	0	0	0
Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score
The SLEDAI-2K is a global SLE disease activity index that focuses on high-impact disease manifestations across 9 organ systems. It includes 24 clinical and laboratory variables with manifestations weighted by the affected organ system. Scores range from 0 to 105, with higher scores indicating more severe disease.
Units: units on a scale
arithmetic mean (standard deviation)	9.1 ± 3.88	8.9 ± 2.75	9.0 ± 2.75	8.8 ± 2.86	9.2 ± 3.18	-
Physician's Global Assessment (PhGA) score
Physician's assessment of patient's overall disease activity due to Systemic Lupus Erythematosus (SLE), as compared with all possible participants with SLE. The benchmarks of the visual analog scale are 0, 1, 2, and 3 on the line corresponding to no, mild, moderate, and severe SLE disease activity, respectively.
Units: units on a scale
arithmetic mean (standard deviation)	1.75 ± 0.440	1.80 ± 0.417	1.70 ± 0.438	1.77 ± 0.422	1.77 ± 0.392	-
Daily dose of corticosteroid
Units: mg/day
arithmetic mean (standard deviation)	7.937 ± 7.1270	6.743 ± 6.3736	6.242 ± 6.0920	6.891 ± 6.1056	6.291 ± 6.1096	-

End points

Top of page

Reporting group title

Elsubrutinib placebo/upadacitinib placebo

Reporting group description

Placebo capsule for elsubrutinib once a day by mouth for up to 48 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for up to 48 weeks

Reporting group title

ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)

Reporting group description

60 mg elsubrutinib capsule once a day by mouth for up to 48 weeks; 30 mg upadacitinib film-coated tablet once a day by mouth for up to 48 weeks

Reporting group title

Elsubrutinib Placebo/Upadacitinib 30 mg

Reporting group description

Placebo capsule for elsubrutinib once a day by mouth for up to 48 weeks; 30 mg upadacitinib film-coated tablet once a day by mouth for up to 48 weeks

Reporting group title

ABBV-599 Low Dose (Elsubrutinib 60 mg/Upadacitinib 15 mg)

Reporting group description

60 mg elsubrutinib capsule once a day by mouth for up to 24 weeks; 15 mg upadacitinib film-coated tablet once a day by mouth for up to 24 weeks

Reporting group title

Elsubrutinib 60 mg/Upadacitinib Placebo

Reporting group description

60 mg elsubrutinib capsule once a day by mouth for up to 24 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for up to 24 weeks

Primary: Percentage of Participants Achieving SLE Responder Index (SRI)-4 and Steroid Dose ≤10 mg Prednisone Equivalent Once a Day (QD) at Week 24

Top of page

End point title

Percentage of Participants Achieving SLE Responder Index (SRI)-4 and Steroid Dose ≤10 mg Prednisone Equivalent Once a Day (QD) at Week 24 ^[1]

End point description

SLE Responder Index (SRI)-4 is defined as follows with all criteria compared to Baseline: • ≥4-point reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score • No worsening of the overall condition (< 0.3 point increase in Physician's Global Assessment [PhGA]) • No new British Isles Lupus Assessment Group (BILAG) A or more than 1 new BILAG B disease activity scores (i.e., no organ system changes from baseline B/C/D/E to A and no more than 1 organ system changes from baseline C/D/E to B). A letter score is assigned to each organ system with following indications: A = severe, B = moderate, C = mild, D = inactive with prior history, and E = inactive with no history.

End point type

Primary

End point timeframe

Baseline, Week 24

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: When 50% of planned participants had completed Week 24 or withdrawn from the study, the ABBV-599 Low Dose and elsubrutinib 60 mg treatment groups were terminated as these groups did not meet projected efficacy. Per protocol, terminated groups were removed from the efficacy analyses.

End point values	Elsubrutinib placebo/upadacitinib placebo	ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)	Elsubrutinib Placebo/Upadacitinib 30 mg
Number of subjects analysed	75 ^[2]	68 ^[3]	62 ^[4]
Units: percentage of participants
number (confidence interval 95%)	37.3 (26.4 to 48.3)	48.5 (36.7 to 60.4)	54.8 (42.5 to 67.2)

Notes
[2] - Subjects rcvd ≥ 1 study drug dose; NRI-C (multiple imputation for missing data due to COVID-19)
[3] - Subjects rcvd ≥ 1 study drug dose; NRI-C (multiple imputation for missing data due to COVID-19)
[4] - Subjects rcvd ≥ 1 study drug dose; NRI-C (multiple imputation for missing data due to COVID-19)

ABBV-599 High Dose vs elsubrutinib/Upa placebo

Statistical analysis description

The difference between the groups was assessed using the Cochran-Mantel-Haenszel (CMH) test, stratified by baseline corticosteroid dose above 10 mg prednisone-equivalent (≤10 mg or > 10 mg), screening SLEDAI-2K (< 10 or ≥10), baseline interferon score (high or low or NA), baseline immunosuppressant (azathioprine, tacrolimus, cyclosporine, methotrexate [MTX], mycophenolate) (yes or no).

Comparison groups

Elsubrutinib placebo/upadacitinib placebo v ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.081

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

12.8

Confidence interval

level

95%

sides

2-sided

lower limit

-1.6

upper limit

27.1

Elsubrutinib/Upa Placebo, Elsubrutinib placebo/Upa

Statistical analysis description

Comparison groups

Elsubrutinib placebo/upadacitinib placebo v Elsubrutinib Placebo/Upadacitinib 30 mg

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.028

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

16.9

Confidence interval

level

95%

sides

2-sided

lower limit

1.8

upper limit

31.9

ABBV-599 High Dose vs Elsubrutinib placebo/Upa

Statistical analysis description

Comparison groups

Elsubrutinib Placebo/Upadacitinib 30 mg v ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)

Number of subjects included in analysis

130

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.566

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

-4.7

Confidence interval

level

95%

sides

2-sided

lower limit

-20.8

upper limit

11.4

Secondary: Percentage of Participants Achieving SLE Responder Index (SRI)-4 at Week 24

Top of page

End point title

Percentage of Participants Achieving SLE Responder Index (SRI)-4 at Week 24 ^[5]

End point description

End point type

Secondary

End point timeframe

Baseline, Week 24

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: When 50% of planned participants had completed Week 24 or withdrawn from the study, the ABBV-599 Low Dose and elsubrutinib 60 mg treatment groups were terminated as these groups did not meet projected efficacy. Per protocol, terminated groups were removed from the efficacy analyses.

End point values	Elsubrutinib placebo/upadacitinib placebo	ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)	Elsubrutinib Placebo/Upadacitinib 30 mg
Number of subjects analysed	75 ^[6]	68 ^[7]	62 ^[8]
Units: percentage of participants
number (confidence interval 95%)	38.7 (27.6 to 49.7)	54.4 (42.6 to 66.2)	56.5 (44.1 to 68.8)

Notes
[6] - Subjects rcvd ≥ 1 study drug dose; NRI-C (multiple imputation for missing data due to COVID-19)
[7] - Subjects rcvd ≥ 1 study drug dose; NRI-C (multiple imputation for missing data due to COVID-19)
[8] - Subjects rcvd ≥ 1 study drug dose; NRI-C (multiple imputation for missing data due to COVID-19)

ABBV-599 High Dose vs elsubrutinib/Upa placebo

Statistical analysis description

Comparison groups

ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) v Elsubrutinib placebo/upadacitinib placebo

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.013

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

18.3

Confidence interval

level

95%

sides

2-sided

lower limit

3.9

upper limit

32.6

Elsubrutinib/Upa Placebo, Elsubrutinib placebo/Upa

Statistical analysis description

Comparison groups

Elsubrutinib placebo/upadacitinib placebo v Elsubrutinib Placebo/Upadacitinib 30 mg

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.018

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

18.1

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

33.2

ABBV-599 High Dose vs Elsubrutinib placebo/Upa

Statistical analysis description

Comparison groups

Elsubrutinib Placebo/Upadacitinib 30 mg v ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)

Number of subjects included in analysis

130

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.882

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

-1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-17.6

upper limit

15.2

Secondary: Percentage of Participants Achieving British Isles Lupus Assessment Group (BILAG) Based Combined Lupus Assessment (BICLA) Response at Week 24

Top of page

End point title

Percentage of Participants Achieving British Isles Lupus Assessment Group (BILAG) Based Combined Lupus Assessment (BICLA) Response at Week 24 ^[9]

End point description

BICLA is a composite responder index. Achievement of BICLA response is defined as improvement in all initial A and B BILAG scores, with no more than one new BILAG B score without worsening of the overall condition (no worsening in Physician's Global Assessment [PhGA], < 0.3 point increase) and no worsening of the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score.

End point type

Secondary

End point timeframe

Baseline, Week 24

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: When 50% of planned participants had completed Week 24 or withdrawn from the study, the ABBV-599 Low Dose and elsubrutinib 60 mg treatment groups were terminated as these groups did not meet projected efficacy. Per protocol, terminated groups were removed from the efficacy analyses.

End point values	Elsubrutinib placebo/upadacitinib placebo	ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)	Elsubrutinib Placebo/Upadacitinib 30 mg
Number of subjects analysed	75 ^[10]	68 ^[11]	62 ^[12]
Units: percentage of participants
number (confidence interval 95%)	42.7 (31.5 to 53.9)	54.4 (42.6 to 66.2)	58.1 (45.8 to 70.3)

Notes
[10] - Subjects rcvd ≥ 1 study drug dose; NRI-C (multiple imputation for missing data due to COVID-19)
[11] - Subjects rcvd ≥ 1 study drug dose; NRI-C (multiple imputation for missing data due to COVID-19)
[12] - Subjects rcvd ≥ 1 study drug dose; NRI-C (multiple imputation for missing data due to COVID-19)

ABBV-599 High Dose vs elsubrutinib/Upa placebo

Statistical analysis description

Comparison groups

Elsubrutinib placebo/upadacitinib placebo v ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.049

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

14.7

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

29.4

Elsubrutinib/Upa Placebo, Elsubrutinib placebo/Upa

Statistical analysis description

Comparison groups

Elsubrutinib placebo/upadacitinib placebo v Elsubrutinib Placebo/Upadacitinib 30 mg

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.091

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

13.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.2

upper limit

30.1

ABBV-599 High Dose vs Elsubrutinib placebo/Upa

Statistical analysis description

Comparison groups

Elsubrutinib Placebo/Upadacitinib 30 mg v ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)

Number of subjects included in analysis

130

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.447

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

-6.3

Confidence interval

level

95%

sides

2-sided

lower limit

-22.5

upper limit

9.9

Secondary: Percentage of Participants Achieving Lupus Low Disease Activity State (LLDAS) at Week 24

Top of page

End point title

Percentage of Participants Achieving Lupus Low Disease Activity State (LLDAS) at Week 24 ^[13]

End point description

LLDAS is a state of low disease activity based on Systemic Lupus Erythematosus Disease Activity Index 2000 score (SLEDAI-2K score ≤4 excluding SLEDAI-2K activity in major organ systems), absence of SLE disease activity in major organ systems and new disease activity, Physician's Global Assessment (PhGA ≤1), and concomitant medication usage (steroid dose ≤7.5 mg QD and toleration of immunosuppressive drugs at standard maintenance doses).

End point type

Secondary

End point timeframe

Baseline, Week 24

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: When 50% of planned participants had completed Week 24 or withdrawn from the study, the ABBV-599 Low Dose and elsubrutinib 60 mg treatment groups were terminated as these groups did not meet projected efficacy. Per protocol, terminated groups were removed from the efficacy analyses.

End point values	Elsubrutinib placebo/upadacitinib placebo	ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)	Elsubrutinib Placebo/Upadacitinib 30 mg
Number of subjects analysed	75 ^[14]	68 ^[15]	62 ^[16]
Units: percentage of participants
number (confidence interval 95%)	13.3 (5.6 to 21.0)	30.9 (19.9 to 41.9)	45.2 (32.8 to 57.5)

Notes
[14] - Subjects rcvd ≥ 1 study drug dose; NRI-C (multiple imputation for missing data due to COVID-19)
[15] - Subjects rcvd ≥ 1 study drug dose; NRI-C (multiple imputation for missing data due to COVID-19)
[16] - Subjects rcvd ≥ 1 study drug dose; NRI-C (multiple imputation for missing data due to COVID-19)

ABBV-599 High Dose vs elsubrutinib/Upa placebo

Statistical analysis description

Comparison groups

Elsubrutinib placebo/upadacitinib placebo v ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.007

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

16.7

Confidence interval

level

95%

sides

2-sided

lower limit

4.5

upper limit

28.9

Elsubrutinib/Upa Placebo, Elsubrutinib placebo/Upa

Statistical analysis description

Comparison groups

Elsubrutinib placebo/upadacitinib placebo v Elsubrutinib Placebo/Upadacitinib 30 mg

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

18.1

upper limit

ABBV-599 High Dose vs Elsubrutinib placebo/Upa

Statistical analysis description

Comparison groups

Elsubrutinib Placebo/Upadacitinib 30 mg v ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)

Number of subjects included in analysis

130

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.068

Method

Cochran-Mantel-Haenszel

Parameter type

Response Rate Difference

Point estimate

-13.7

Confidence interval

level

95%

sides

2-sided

lower limit

-28.4

upper limit

Secondary: Change From Baseline in Daily Prednisone Dose at Week 24

Top of page

End point title

Change From Baseline in Daily Prednisone Dose at Week 24 ^[17]

End point description

Participants’current use of steroid therapy was assessed at each study visit, and the amount of daily prednisone was documented.

End point type

Secondary

End point timeframe

From Baseline to Week 24

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: When 50% of planned participants had completed Week 24 or withdrawn from the study, the ABBV-599 Low Dose and elsubrutinib 60 mg treatment groups were terminated as these groups did not meet projected efficacy. Per protocol, terminated groups were removed from the efficacy analyses.

End point values	Elsubrutinib placebo/upadacitinib placebo	ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)	Elsubrutinib Placebo/Upadacitinib 30 mg
Number of subjects analysed	56 ^[18]	54 ^[19]	48 ^[20]
Units: mg
least squares mean (confidence interval 95%)	-0.65 (-1.57 to 0.28)	-0.45 (-1.38 to 0.48)	-0.62 (-1.60 to 0.36)

Notes
[18] - Subjects who rcvd ≥ 1 study drug dose w/ available data; Mixed-Effect Model Repeat Measurement used
[19] - Subjects who rcvd ≥ 1 study drug dose w/ available data; Mixed-Effect Model Repeat Measurement used
[20] - Subjects who rcvd ≥ 1 study drug dose w/ available data; Mixed-Effect Model Repeat Measurement used

ABBV-599 High Dose vs elsubrutinib/Upa placebo

Statistical analysis description

The Mixed-Effect Model Repeat Measurement model included fixed effects of Tx, visit and Tx-by-visit interaction, stratification factors (Baseline corticosteroid dose > 10 mg prednisone-equivalent (≤10 mg or >10 mg), screening SLEDAI-2K (<10 or ≥10), baseline interferon score (high/low/NA, baseline immunosuppressant (yes/no)), and continuous fixed covariates of measurements at Baseline.

Comparison groups

Elsubrutinib placebo/upadacitinib placebo v ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.71

Method

Mixed-effect model repeat measurement

Parameter type

LS Mean Difference

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.84

upper limit

1.23

Variability estimate

Standard error of the mean

Dispersion value

0.527

Elsubrutinib/Upa Placebo, Elsubrutinib placebo/Upa

Statistical analysis description

Comparison groups

Elsubrutinib placebo/upadacitinib placebo v Elsubrutinib Placebo/Upadacitinib 30 mg

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.963

Method

Mixed-effect model repeat measurement

Parameter type

LS Mean Difference

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-1.05

upper limit

1.1

Variability estimate

Standard error of the mean

Dispersion value

0.545

ABBV-599 High Dose vs Elsubrutinib placebo/Upa

Statistical analysis description

Comparison groups

Elsubrutinib Placebo/Upadacitinib 30 mg v ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.754

Method

Mixed-effect model repeat measurement

Parameter type

LS Mean Difference

Point estimate

0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

1.25

Variability estimate

Standard error of the mean

Dispersion value

0.547

Secondary: Number of Flares Per Patient-year by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index Through Week 24

Top of page

End point title

Number of Flares Per Patient-year by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index Through Week 24 ^[21]

End point description

The SELENA SLEDAI flare index defines mild/moderate or severe SLE flares using the SLEDAI score, definitions of worsening signs and symptoms, treatment changes, and Physician's Global Assessment of Disease Activity.

End point type

Secondary

End point timeframe

From Baseline to Week 24

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: When 50% of planned participants had completed Week 24 or withdrawn from the study, the ABBV-599 Low Dose and elsubrutinib 60 mg treatment groups were terminated as these groups did not meet projected efficacy. Per protocol, terminated groups were removed from the efficacy analyses.

End point values	Elsubrutinib placebo/upadacitinib placebo	ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)	Elsubrutinib Placebo/Upadacitinib 30 mg
Number of subjects analysed	75 ^[22]	68 ^[23]	62 ^[24]
Units: Events per patient-year
number (confidence interval 95%)
Mild/Moderate	2.45 (1.92 to 2.99)	1.39 (0.97 to 1.81)	1.76 (1.28 to 2.25)
Severe	0.36 (0.16 to 0.56)	0.26 (0.08 to 0.44)	0.10 (-0.01 to 0.22)
Overall	2.81 (2.24 to 3.38)	1.65 (1.20 to 2.10)	1.87 (1.37 to 2.36)

Notes
[22] - Subjects who rcvd ≥ 1 study drug dose w/ available data; data as observed
[23] - Subjects who rcvd ≥ 1 study drug dose w/ available data; data as observed
[24] - Subjects who rcvd ≥ 1 study drug dose w/ available data; data as observed

ABBV-599 High Dose vs elsubrutinib/Upa placebo

Statistical analysis description

Mild/Moderate A negative binomial regression model was used to assess treatment effect with treatment, visit, and stratification factors as covariates.

Comparison groups

Elsubrutinib placebo/upadacitinib placebo v ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

Binomial regression

Parameter type

Rate difference

Point estimate

-1.06

Confidence interval

level

95%

sides

2-sided

lower limit

-1.74

upper limit

-0.39

Elsubrutinib/Upa Placebo, Elsubrutinib placebo/Upa

Statistical analysis description

Mild/Moderate A negative binomial regression model was used to assess treatment effect with treatment, visit, and stratification factors as covariates.

Comparison groups

Elsubrutinib placebo/upadacitinib placebo v Elsubrutinib Placebo/Upadacitinib 30 mg

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.059

Method

Binomial regression

Parameter type

Rate difference

Point estimate

-0.69

Confidence interval

level

95%

sides

2-sided

lower limit

-1.41

upper limit

0.03

ABBV-599 High Dose vs Elsubrutinib placebo/Upa

Statistical analysis description

Mild/Moderate A negative binomial regression model was used to assess treatment effect with treatment, visit, and stratification factors as covariates.

Comparison groups

Elsubrutinib Placebo/Upadacitinib 30 mg v ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)

Number of subjects included in analysis

130

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.252

Method

Binomial regression

Parameter type

Rate difference

Point estimate

-0.37

Confidence interval

level

95%

sides

2-sided

lower limit

-1.01

upper limit

0.27

ABBV-599 High Dose vs elsubrutinib/Upa placebo

Statistical analysis description

SEVERE A negative binomial regression model was used to assess treatment effect with treatment, visit, and stratification factors as covariates.

Comparison groups

ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) v Elsubrutinib placebo/upadacitinib placebo

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.467

Method

Binomial regression

Parameter type

Rate difference

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.37

upper limit

0.17

Elsubrutinib/Upa Placebo, Elsubrutinib placebo/Upa

Statistical analysis description

SEVERE A negative binomial regression model was used to assess treatment effect with treatment, visit, and stratification factors as covariates.

Comparison groups

Elsubrutinib Placebo/Upadacitinib 30 mg v Elsubrutinib placebo/upadacitinib placebo

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.033

Method

Binomial regression

Parameter type

Rate difference

Point estimate

-0.26

Confidence interval

level

95%

sides

2-sided

lower limit

-0.49

upper limit

-0.02

ABBV-599 High Dose vs Elsubrutinib placebo/Upa

Statistical analysis description

SEVERE A negative binomial regression model was used to assess treatment effect with treatment, visit, and stratification factors as covariates.

Comparison groups

Elsubrutinib Placebo/Upadacitinib 30 mg v ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)

Number of subjects included in analysis

130

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.156

Method

Binomial regression

Parameter type

Rate difference

Point estimate

0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.06

upper limit

0.37

ABBV-599 High Dose vs elsubrutinib/Upa placebo

Statistical analysis description

OVERALL A negative binomial regression model was used to assess treatment effect with treatment, visit, and stratification factors as covariates.

Comparison groups

ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg) v Elsubrutinib placebo/upadacitinib placebo

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002

Method

Binomial regression

Parameter type

Rate difference

Point estimate

-1.16

Confidence interval

level

95%

sides

2-sided

lower limit

-1.89

upper limit

-0.44

Elsubrutinib/Upa Placebo, Elsubrutinib placebo/Upa

Statistical analysis description

OVERALL A negative binomial regression model was used to assess treatment effect with treatment, visit, and stratification factors as covariates.

Comparison groups

Elsubrutinib placebo/upadacitinib placebo v Elsubrutinib Placebo/Upadacitinib 30 mg

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.014

Method

Binomial regression

Parameter type

Rate difference

Point estimate

-0.95

Confidence interval

level

95%

sides

2-sided

lower limit

-1.7

upper limit

-0.19

ABBV-599 High Dose vs Elsubrutinib placebo/Upa

Statistical analysis description

OVERALL A negative binomial regression model was used to assess treatment effect with treatment, visit, and stratification factors as covariates.

Comparison groups

Elsubrutinib Placebo/Upadacitinib 30 mg v ABBV-599 High Dose (Elsubrutinib 60 mg/upadacitinib 30 mg)

Number of subjects included in analysis

130

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.526

Method

Binomial regression

Parameter type

Rate difference

Point estimate

-0.22

Confidence interval

level

95%

sides

2-sided

lower limit

-0.89

upper limit

0.46

Adverse events

Top of page

Timeframe for reporting adverse events

All-cause mortality is reported from enrollment to end of study; median time on follow-up was 337.0, 337.0, 338.5, 281.0, and 295.0 days for the placebo, ABBV-599 High Dose, upadacitinib, ABBV-599 Low Dose, and elsubrutinib groups, respectively.

Adverse event reporting additional description

TEAEs and SAEs were collected from first dose of study drug until 30 days after last dose of study drug; mean time on treatment was 286.1 days, 289.8 days, 297.7 days, 226.4 days, and 228.6 days, for the placebo, ABBV-599 High Dose, upadacitinib, ABBV-599 Low Dose, and elsubrutinib groups, respectively.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Elsubrutinib Placebo/Upadacitinib Placebo

Reporting group description

Placebo capsule for elsubrutinib once a day by mouth for up to 48 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for up to 48 weeks

Reporting group title

Elsubrutinib Placebo/Upadacitinib 30 mg

Reporting group description

Placebo capsule for elsubrutinib once a day by mouth for up to 48 weeks; 30 mg upadacitinib film-coated tablet once a day by mouth for up to 48 weeks

Reporting group title

ABBV-599 High Dose (Elsubrutinib 60 mg/Upadacitinib 30 mg)

Reporting group description

60 mg elsubrutinib capsule once a day by mouth for up to 48 weeks; 30 mg upadacitinib film-coated tablet once a day by mouth for up to 48 weeks

Reporting group title

ABBV-599 Low Dose (Elsubrutinib 60 mg/Upadacitinib 15 mg)

Reporting group description

60 mg elsubrutinib capsule once a day by mouth for up to 24 weeks; 15 mg upadacitinib film-coated tablet once a day by mouth for up to 24 weeks

Reporting group title

Elsubrutinib 60 mg/Upadacitinib Placebo

Reporting group description

60 mg elsubrutinib capsule once a day by mouth for up to 24 weeks; placebo film-coated tablet for upadacitinib once a day by mouth for up to 24 weeks

Serious adverse events	Elsubrutinib Placebo/Upadacitinib Placebo	Elsubrutinib Placebo/Upadacitinib 30 mg	ABBV-599 High Dose (Elsubrutinib 60 mg/Upadacitinib 30 mg)	ABBV-599 Low Dose (Elsubrutinib 60 mg/Upadacitinib 15 mg)	Elsubrutinib 60 mg/Upadacitinib Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	13 / 75 (17.33%)	13 / 62 (20.97%)	7 / 68 (10.29%)	9 / 69 (13.04%)	7 / 67 (10.45%)
number of deaths (all causes)	0	0	2	0	2
number of deaths resulting from adverse events	0	0	1	0	2
Vascular disorders
VENOUS THROMBOSIS LIMB
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	1 / 68 (1.47%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERTENSIVE URGENCY
subjects affected / exposed	1 / 75 (1.33%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
ABORTION INDUCED
subjects affected / exposed	2 / 75 (2.67%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
ACCIDENTAL DEATH
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Reproductive system and breast disorders
BREAST MASS
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	0 / 68 (0.00%)	1 / 69 (1.45%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
ACUTE RESPIRATORY FAILURE
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	1 / 68 (1.47%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
PNEUMONITIS
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	1 / 68 (1.47%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
EPISTAXIS
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	1 / 68 (1.47%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
BIPOLAR DISORDER
subjects affected / exposed	1 / 75 (1.33%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
SYSTEMIC LUPUS ERYTHEMATOSUS DISEASE ACTIVITY INDEX INCREASED
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	0 / 68 (0.00%)	1 / 69 (1.45%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
JOINT INJURY
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FALL
subjects affected / exposed	1 / 75 (1.33%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TIBIA FRACTURE
subjects affected / exposed	1 / 75 (1.33%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
ACUTE MYOCARDIAL INFARCTION
subjects affected / exposed	1 / 75 (1.33%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PERICARDIAL EFFUSION
subjects affected / exposed	1 / 75 (1.33%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
STRESS CARDIOMYOPATHY
subjects affected / exposed	0 / 75 (0.00%)	1 / 62 (1.61%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
CENTRAL NERVOUS SYSTEM LUPUS
subjects affected / exposed	0 / 75 (0.00%)	1 / 62 (1.61%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CEREBROVASCULAR ACCIDENT
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	1 / 68 (1.47%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MIGRAINE
subjects affected / exposed	0 / 75 (0.00%)	1 / 62 (1.61%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RUPTURED CEREBRAL ANEURYSM
subjects affected / exposed	0 / 75 (0.00%)	1 / 62 (1.61%)	1 / 68 (1.47%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SUBARACHNOID HAEMORRHAGE
subjects affected / exposed	0 / 75 (0.00%)	1 / 62 (1.61%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SPINAL CORD COMPRESSION
subjects affected / exposed	0 / 75 (0.00%)	1 / 62 (1.61%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
NEUTROPENIA
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	0 / 68 (0.00%)	1 / 69 (1.45%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
THROMBOCYTOPENIA
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	1 / 68 (1.47%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
DYSPHAGIA
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	0 / 68 (0.00%)	1 / 69 (1.45%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTRITIS
subjects affected / exposed	1 / 75 (1.33%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OESOPHAGITIS
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	0 / 68 (0.00%)	1 / 69 (1.45%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
LUPUS NEPHRITIS
subjects affected / exposed	0 / 75 (0.00%)	1 / 62 (1.61%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ACUTE KIDNEY INJURY
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	1 / 68 (1.47%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URETEROLITHIASIS
subjects affected / exposed	2 / 75 (2.67%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NEPHROLITHIASIS
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	1 / 68 (1.47%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
OSTEONECROSIS
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	0 / 68 (0.00%)	1 / 69 (1.45%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SYSTEMIC LUPUS ERYTHEMATOSUS
subjects affected / exposed	1 / 75 (1.33%)	1 / 62 (1.61%)	1 / 68 (1.47%)	2 / 69 (2.90%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
ABSCESS LIMB
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19 PNEUMONIA
subjects affected / exposed	0 / 75 (0.00%)	1 / 62 (1.61%)	1 / 68 (1.47%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	1 / 75 (1.33%)	0 / 62 (0.00%)	1 / 68 (1.47%)	0 / 69 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
DISSEMINATED VARICELLA ZOSTER VIRUS INFECTION
subjects affected / exposed	0 / 75 (0.00%)	1 / 62 (1.61%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIVERTICULITIS
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	0 / 68 (0.00%)	1 / 69 (1.45%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTROENTERITIS VIRAL
subjects affected / exposed	0 / 75 (0.00%)	1 / 62 (1.61%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTROENTERITIS
subjects affected / exposed	0 / 75 (0.00%)	1 / 62 (1.61%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ESCHERICHIA SEPSIS
subjects affected / exposed	1 / 75 (1.33%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ENDOCARDITIS BACTERIAL
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	1 / 68 (1.47%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PELVIC ABSCESS
subjects affected / exposed	1 / 75 (1.33%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MYCOPLASMA INFECTION
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MENINGITIS TUBERCULOUS
subjects affected / exposed	1 / 75 (1.33%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OESOPHAGEAL CANDIDIASIS
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HERPES ZOSTER
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	1 / 68 (1.47%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMOCYSTIS JIROVECII PNEUMONIA
subjects affected / exposed	0 / 75 (0.00%)	1 / 62 (1.61%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	0 / 75 (0.00%)	2 / 62 (3.23%)	0 / 68 (0.00%)	1 / 69 (1.45%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA PNEUMOCOCCAL
subjects affected / exposed	1 / 75 (1.33%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA FUNGAL
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	1 / 68 (1.47%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA RESPIRATORY SYNCYTIAL VIRAL
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	1 / 68 (1.47%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URINARY TRACT INFECTION
subjects affected / exposed	1 / 75 (1.33%)	0 / 62 (0.00%)	0 / 68 (0.00%)	1 / 69 (1.45%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SEPSIS
subjects affected / exposed	0 / 75 (0.00%)	0 / 62 (0.00%)	1 / 68 (1.47%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
DIABETES MELLITUS
subjects affected / exposed	1 / 75 (1.33%)	0 / 62 (0.00%)	0 / 68 (0.00%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Elsubrutinib Placebo/Upadacitinib Placebo	Elsubrutinib Placebo/Upadacitinib 30 mg	ABBV-599 High Dose (Elsubrutinib 60 mg/Upadacitinib 30 mg)	ABBV-599 Low Dose (Elsubrutinib 60 mg/Upadacitinib 15 mg)	Elsubrutinib 60 mg/Upadacitinib Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	39 / 75 (52.00%)	35 / 62 (56.45%)	38 / 68 (55.88%)	28 / 69 (40.58%)	36 / 67 (53.73%)
Investigations
WEIGHT INCREASED
subjects affected / exposed	1 / 75 (1.33%)	1 / 62 (1.61%)	4 / 68 (5.88%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences all number	1	2	8	0	0
Nervous system disorders
HEADACHE
subjects affected / exposed	9 / 75 (12.00%)	2 / 62 (3.23%)	4 / 68 (5.88%)	7 / 69 (10.14%)	10 / 67 (14.93%)
occurrences all number	13	2	4	8	12
General disorders and administration site conditions
PYREXIA
subjects affected / exposed	6 / 75 (8.00%)	3 / 62 (4.84%)	3 / 68 (4.41%)	2 / 69 (2.90%)	1 / 67 (1.49%)
occurrences all number	6	3	3	2	1
FATIGUE
subjects affected / exposed	2 / 75 (2.67%)	0 / 62 (0.00%)	4 / 68 (5.88%)	1 / 69 (1.45%)	3 / 67 (4.48%)
occurrences all number	2	0	4	1	3
Gastrointestinal disorders
NAUSEA
subjects affected / exposed	6 / 75 (8.00%)	4 / 62 (6.45%)	4 / 68 (5.88%)	2 / 69 (2.90%)	6 / 67 (8.96%)
occurrences all number	11	4	4	2	6
GASTRITIS
subjects affected / exposed	0 / 75 (0.00%)	2 / 62 (3.23%)	0 / 68 (0.00%)	0 / 69 (0.00%)	4 / 67 (5.97%)
occurrences all number	0	2	0	0	4
DIARRHOEA
subjects affected / exposed	6 / 75 (8.00%)	4 / 62 (6.45%)	3 / 68 (4.41%)	3 / 69 (4.35%)	2 / 67 (2.99%)
occurrences all number	6	5	4	4	3
CONSTIPATION
subjects affected / exposed	4 / 75 (5.33%)	1 / 62 (1.61%)	1 / 68 (1.47%)	4 / 69 (5.80%)	1 / 67 (1.49%)
occurrences all number	4	1	1	4	1
VOMITING
subjects affected / exposed	3 / 75 (4.00%)	4 / 62 (6.45%)	2 / 68 (2.94%)	2 / 69 (2.90%)	2 / 67 (2.99%)
occurrences all number	3	6	3	2	2
Skin and subcutaneous tissue disorders
ACNE
subjects affected / exposed	1 / 75 (1.33%)	2 / 62 (3.23%)	4 / 68 (5.88%)	4 / 69 (5.80%)	0 / 67 (0.00%)
occurrences all number	2	2	4	7	0
Psychiatric disorders
INSOMNIA
subjects affected / exposed	2 / 75 (2.67%)	4 / 62 (6.45%)	2 / 68 (2.94%)	0 / 69 (0.00%)	0 / 67 (0.00%)
occurrences all number	2	4	2	0	0
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	5 / 75 (6.67%)	1 / 62 (1.61%)	3 / 68 (4.41%)	2 / 69 (2.90%)	5 / 67 (7.46%)
occurrences all number	5	1	3	3	5
BACK PAIN
subjects affected / exposed	4 / 75 (5.33%)	1 / 62 (1.61%)	3 / 68 (4.41%)	2 / 69 (2.90%)	2 / 67 (2.99%)
occurrences all number	5	1	3	2	2
Infections and infestations
COVID-19
subjects affected / exposed	8 / 75 (10.67%)	7 / 62 (11.29%)	3 / 68 (4.41%)	2 / 69 (2.90%)	8 / 67 (11.94%)
occurrences all number	8	7	3	2	8
BRONCHITIS
subjects affected / exposed	1 / 75 (1.33%)	4 / 62 (6.45%)	1 / 68 (1.47%)	0 / 69 (0.00%)	1 / 67 (1.49%)
occurrences all number	1	4	1	0	1
HERPES ZOSTER
subjects affected / exposed	3 / 75 (4.00%)	3 / 62 (4.84%)	7 / 68 (10.29%)	3 / 69 (4.35%)	1 / 67 (1.49%)
occurrences all number	3	3	7	3	1
ORAL HERPES
subjects affected / exposed	1 / 75 (1.33%)	3 / 62 (4.84%)	5 / 68 (7.35%)	3 / 69 (4.35%)	0 / 67 (0.00%)
occurrences all number	1	4	11	3	0
NASOPHARYNGITIS
subjects affected / exposed	3 / 75 (4.00%)	1 / 62 (1.61%)	6 / 68 (8.82%)	5 / 69 (7.25%)	0 / 67 (0.00%)
occurrences all number	3	1	6	6	0
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	8 / 75 (10.67%)	5 / 62 (8.06%)	7 / 68 (10.29%)	5 / 69 (7.25%)	5 / 67 (7.46%)
occurrences all number	10	6	13	5	6
URINARY TRACT INFECTION
subjects affected / exposed	9 / 75 (12.00%)	11 / 62 (17.74%)	8 / 68 (11.76%)	5 / 69 (7.25%)	4 / 67 (5.97%)
occurrences all number	10	15	14	9	4

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Were there any global substantial amendments to the protocol? Yes

02 Jul 2019

Protocol Amendment 1 ○ Clarified eligibility criteria ○ Introduction of certain prohibited medications as a result of the development or worsening of lupus manifestation was prioritized by moving to the top of the list ○ Clarified that subjects must be discontinued from study drug for an ECG change considered clinically significant and with reasonable possibility of relationship to study drug OR a confirmed absolute QTcF value > 500 msec or confirmed increase of ≥60 msec from baseline ○ Added 12-lead ECG at Week 36

25 Jul 2019

Protocol Amendment 2 ○ Clarified that if different national regulations exist for TB testing, those regulations should be applied ○ Clarified consent criterion with respect to legally authorized representation with respect to Germany ○ Clarified that at Week 24 the investigator should assess if continuing in the study is in the best interest of the patient

12 Dec 2019

Protocol Amendment 3 ○ Added text about approval of upadacitinib in US and EU ○ Added deep vein thrombosis and pulmonary embolism as events reported in patients receiving JAK inhibitors ○ Provided preclinical information indicating that upadacitinib is not genotoxic but is teratogenic ○ Added definition of SLE Responder Index (SRI)-4 ○ Revised wording for secondary endpoints 8, 9, and 10 ○ Removed CPK elevation as an adverse event area of safety interest ○ Clarified that optionality of collection/analysis is given through ICF ○ Included footnote clarifying that study will go from double-blind to single-blind when the Study Team is unblinded after Week 24 primary efficacy endpoint analysis is completed ○ SLEDAI-2K ≥6 score at Screening must be re-confirmed at Baseline Visit ○ Clarified that subjects must be on background treatment, stable for 30 days prior to Baseline, and background treatment may include prednisone equivalent ○ Updated Eligibility #9, #18, #30, #32, #33, and #36 ○ Clarified wording for the following contraceptive guideline: Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram confirms success of the procedure). ○ Added Traditional Chinese Medicines as prohibited medication while on study drug ○ Clarified that, at Week 24, the Investigator must assess and document in source that continuing in the study is in the best interest of the subject ○ Clarified that subject may request withdrawal from study drug/study ○ Noted that a subject will be discontinued from study drug immediately if diagnosis of deep vein thrombosis, pulmonary embolus, or non-cardiac, non-neurologic arterial thrombosis is confirmed ○ Clarified that worsening SLE including flares will be captured and analyzed by the 4 disease activity forms and will not be captured as AEs unless they result in serious outcomes ○ Elevated CPK removed as an AESI ○ Updated Toxicity Management ○ Updated Activity Schedule

04 Jun 2020

Protocol Amendment 4 ○ Updated synopsis ○ Updated text to indicate that BTK is expressed in multiple immune cell types associated with the pathogenesis of SLE (in addition to RA and other autoimmune diseases). Deleted text describing the comparative selectivity of elsubrutinib. Added text regarding approval of upadacitinib for the treatment of adults with RA in the US, EU, and Japan. Deleted text describing the total number of subjects who have received upadacitinib and in the respective indications. ○ Updated Background and Rationale and Benefits and Risks to Subjects ○ Updated Contraception Recommendations ○ Updated Secondary Endpoints ○ Updated Safety and Complaints and Adverse Events and Toxicity Management ○ Updated Biomarker Research ○ Clarified that the sites and subjects will remain blinded throughout the remainder of the study. ○ Updated Overall Study Design and Plan and Discussion of Study Design ○ Updated Eligibility Criteria #1, #4, #10, #11, #24, #30, and #31 ○ Updated Prohibited Medications and Therapy and Concomitant Therapy ○ Updated Withdrawal of Subjects and Discontinuation of Study ○ Updated Follow-Up After Subject Discontinuation of Study Drug or from Study ○ Updated Randomization/Drug Assignment ○ Updated Protocol Deviations ○ Updated Statistical and Analytical Plans and Statistical Analyses for Efficacy ○ Updated Activity Schedule ○ Updated Completion of the Study and References sections ○ Updated Appendix E

15 Oct 2020

Protocol Amendment 5 ○ Made COVID-19 pandemic-related changes ○ Updated Synopsis ○ Updated Background and Rationale ○ Updated Objectives and Hypotheses ○ Updated Primary, Secondary, and Additional Efficacy Endpoints ○ Updated Safety and Data Monitoring Committee ○ Updated Biomarker Research ○ Updated Overall Study Design and Plan and Randomization/Drug Assignment ○ Updated Discussion of Study Design ○ Updated Eligibility Criteria #8, #14, #15 and #32 ○ Updated Prohibited Medications and Therapy and Concomitant Therapy ○ Updated Withdrawal of Subjects and Discontinuation of Study ○ Updated Follow-Up After Subject Discontinuation of Study Drug or from Study ○ Updated Data Monitoring Committee ○ Updated Complaints and Adverse Events and Toxicity Management ○ Updated Statistical and Analytical Plans and Statistical Analyses for Efficacy (Added text to indicate that the unblinded interim analysis will be performed by an independent team at AbbVie after 50% of subjects have completed Week 24 assessments, and that the study team will remain blinded.) ○ Added a new section, Section 7.5, with details regarding the conduct of the unblinded interim analysis. These details were also added to the Synopsis. ○ Created a new section, Section 7.6, with details regarding the statistical tests to be used for this study and clarified that no multiplicity adjustment will be applied because this is a Phase 2 study ○ Updated the version number and date of issue of the upadacitinib Investigator's Brochure ○ Updated Activity Schedule

25 Oct 2021

Protocol Amendment 6 ○ Clarified the adjustment of treatment groups in Study M19-130 as a result of the completed 50% interim analysis at Week 24 ○ If the study is partially terminated (i.e., only certain groups are discontinued), details for follow-up of subjects were provided

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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A Phase 2 Study to Investigate the Safety and Efficacy of Elsubrutinib and Upadacitinib Given Alone or in Combination (ABBV-599 Combination) in Subjects With Moderately to Severely Active Systemic Lupus Erythematosus

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Primary: Percentage of Participants Achieving SLE Responder Index (SRI)-4 and Steroid Dose ≤10 mg Prednisone Equivalent Once a Day (QD) at Week 24

Primary: Percentage of Participants Achieving SLE Responder Index (SRI)-4 and Steroid Dose ≤10 mg Prednisone Equivalent Once a Day (QD) at Week 24

Secondary: Percentage of Participants Achieving SLE Responder Index (SRI)-4 at Week 24

Secondary: Percentage of Participants Achieving SLE Responder Index (SRI)-4 at Week 24

Secondary: Percentage of Participants Achieving British Isles Lupus Assessment Group (BILAG) Based Combined Lupus Assessment (BICLA) Response at Week 24

Secondary: Percentage of Participants Achieving British Isles Lupus Assessment Group (BILAG) Based Combined Lupus Assessment (BICLA) Response at Week 24

Secondary: Percentage of Participants Achieving Lupus Low Disease Activity State (LLDAS) at Week 24

Secondary: Percentage of Participants Achieving Lupus Low Disease Activity State (LLDAS) at Week 24

Secondary: Change From Baseline in Daily Prednisone Dose at Week 24

Secondary: Change From Baseline in Daily Prednisone Dose at Week 24

Secondary: Number of Flares Per Patient-year by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index Through Week 24

Secondary: Number of Flares Per Patient-year by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index Through Week 24

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Clinical trials

Clinical Trial Results: A Phase 2 Study to Investigate the Safety and Efficacy of Elsubrutinib and Upadacitinib Given Alone or in Combination (ABBV-599 Combination) in Subjects With Moderately to Severely Active Systemic Lupus Erythematosus

Trial information

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Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants Achieving SLE Responder Index (SRI)-4 and Steroid Dose ≤10 mg Prednisone Equivalent Once a Day (QD) at Week 24

Primary: Percentage of Participants Achieving SLE Responder Index (SRI)-4 and Steroid Dose ≤10 mg Prednisone Equivalent Once a Day (QD) at Week 24

Secondary: Percentage of Participants Achieving SLE Responder Index (SRI)-4 at Week 24

Secondary: Percentage of Participants Achieving SLE Responder Index (SRI)-4 at Week 24

Secondary: Percentage of Participants Achieving British Isles Lupus Assessment Group (BILAG) Based Combined Lupus Assessment (BICLA) Response at Week 24

Secondary: Percentage of Participants Achieving British Isles Lupus Assessment Group (BILAG) Based Combined Lupus Assessment (BICLA) Response at Week 24

Secondary: Percentage of Participants Achieving Lupus Low Disease Activity State (LLDAS) at Week 24

Secondary: Percentage of Participants Achieving Lupus Low Disease Activity State (LLDAS) at Week 24

Secondary: Change From Baseline in Daily Prednisone Dose at Week 24

Secondary: Change From Baseline in Daily Prednisone Dose at Week 24

Secondary: Number of Flares Per Patient-year by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index Through Week 24

Secondary: Number of Flares Per Patient-year by Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Flare Index Through Week 24

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Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 2 Study to Investigate the Safety and Efficacy of Elsubrutinib and Upadacitinib Given Alone or in Combination (ABBV-599 Combination) in Subjects With Moderately to Severely Active Systemic Lupus Erythematosus