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Clinical Trial Results:
A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the Safety, Pharmacokinetics, and Efficacy of KPL-404 in Subjects with Moderate to Severe, Active Rheumatoid Arthritis with Inadequate Response or Intolerance to at Least One Biologic Disease modifying Anti-rheumatic Drug or a Janus Kinase Inhibitor

Summary
EudraCT number	2022-000169-42
Trial protocol	DE CZ HU BG
Global end of trial date	06 May 2024

Results information
Results version number	v1(current)
This version publication date	21 May 2025
First version publication date	21 May 2025
Other versions

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

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Trial information

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Sponsor protocol code

KPL-404-C211

ISRCTN number

US NCT number

NCT05198310

WHO universal trial number (UTN)

Other trial identifiers

IND: 155,963

Sponsor organisation name

Kiniksa Pharmaceuticals, Ltd.

Sponsor organisation address

c/o Kiniksa Pharmaceuticals Corp., 100 Hayden Avenue, Lexington, MA, United States, 02421

Public contact

Clinical Trials Manager, Kiniksa Pharmaceuticals, Ltd., +1 7814319100, studyinfo@Kiniksa.com

Scientific contact

Clinical Trials Manager, Kiniksa Pharmaceuticals, Ltd., +1 7814319100, studyinfo@Kiniksa.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

06 May 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

06 May 2024

Was the trial ended prematurely?

Main objective of the trial

Cohorts 1 and 2: To evaluate the dose response relationship as measured by safety, tolerability, and pharmacokinetics (PK) of multiple subcutaneous (SC) doses of KPL-404 versus placebo. Cohorts 3 and 4: To evaluate the efficacy of multiple SC doses of KPL-404 versus placebo for the treatment of rheumatoid arthritis (RA).

Protection of trial subjects

Before initiating a trial, the investigator/Institution must obtain approval/favorable opinion from the IRB or Independent Ethics Committee (IEC) for the trial protocol, written informed consent form, consent form updates, subject recruitment procedures, and any other written information to be provided to subjects.

Background therapy

Evidence for comparator

Actual start date of recruitment

17 Nov 2021

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 21

Country: Number of subjects enrolled

Bulgaria: 6

Country: Number of subjects enrolled

Czechia: 14

Country: Number of subjects enrolled

Hungary: 17

Country: Number of subjects enrolled

Georgia: 14

Country: Number of subjects enrolled

South Africa: 18

Country: Number of subjects enrolled

United States: 55

Worldwide total number of subjects

145

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

This study included a screening period of up to 4 weeks.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Subject

Blinding implementation details

This was a double-blind, placebo-controlled study. Investigators, the remaining clinical site staff, and the subjects were blinded to treatment throughout the course of the study. The Sponsor was also blinded to subject treatment assignment while each cohort’s enrollment and subject follow-up was ongoing.

Are arms mutually exclusive

Yes

Cohort 1 KPL-404 2 mg/kg every 2 weeks (q2wk)

Arm description

KPL-404 2 mg/kg subcutaneous (SC) q2wk for 12 weeks

Arm type

Experimental

Investigational medicinal product name

KPL-404

Investigational medicinal product code

Other name

abiprubart

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Cohort 1: 2 mg/kg KPL-404 q2wk

Cohort 2 KPL-404 5 mg/kg q2wk

Arm description

KPL-404 5 mg/kg SC q2wk for 12 weeks

Arm type

Experimental

Investigational medicinal product name

KPL-404

Investigational medicinal product code

Other name

abiprubart

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Cohort 2: 5 mg/kg KPL-404 q2wk

Cohort 1/2 Placebo

Arm description

Placebo SC q2wk for 12 weeks

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo volume was to be matched to abiprubart at the corresponding dosage level.

Cohort 3 KPL-404 5 mg/kg qwk

Arm description

KPL-404 5 mg/kg SC once weekly (qwk) for 12 weeks

Arm type

Experimental

Investigational medicinal product name

KPL-404

Investigational medicinal product code

Other name

abiprubart

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Cohort 3: 5 mg/kg SC qwk

Cohort 3 KPL-404 5 mg/kg q2wk

Arm description

KPL-404 5 mg/kg SC q2wk with alternating weekly administrations of KPL-404 or placebo SC for 12 weeks

Arm type

Experimental

Investigational medicinal product name

KPL-404

Investigational medicinal product code

Other name

abiprubart

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Cohort 3: 5 mg/kg SC q2w (weekly dosing with alternating administration of KPL 404 q2wk or placebo q2wk)

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo volume was to be matched to abiprubart at the corresponding dosage level. In Cohort 3 in the q2wk dosage group, placebo was to be alternated with abiprubart administration.

Cohort 3 Placebo

Arm description

Placebo SC qwk for 12 weeks

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo volume was to be matched to abiprubart at the corresponding dosage level. In Cohort 3 in the placebo group, placebo was to be given qwk.

Cohort 4: KPL-404 400 mg q4wk

Arm description

KPL-404 SC every 4 weeks (q4wk) for 12 weeks: 600 mg loading dose at baseline followed by 400 mg at Weeks 4 and 8

Arm type

Experimental

Investigational medicinal product name

KPL-404

Investigational medicinal product code

Other name

abiprubart

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Cohort 4: KPL-404 SC q4wk (600 mg loading dose followed by maintenance dosing 400 mg q4wk at Weeks 4 and 8)

Cohort 4 Placebo

Arm description

Placebo SC q4wk for 12 weeks

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo volume was to be matched to abiprubart at the corresponding dosage level. In Cohort 4, placebo was to be administered as a volume-equivalent of abiprubart: a loading dose (i.e., 3 mL) followed by maintenance dosing (i.e., 2 mL) q4wk.

Number of subjects in period 1	Cohort 1 KPL-404 2 mg/kg every 2 weeks (q2wk)	Cohort 2 KPL-404 5 mg/kg q2wk	Cohort 1/2 Placebo	Cohort 3 KPL-404 5 mg/kg qwk	Cohort 3 KPL-404 5 mg/kg q2wk	Cohort 3 Placebo	Cohort 4: KPL-404 400 mg q4wk	Cohort 4 Placebo
Started	6	6	4	27	25	26	31	20
Completed	6	5	4	25	25	24	30	17
Not completed	0	1	0	2	0	2	1	3
Consent withdrawn by subject	-	-	-	2	-	2	1	3
Lost to follow-up	-	1	-	-	-	-	-	-

Baseline characteristics

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Reporting group title

Cohort 1 KPL-404 2 mg/kg every 2 weeks (q2wk)

Reporting group description

KPL-404 2 mg/kg subcutaneous (SC) q2wk for 12 weeks

Reporting group title

Cohort 2 KPL-404 5 mg/kg q2wk

Reporting group description

KPL-404 5 mg/kg SC q2wk for 12 weeks

Reporting group title

Cohort 1/2 Placebo

Reporting group description

Placebo SC q2wk for 12 weeks

Reporting group title

Cohort 3 KPL-404 5 mg/kg qwk

Reporting group description

KPL-404 5 mg/kg SC once weekly (qwk) for 12 weeks

Reporting group title

Cohort 3 KPL-404 5 mg/kg q2wk

Reporting group description

KPL-404 5 mg/kg SC q2wk with alternating weekly administrations of KPL-404 or placebo SC for 12 weeks

Reporting group title

Cohort 3 Placebo

Reporting group description

Placebo SC qwk for 12 weeks

Reporting group title

Cohort 4: KPL-404 400 mg q4wk

Reporting group description

KPL-404 SC every 4 weeks (q4wk) for 12 weeks: 600 mg loading dose at baseline followed by 400 mg at Weeks 4 and 8

Reporting group title

Cohort 4 Placebo

Reporting group description

Placebo SC q4wk for 12 weeks

Reporting group values	Cohort 1 KPL-404 2 mg/kg every 2 weeks (q2wk)	Cohort 2 KPL-404 5 mg/kg q2wk	Cohort 1/2 Placebo	Cohort 3 KPL-404 5 mg/kg qwk	Cohort 3 KPL-404 5 mg/kg q2wk	Cohort 3 Placebo	Cohort 4: KPL-404 400 mg q4wk	Cohort 4 Placebo	Total
Number of subjects	6	6	4	27	25	26	31	20	145
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	56.8 ( 15.59 )	56.3 ( 13.29 )	59.8 ( 13.05 )	58.5 ( 9.68 )	60.0 ( 10.10 )	57.6 ( 9.90 )	58.8 ( 9.45 )	58.3 ( 11.81 )	-
Gender categorical
Units: Subjects
Female	5	5	4	22	20	24	25	15	120
Male	1	1	0	5	5	2	6	5	25
Ethnicity
Units: Subjects
Hispanic or Latino	1	4	2	2	3	6	5	1	24
Not Hispanic or Latino	5	2	2	25	22	20	26	19	121
Race
Units: Subjects
Asian	0	0	0	1	0	0	2	2	5
Black or African American	1	0	0	1	2	2	3	1	10
White	5	6	4	25	23	24	26	17	130

End points

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Reporting group title

Cohort 1 KPL-404 2 mg/kg every 2 weeks (q2wk)

Reporting group description

KPL-404 2 mg/kg subcutaneous (SC) q2wk for 12 weeks

Reporting group title

Cohort 2 KPL-404 5 mg/kg q2wk

Reporting group description

KPL-404 5 mg/kg SC q2wk for 12 weeks

Reporting group title

Cohort 1/2 Placebo

Reporting group description

Placebo SC q2wk for 12 weeks

Reporting group title

Cohort 3 KPL-404 5 mg/kg qwk

Reporting group description

KPL-404 5 mg/kg SC once weekly (qwk) for 12 weeks

Reporting group title

Cohort 3 KPL-404 5 mg/kg q2wk

Reporting group description

KPL-404 5 mg/kg SC q2wk with alternating weekly administrations of KPL-404 or placebo SC for 12 weeks

Reporting group title

Cohort 3 Placebo

Reporting group description

Placebo SC qwk for 12 weeks

Reporting group title

Cohort 4: KPL-404 400 mg q4wk

Reporting group description

KPL-404 SC every 4 weeks (q4wk) for 12 weeks: 600 mg loading dose at baseline followed by 400 mg at Weeks 4 and 8

Reporting group title

Cohort 4 Placebo

Reporting group description

Placebo SC q4wk for 12 weeks

Primary: Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

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End point title

Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) ^[1] ^[2]

End point description

Adverse event (AE): any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. Serious AE (SAE): AE that: results in death; is immediately life-threatening; requires in-patient hospitalization/prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital abnormality/birth defect; is an important medical event. TEAEs: AEs not present before exposure to study drug or any event already present that worsens in either intensity or frequency after exposure to study drug during treatment period. AE severity: mild (Grade [Gr] 1); moderate (Gr 2); severe (Gr 3); potentially life threatening (Gr 4); death (Gr 5). AEs of special interest: thrombosis, serious infection, serious and non-serious bacterial infections, eye disorders, and anaphylaxis/hypersensitivity reactions. Safety Population: Randomized participants who received ≥ 1 dose of study drug.

End point type

Primary

End point timeframe

From first dose of study drug to 24 weeks

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses are presented in the data table.
[2] - 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: Per protocol, this endpoint applied only to Cohorts 1 and 2.

End point values	Cohort 1 KPL-404 2 mg/kg every 2 weeks (q2wk)	Cohort 2 KPL-404 5 mg/kg q2wk	Cohort 1/2 Placebo
Number of subjects analysed	6	6	4
Units: participants
TEAEs	2	2	3
Drug-related TEAEs	1	1	1
TEAEs by maximum severity	2	2	3
Maximum Severity = Mild	1	1	1
Maximum Severity = Moderate	1	1	2
Maximum Severity = Severe	0	0	0
Maximum Severity = Potentially Life threatening	0	0	0
Maximum Severity = Fatal	0	0	0
Serious TEAEs	0	0	0
Drug-related SAEs	0	0	0
TEAEs leading to death	0	0	0
TEAEs leading to dose interruption	1	1	0
TEAEs leading to treatment discontinuation	0	0	0
TEAEs of special interest	0	0	0
Injection site reactions	0	1	0

No statistical analyses for this end point

Primary: Cohorts 1 and 2: Maximum Serum Concentration (Cmax)

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End point title

Cohorts 1 and 2: Maximum Serum Concentration (Cmax) ^[3] ^[4]

End point description

Participants treated with KPL-404, with an evaluable PK sample at given time point.

End point type

Primary

End point timeframe

Days 1 (Dose 1) and 57 (Dose 4)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses are presented in the data table.
[4] - 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: Per protocol, this endpoint applied only to Cohorts 1 and 2.

End point values	Cohort 1 KPL-404 2 mg/kg every 2 weeks (q2wk)	Cohort 2 KPL-404 5 mg/kg q2wk
Number of subjects analysed	5 ^[5]	6 ^[6]
Units: μg/mL
arithmetic mean (standard deviation)
Day 1; n=5, 6	7.57 ( 7.52 )	28.0 ( 13.5 )
Day 57; n=3, 6	17.8 ( 13.9 )	68.3 ( 25.1 )

Notes
[5] - n=number of participants with an assessment at given timepoint.
[6] - n=number of participants with an assessment at given timepoint.

No statistical analyses for this end point

Primary: Cohorts 1 and 2: Area Under the Serum Concentration-time Curve From Time 0 to the End of the Dosing Interval (AUCtau)

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End point title

Cohorts 1 and 2: Area Under the Serum Concentration-time Curve From Time 0 to the End of the Dosing Interval (AUCtau) ^[7] ^[8]

End point description

Participants treated with KPL-404, with an evaluable PK sample at given time point.

End point type

Primary

End point timeframe

Days 1 (Dose 1) and 57 (Dose 4)

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analyses are presented in the data table.
[8] - 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: Per protocol, this endpoint applied only to Cohorts 1 and 2.

End point values	Cohort 1 KPL-404 2 mg/kg every 2 weeks (q2wk)	Cohort 2 KPL-404 5 mg/kg q2wk
Number of subjects analysed	5 ^[9]	6 ^[10]
Units: μg·day/mL
arithmetic mean (standard deviation)
Day 1; n=5, 6	59.0 ( 51.1 )	303 ( 148 )
Day 57; n=3, 6	162 ( 114 )	810 ( 290 )

Notes
[9] - n=number of participants with an assessment at given timepoint.
[10] - n=number of participants with an assessment at given timepoint.

No statistical analyses for this end point

Primary: Cohort 3 and 4: Change From Baseline in Disease Activity Score of 28 Joints Using C-reactive Protein (DAS28-CRP) at Week 12

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End point title

Cohort 3 and 4: Change From Baseline in Disease Activity Score of 28 Joints Using C-reactive Protein (DAS28-CRP) at Week 12 ^[11]

End point description

DAS28 is a measure based on assessment of 28 joints for tenderness and swelling (tender and swollen joint counts). DAS28-CRP is derived using differential weighting given to 4 components: tender joint count (range: 0-28), swollen joint count (range: 0-28), patient global assessment (recorded on a visual analog scale [VAS] scale of 0-100 mm), and CRP (milligram per liter). DAS28-CRP score ranges from 0 to 9.4. The lower the DAS28-CRP score is, the better the participant has response (remission = score < 2.6, low disease activity = score < 3.2). A negative value in change from BL indicates an improvement. Modified Intent-to-Treat (mITT) population: All randomized participants who received at least one dose of study drug and who had at least one postbaseline assessment for the primary efficacy endpoint.

End point type

Primary

End point timeframe

Baseline, Week 12

Notes
[11] - 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: Per protocol, this endpoint applied only to Cohorts 3 and 4.

End point values	Cohort 3 KPL-404 5 mg/kg qwk	Cohort 3 KPL-404 5 mg/kg q2wk	Cohort 3 Placebo	Cohort 4: KPL-404 400 mg q4wk	Cohort 4 Placebo
Number of subjects analysed	27	25	26	31	20
Units: score on a scale
least squares mean (standard error)	-2.17 ( 0.216 )	-1.96 ( 0.220 )	-1.61 ( 0.218 )	-1.87 ( 0.331 )	-1.30 ( 0.338 )

Statistical Analysis 1

Comparison groups

Cohort 3 Placebo v Cohort 3 KPL-404 5 mg/kg qwk

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.047 ^[12]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.57

Confidence interval

level

95%

sides

2-sided

lower limit

-1.13

upper limit

-0.01

Variability estimate

Standard error of the mean

Dispersion value

0.281

Notes
[12] - Analyzed using ANCOVA model with baseline value and stratification factor (≤1 vs. ≥2 classes of advanced targeted therapies) as covariates.

Statistical Analysis 2

Comparison groups

Cohort 3 KPL-404 5 mg/kg q2wk v Cohort 3 Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2124 ^[13]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.36

Confidence interval

level

95%

sides

2-sided

lower limit

-0.92

upper limit

0.21

Variability estimate

Standard error of the mean

Dispersion value

0.282

Notes
[13] - Analyzed using ANCOVA model with baseline value and stratification factor (≤1 vs. ≥2 classes of advanced targeted therapies) as covariates.

Statistical Analysis 3

Comparison groups

Cohort 4 Placebo v Cohort 4: KPL-404 400 mg q4wk

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1091 ^[14]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.58

Confidence interval

level

95%

sides

2-sided

lower limit

-1.28

upper limit

0.13

Variability estimate

Standard error of the mean

Dispersion value

0.352

Notes
[14] - Analyzed using ANCOVA model with baseline value and stratification factor (≤1 vs. ≥2 classes of advanced targeted therapies) as covariates.

Secondary: Cohorts 1 and 2: Change From Baseline in DAS28-CRP at Week 12

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End point title

Cohorts 1 and 2: Change From Baseline in DAS28-CRP at Week 12 ^[15]

End point description

End point type

Secondary

End point timeframe

Baseline, Week 12

Notes
[15] - 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: Per protocol, this endpoint applied only to Cohorts 1 and 2.

End point values	Cohort 1 KPL-404 2 mg/kg every 2 weeks (q2wk)	Cohort 2 KPL-404 5 mg/kg q2wk	Cohort 1/2 Placebo
Number of subjects analysed	6	6	4
Units: score on a scale
arithmetic mean (standard deviation)	-3.16 ( 1.130 )	-3.44 ( 1.450 )	-1.09 ( 1.373 )

Statistical Analysis 1

Comparison groups

Cohort 1 KPL-404 2 mg/kg every 2 weeks (q2wk) v Cohort 1/2 Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0312

Method

t-test

Confidence interval

Statistical Analysis 2

Comparison groups

Cohort 1/2 Placebo v Cohort 2 KPL-404 5 mg/kg q2wk

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0338

Method

t-test

Confidence interval

Secondary: Cohorts 3 and 4: Number of Participants With TEAEs

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End point title

Cohorts 3 and 4: Number of Participants With TEAEs ^[16]

End point description

End point type

Secondary

End point timeframe

From first dose of study drug to 24 weeks

Notes
[16] - 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: Per protocol, this endpoint applied only to Cohorts 3 and 4.

End point values	Cohort 3 KPL-404 5 mg/kg qwk	Cohort 3 KPL-404 5 mg/kg q2wk	Cohort 3 Placebo	Cohort 4: KPL-404 400 mg q4wk	Cohort 4 Placebo
Number of subjects analysed	27	25	26	31	20
Units: participants
TEAEs	12	6	8	9	8
Drug-related TEAEs	2	2	2	3	1
TEAEs by maximum severity	12	6	8	9	8
Maximum Severity = Mild	8	3	4	4	5
Maximum Severity = Moderate	4	3	4	5	3
Maximum Severity = Severe	0	0	0	0	0
Maximum Severity = Potentially Life threatening	0	0	0	0	0
Maximum Severity = Fatal	0	0	0	0	0
Serious TEAEs	1	0	0	0	0
Drug-related SAEs	0	0	0	0	0
TEAEs leading to death	0	0	0	0	0
TEAEs leading to dose interruption	1	0	1	0	0
TEAEs leading to treatment discontinuation	0	0	0	1	1
TEAEs of special interest	1	1	0	1	2
Injection site reactions	1	1	0	2	0

No statistical analyses for this end point

Secondary: Cohort 3 and 4: Cmax

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End point title

Cohort 3 and 4: Cmax ^[17]

End point description

Participants treated with KPL-404, with an evaluable PK sample at given time point.

End point type

Secondary

End point timeframe

Days 1 (Dose 1) and 57 (Dose 4 or 8)

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: Per protocol, this endpoint applied only to Cohorts 3 and 4.

End point values	Cohort 3 KPL-404 5 mg/kg qwk	Cohort 3 KPL-404 5 mg/kg q2wk	Cohort 4: KPL-404 400 mg q4wk
Number of subjects analysed	27 ^[18]	25 ^[19]	30 ^[20]
Units: μg/mL
arithmetic mean (standard deviation)
Day 1; n=27, 25, 30	27.1 ( 11.0 )	29.4 ( 10.3 )	48.5 ( 18.2 )
Day 57; n=22, 25, 27	145 ( 41.0 )	70.9 ( 21.5 )	45.6 ( 21.4 )

Notes
[18] - n=number of participants with an assessment at given timepoint.
[19] - n=number of participants with an assessment at given timepoint.
[20] - n=number of participants with an assessment at given timepoint.

No statistical analyses for this end point

Secondary: Cohort 3 and 4: AUCtau

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End point title

Cohort 3 and 4: AUCtau ^[21]

End point description

Participants treated with KPL-404, with an evaluable PK sample at given time point.

End point type

Secondary

End point timeframe

Days 1 (Dose 1) and 57 (Dose 4 or 8)

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: Per protocol, this endpoint applied only to Cohorts 3 and 4.

End point values	Cohort 3 KPL-404 5 mg/kg qwk	Cohort 3 KPL-404 5 mg/kg q2wk	Cohort 4: KPL-404 400 mg q4wk
Number of subjects analysed	27	25	30
Units: μg·day/mL
arithmetic mean (standard deviation)
Day 1; n=27, 25, 30	139 ( 63.4 )	310 ( 105 )	873 ( 363 )
Day 57; n=22, 25, 27	975 ( 291 )	849 ( 267 )	843 ( 466 )

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12

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End point title

Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12

End point description

An ACR20 response is defined as at least a 20% improvement in both tender joint count (TJC) and swollen joint count (SJC), and at least a 20% improvement in three of the following five criteria: patient global assessment (PGA), physician global assessment (PhGA), functional ability measure [Health Assessment Questionnaire (HAQ)], patient's assessment of pain (visual analog scale; VAS) and C-reactive protein (CRP). mITT population: All randomized participants who received at least one dose of study drug and who had at least one post-baseline assessment for the primary efficacy endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Cohort 1 KPL-404 2 mg/kg every 2 weeks (q2wk)	Cohort 2 KPL-404 5 mg/kg q2wk	Cohort 1/2 Placebo	Cohort 3 KPL-404 5 mg/kg qwk	Cohort 3 KPL-404 5 mg/kg q2wk	Cohort 3 Placebo	Cohort 4: KPL-404 400 mg q4wk	Cohort 4 Placebo
Number of subjects analysed	6	6	4	27	25	26	31	20
Units: percentage of participants
number (not applicable)	100	83.3	25.0	74.1	60.0	50.0	80.6	40.0

Statistical Analysis 1

Comparison groups

Cohort 1 KPL-404 2 mg/kg every 2 weeks (q2wk) v Cohort 1/2 Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0333

Method

Fisher exact test

Confidence interval

Statistical Analysis 2

Comparison groups

Cohort 1/2 Placebo v Cohort 2 KPL-404 5 mg/kg q2wk

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1905

Method

Fisher exact test

Confidence interval

Statistical Analysis 3

Comparison groups

Cohort 3 KPL-404 5 mg/kg qwk v Cohort 3 Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0716

Method

CMH test

Parameter type

Odds ratio (OR)

Point estimate

2.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

9.65

Statistical Analysis 4

Comparison groups

Cohort 3 Placebo v Cohort 3 KPL-404 5 mg/kg q2wk

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.471

Method

CMH test

Parameter type

Odds ratio (OR)

Point estimate

1.52

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

4.67

Statistical Analysis 5

Comparison groups

Cohort 4: KPL-404 400 mg q4wk v Cohort 4 Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0057

Method

CMH test

Parameter type

Odds ratio (OR)

Point estimate

6.09

Confidence interval

level

95%

sides

2-sided

lower limit

1.62

upper limit

22.88

Secondary: Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Week 12

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End point title

Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Week 12

End point description

An ACR50 response is defined as at least a 50% improvement in both tender joint count (TJC) and swollen joint count (SJC), and at least a 50% improvement in three of the following five criteria: patient global assessment (PGA), physician global assessment (PhGA), functional ability measure [Health Assessment Questionnaire (HAQ)], patient's assessment of pain (visual analog scale; VAS) and C-reactive protein (CRP). mITT population: All randomized participants who received at least one dose of study drug and who had at least one post-baseline assessment for the primary efficacy endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Cohort 1 KPL-404 2 mg/kg every 2 weeks (q2wk)	Cohort 2 KPL-404 5 mg/kg q2wk	Cohort 1/2 Placebo	Cohort 3 KPL-404 5 mg/kg qwk	Cohort 3 KPL-404 5 mg/kg q2wk	Cohort 3 Placebo	Cohort 4: KPL-404 400 mg q4wk	Cohort 4 Placebo
Number of subjects analysed	6	6	4	27	25	26	31	20
Units: percentage of participants
number (not applicable)	66.7	16.7	0	33.3	36.0	23.1	32.3	30.0

Statistical Analysis 1

Comparison groups

Cohort 1 KPL-404 2 mg/kg every 2 weeks (q2wk) v Cohort 1/2 Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0762

Method

Fisher exact test

Confidence interval

Statistical Analysis 2

Comparison groups

Cohort 1/2 Placebo v Cohort 2 KPL-404 5 mg/kg q2wk

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1

Method

Fisher exact test

Confidence interval

Statistical Analysis 3

Comparison groups

Cohort 3 KPL-404 5 mg/kg qwk v Cohort 3 Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4172

Method

CMH test

Parameter type

Odds ratio (OR)

Point estimate

1.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.49

upper limit

5.62

Statistical Analysis 4

Comparison groups

Cohort 3 Placebo v Cohort 3 KPL-404 5 mg/kg q2wk

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3144

Method

CMH test

Parameter type

Odds ratio (OR)

Point estimate

1.89

Confidence interval

level

95%

sides

2-sided

lower limit

0.55

upper limit

6.45

Statistical Analysis 5

Comparison groups

Cohort 4: KPL-404 400 mg q4wk v Cohort 4 Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.956

Method

CMH test

Parameter type

Odds ratio (OR)

Point estimate

0.97

Confidence interval

level

95%

sides

2-sided

lower limit

0.28

upper limit

3.39

Secondary: Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at Week 12

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End point title

Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at Week 12

End point description

An ACR70 response is defined as at least a 70% improvement in both tender joint count (TJC) and swollen joint count (SJC), and at least a 70% improvement in three of the following five criteria: patient global assessment (PGA), physician global assessment (PhGA), functional ability measure [Health Assessment Questionnaire (HAQ)], patient's assessment of pain (visual analog scale; VAS) and C-reactive protein (CRP). mITT population: All randomized participants who received at least one dose of study drug and who had at least one post-baseline assessment for the primary efficacy endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Cohort 1 KPL-404 2 mg/kg every 2 weeks (q2wk)	Cohort 2 KPL-404 5 mg/kg q2wk	Cohort 1/2 Placebo	Cohort 3 KPL-404 5 mg/kg qwk	Cohort 3 KPL-404 5 mg/kg q2wk	Cohort 3 Placebo	Cohort 4: KPL-404 400 mg q4wk	Cohort 4 Placebo
Number of subjects analysed	6	6	4	27	25	26	31	20
Units: percentage of participants
number (not applicable)	33.3	16.7	0	7.4	20.0	3.8	9.7	25.0

Statistical Analysis 1

Comparison groups

Cohort 1 KPL-404 2 mg/kg every 2 weeks (q2wk) v Cohort 1/2 Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4667

Method

Fisher exact test

Confidence interval

Statistical Analysis 2

Comparison groups

Cohort 2 KPL-404 5 mg/kg q2wk v Cohort 1/2 Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1

Method

Fisher exact test

Confidence interval

Statistical Analysis 3

Comparison groups

Cohort 3 KPL-404 5 mg/kg qwk v Cohort 3 Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5789

Method

CMH test

Parameter type

Odds ratio (OR)

Point estimate

1.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.17

upper limit

22.3

Statistical Analysis 4

Comparison groups

Cohort 3 Placebo v Cohort 3 KPL-404 5 mg/kg q2wk

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0799

Method

CMH test

Parameter type

Odds ratio (OR)

Point estimate

6.12

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

60.1

Statistical Analysis 5

Comparison groups

Cohort 4: KPL-404 400 mg q4wk v Cohort 4 Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1034

Method

CMH test

Parameter type

Odds ratio (OR)

Point estimate

0.28

Confidence interval

level

95%

sides

2-sided

lower limit

0.06

upper limit

1.35

Adverse events

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Timeframe for reporting adverse events

Up to 28 weeks

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

27.0

Reporting group title

Cohort 1 KPL-404 2 mg/kg q2wk

Reporting group description

KPL-404 2 mg/kg subcutaneous (SC) every 2 weeks (q2wk) for 12 weeks

Reporting group title

Cohort 2 KPL-404 5 mg/kg q2wk

Reporting group description

KPL-404 5 mg/kg SC q2wk for 12 weeks

Reporting group title

Cohort 1/2 Placebo

Reporting group description

Placebo SC q2wk for 12 weeks

Reporting group title

Cohort 3 KPL-404 5 mg/kg qwk

Reporting group description

KPL-404 5 mg/kg SC once weekly (qwk) for 12 weeks

Reporting group title

Cohort 3 KPL-404 5 mg/kg q2wk

Reporting group description

KPL-404 5 mg/kg SC q2wk with alternating weekly administrations of KPL-404 or placebo SC for 12 weeks

Reporting group title

Cohort 3 Placebo

Reporting group description

Placebo SC qwk for 12 weeks

Reporting group title

Cohort 4: KPL-404 400 mg q4wk

Reporting group description

KPL-404 SC every 4 weeks (q4wk) for 12 weeks: 600 mg loading dose at baseline followed by 400 mg at Weeks 4 and 8

Reporting group title

Cohort 4 Placebo

Reporting group description

Placebo SC q4wk for 12 weeks

Serious adverse events	Cohort 1 KPL-404 2 mg/kg q2wk	Cohort 2 KPL-404 5 mg/kg q2wk	Cohort 1/2 Placebo	Cohort 3 KPL-404 5 mg/kg qwk	Cohort 3 KPL-404 5 mg/kg q2wk	Cohort 3 Placebo	Cohort 4: KPL-404 400 mg q4wk	Cohort 4 Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 31 (0.00%)	0 / 20 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events
Ear and labyrinth disorders
Sudden hearing loss
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyponatraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 31 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cohort 1 KPL-404 2 mg/kg q2wk	Cohort 2 KPL-404 5 mg/kg q2wk	Cohort 1/2 Placebo	Cohort 3 KPL-404 5 mg/kg qwk	Cohort 3 KPL-404 5 mg/kg q2wk	Cohort 3 Placebo	Cohort 4: KPL-404 400 mg q4wk	Cohort 4 Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	2 / 6 (33.33%)	2 / 6 (33.33%)	3 / 4 (75.00%)	6 / 27 (22.22%)	5 / 25 (20.00%)	4 / 26 (15.38%)	5 / 31 (16.13%)	8 / 20 (40.00%)
Investigations
Fibrin D dimer increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 31 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1	0	1
Injury, poisoning and procedural complications
Animal scratch
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)	0 / 25 (0.00%)	1 / 26 (3.85%)	1 / 31 (3.23%)	0 / 20 (0.00%)
occurrences all number	0	0	0	2	0	1	1	0
Nervous system disorders
Headache
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 27 (3.70%)	0 / 25 (0.00%)	2 / 26 (7.69%)	1 / 31 (3.23%)	0 / 20 (0.00%)
occurrences all number	0	0	1	1	0	2	1	0
Sinus headache
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Injection site erythema
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Injection site pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	2 / 25 (8.00%)	0 / 26 (0.00%)	1 / 31 (3.23%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	2	0	1	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)	0 / 25 (0.00%)	0 / 26 (0.00%)	1 / 31 (3.23%)	0 / 20 (0.00%)
occurrences all number	0	0	0	2	0	0	1	0
Abdominal discomfort
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Reproductive system and breast disorders
Prostatitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	0	0	0	0	0	0	1
Dyspnoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	1
Interstitial lung disease
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 27 (3.70%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Arthritis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	1
Pain in extremity
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Rheumatoid arthritis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	2 / 25 (8.00%)	1 / 26 (3.85%)	2 / 31 (6.45%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	2	1	2	1
Infections and infestations
COVID-19
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 27 (3.70%)	0 / 25 (0.00%)	1 / 26 (3.85%)	0 / 31 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	1	0	1	0	1	0	0
Campylobacter infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	1
Gastroenteritis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1	0	0	1
Nasopharyngitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	2 / 25 (8.00%)	0 / 26 (0.00%)	2 / 31 (6.45%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	2	0	2	1
Sinusitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 4 (50.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	2	0	0	0	0	0
Urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	1 / 25 (4.00%)	0 / 26 (0.00%)	2 / 31 (6.45%)	2 / 20 (10.00%)
occurrences all number	0	0	0	0	1	0	4	2
Bronchitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	1	0	0	0	1
Rhinitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	1
Upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	4 / 27 (14.81%)	0 / 25 (0.00%)	2 / 26 (7.69%)	2 / 31 (6.45%)	0 / 20 (0.00%)
occurrences all number	0	0	1	4	0	3	2	0
Metabolism and nutrition disorders
Hypercholesterolaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)	0 / 25 (0.00%)	0 / 26 (0.00%)	1 / 31 (3.23%)	1 / 20 (5.00%)
occurrences all number	0	0	0	1	0	0	1	1
Hyperuricaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 26 (0.00%)	0 / 31 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

12 Aug 2021

• Study design was revised to increase volume of safety data available to inform the dose escalation decision. • A 2-sided type 1 error rate of 0.1 was specified for the efficacy analysis. • Additional detail was provided regarding statistical methodology. • Description of Safety Review Committee (SRC) was revised to increase its independence and prevent bias in study management. • More stringent stopping rules were provided allowing for safety review. • Description of efficacy endpoints was clarified.

09 Dec 2021

• Description of primary endpoints was clarified. • Text was added to reflect changes to study design specific to Cohort 4, including an increase in sample size from 60 to 75 participants. • Text was added to reflect changes to randomization and stratification factors based on changes to entry criteria. • Study schema was updated to include changes to Cohort 4. • Contraception requirements were clarified. • Text was added to distinguish between treatment discontinuation, withdrawal of consent, and lost-to-follow up. • Text was added to clarify details relative to study drug packaging and labeling that appear elsewhere. • Criteria for assessments that do not need to be done in a specific order were updated. • Text was updated to better describe the clinical outcome assessment measurements being collected. • Synovial biopsy substudy was deleted. • Timing for collection of anti-drug antibody (ADA) blood samples was clarified. • Cannabinoids were deleted from urine drug screen. • Description of adverse event of special interest (AESIs) was clarified. • Interim analysis plans were clarified.

12 Aug 2022

• Sponsor personnel were updated. • Study design was changed to facilitate investigation of the 5 mg/kg SC dose level (qwk and q2wk). • Alpha 0.05 was selected for the determination of sample size to provide a tight control of type 1 error. • Study objectives, blinding rules, randomization schema, and study schema were revised to align with the new study design. • The SRC schedule for Cohort 3 was revised to provide safety oversight for the proof-of-concept Cohort 3 portion of the study. • Relatedness language was revised. • Dose justification was revised to include pharmacodynamics and additional pharmacokinetics information. • Schedule of Activities was added for Cohort 3. • Blood collection for circulating transcriptomic biomarkers were removed for Cohorts 2 and 3.

31 Mar 2023

• Sponsor personnel was updated. • Text was modified to clarify the end of study follow-up period and collection of AEs/SAEs. • Study Schema was updated to correctly represent new elements of the protocol amendment. • Body weight limit was increased to allow expansion of RA participant population. • Inclusion criteria were updated to reflect available advanced targeted therapies for treatment of RA. • CRP limit inclusion criterion was updated to reflect and align with clinical trial practice in RA. • Rheumatoid factor (RF) and/or anti-citrullinated protein antibody (ACPA) inclusion criteria were updated to provide operational flexibility to investigational sites. • Inclusion criterion for potential participants already receiving opiate analgesia was updated to a dose no greater than 50 MME/day. • Exclusion criterion was updated to accept participants with TB who had been appropriately treated. • Stratification factors were updated to stratify based on the number of prior classes of advanced targeted therapies to which they had demonstrated inadequate therapeutic response (≤1 vs ≥2). • Blinding language was clarified to allow treatment assignment unblinding of completed cohorts. • Text was added clarifying IP administration within protocol-specified time window. • Collection of medication history was revised for clarity. • Interim analysis text was revised. • Analysis method was changed to better account for the new stratification scheme.

28 Jun 2023

• The objectives and endpoints, sample size, randomization, rationale, dose levels and dose administration, Schedule of Assessments, and Study Schema were updated/added to include the new Cohort 4. • Text was added to describe when SRC meetings would begin and how frequently they would occur for Cohorts 3 and 4. • Text was added to describe when participants should return for an end-of-treatment visit following premature discontinuation of treatment. • Text was added to clarify the mITT population definition and to align this definition with the Statistical Analysis Plan. • Text was revised to clarify the definitions of low disease activity and complete response and to align these definitions with the Statistical Analysis Plan. • Text was added to align with the Statistical Analysis Plan definitions of TEAEs.

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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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

Primary: Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

Primary: Cohorts 1 and 2: Maximum Serum Concentration (Cmax)

Primary: Cohorts 1 and 2: Maximum Serum Concentration (Cmax)

Primary: Cohorts 1 and 2: Area Under the Serum Concentration-time Curve From Time 0 to the End of the Dosing Interval (AUCtau)

Primary: Cohorts 1 and 2: Area Under the Serum Concentration-time Curve From Time 0 to the End of the Dosing Interval (AUCtau)

Primary: Cohort 3 and 4: Change From Baseline in Disease Activity Score of 28 Joints Using C-reactive Protein (DAS28-CRP) at Week 12

Primary: Cohort 3 and 4: Change From Baseline in Disease Activity Score of 28 Joints Using C-reactive Protein (DAS28-CRP) at Week 12

Secondary: Cohorts 1 and 2: Change From Baseline in DAS28-CRP at Week 12

Secondary: Cohorts 1 and 2: Change From Baseline in DAS28-CRP at Week 12

Secondary: Cohorts 3 and 4: Number of Participants With TEAEs

Secondary: Cohorts 3 and 4: Number of Participants With TEAEs

Secondary: Cohort 3 and 4: Cmax

Secondary: Cohort 3 and 4: Cmax

Secondary: Cohort 3 and 4: AUCtau

Secondary: Cohort 3 and 4: AUCtau

Secondary: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12

Secondary: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12

Secondary: Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Week 12

Secondary: Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Week 12

Secondary: Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at Week 12

Secondary: Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at Week 12

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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