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Clinical Trial Results:
A randomised, double blind, placebo-controlled, multiple dose, phase 2b, 24 week trial followed by an open label extension of NNC0109-0012, an anti-IL-20 biologic, in patients with active rheumatoid arthritis who are inadequate responders to anti-TNFα biologics.

Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.

Summary
EudraCT number	2012-000609-58
Trial protocol	BE HU GB CZ DE ES IT
Global end of trial date	11 Nov 2014

Results information
Results version number	v1(current)
This version publication date	24 Jun 2016
First version publication date	24 Jun 2016
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

NN8226-3612

ISRCTN number

US NCT number

NCT01636817

WHO universal trial number (UTN)

U1111-1127-9273

Sponsor organisation name

Novo Nordisk A/S

Sponsor organisation address

Novo Allé,, Bagsvaerd,, Denmark, 2880

Public contact

Global Clinical Registry (GCR, 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com

Scientific contact

Global Clinical Registry (GCR, 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.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 Jul 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

11 Nov 2014

Global end of trial reached?

Yes

Global end of trial date

11 Nov 2014

Was the trial ended prematurely?

Yes

Main objective of the trial

To investigate the clinical efficacy of NNC0109-0012 compared to placebo when administered as weekly repeat s.c. injections in patients with active rheumatoid arthritis (RA) who are inadequate responders to anti-TNFα biologics and are on a stable background of methotrexate (MTX) therapy.

Protection of trial subjects

The trial was conducted in accordance with the Declaration of Helsinki, October 2000, Amended 2002, 2004 and 2008, ICH Good Clinical Practice, May 1996. FDA 21 CFR 312.120, and 21 Code of Federal Regulations, parts 312, 50, and 56 were followed for US trial sites.

Background therapy

All subjects were on a stable background treatment with methotrexate (MTX). The therapy included MTX treatment (≥ 15.0 mg/week) for at least 16 weeks and at doses (≥ 15.0 mg/week to ≤ 25 mg/week) for at least 8 weeks prior to screening visit. Subjects could be on MTX dosing as low as 10 mg/week only if due to documented MTX intolerance. Additional background treatments could have included hydroxychloroqine/chloroquine, non-steroidal anti-inflammatory drugs (NSAIDs) or steroidal medication.

Evidence for comparator

Not applicable

Actual start date of recruitment

06 Aug 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 46

Country: Number of subjects enrolled

Belgium: 2

Country: Number of subjects enrolled

Brazil: 36

Country: Number of subjects enrolled

Czech Republic: 3

Country: Number of subjects enrolled

France: 1

Country: Number of subjects enrolled

Germany: 1

Country: Number of subjects enrolled

Hungary: 3

Country: Number of subjects enrolled

Italy: 2

Country: Number of subjects enrolled

Mexico: 39

Country: Number of subjects enrolled

Poland: 7

Country: Number of subjects enrolled

Spain: 16

Country: Number of subjects enrolled

United States: 83

Worldwide total number of subjects

239

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)

205

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The trial was conducted at 79 sites in 12 countries : Argentina: 5 sites; Belgium: 1 site; Brazil: 9 sites; Czech Republic: 2 sites; France: 1 site; Germany: 1 site; Hungary: 1 site; Italy: 1 site; Mexico: 8 sites; Poland: 2 sites; Spain: 4 sites; United States: 44 sites.

Screening details

Of 654 subjects screened, 415 were screen failures and 239 were randomised to either placebo or one of the 3 doses of NNC0109-0012 (i.e., 60 mg/120 mg/240 mg).

Period 1 title

Main Trial Period (week 0-24)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

The trial period consisted of a 24-week double-blinded period and a 28-week open-label extension during which investigators and patients remained blinded. Blinding was kept for all staff involved in trial-related activities at the site and at the sponsor. After the failure of the NN8226-3613 (EudraCT no: 2012-000610-11) trial with NNC0109-0012 in RA to achieve its primary efficacy endpoint in a partial data base lock (DBL) analysis, this trial was prematurely terminated.

Are arms mutually exclusive

Yes

Main-Placebo

Arm description

All subjects in this arm received NNC0109-0012 placebo once weekly for a period of 24-weeks (double-blinded main treatment period).

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

NNC0109-0012 placebo, 0 mg/mL was administered into either the abdomen or thigh once weekly with NovoPen® 4 by subcutaneous (s.c., under the skin) injection.

Main-60 mg

Arm description

All subjects in this arm received 60 mg of NNC0109-0012, once weekly for a period of 24-weeks (double-blinded main treatment period).

Arm type

Experimental

Investigational medicinal product name

NNC0109-0012

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

NNC0109-0012, 60 mg was administered into either the abdomen or thigh once weekly with NovoPen® 4 by subcutaneous (s.c., under the skin) injection.

Main-120 mg

Arm description

All subjects in this arm received 120 mg of NNC0109-0012, once weekly for a period of 24-weeks (double-blinded main treatment period).

Arm type

Experimental

Investigational medicinal product name

NNC0109-0012

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

NNC0109-0012, 120mg was administered into either the abdomen or thigh once weekly with NovoPen® 4 by subcutaneous (s.c., under the skin) injection.

Main-240 mg

Arm description

All subjects in this arm received 240 mg of NNC0109-0012, once weekly for a period of 24-weeks (double-blinded main treatment period).

Arm type

Experimental

Investigational medicinal product name

NNC0109-0012

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

NNC0109-0012, 240 mg was administered into either the abdomen or thigh once weekly with NovoPen® 4 by subcutaneous (s.c., under the skin) injection.

Number of subjects in period 1	Main-Placebo	Main-60 mg	Main-120 mg	Main-240 mg
Started	61	61	58	59
Exposed	61	61	58	57
Completed	29	31	31	32
Not completed	32	30	27	27
Adverse event, serious fatal	1	-	-	-
Adverse event, non-fatal	3	3	1	1
Withdrawal criteria	27	26	24	24
Unclassified	-	-	-	1
Lost to follow-up	-	-	2	-
Lack of efficacy	1	1	-	-
Protocol deviation	-	-	-	1

Period 2 title

Extension Trial Period (Week 25-52)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

The trial consisted of a 24-week double-blinded period and a 28 week open-label extension during which investigators and patients remained blinded.

Are arms mutually exclusive

Yes

Extension-Placebo-240 mg

Arm description

The subjects in this arm who demonstrated 20% or more improvement in tender and swollen joint counts in the main treatment period (at week 24) were eligible to enter the 28 week open-label extension treatment period. Subjects randomised to placebo in the main treatment period were to be switched to receive 240 mg of NNC0109-0012 subcutaneous (s.c.), once-weekly in the 28-week extension treatment period.

Arm type

Experimental

Investigational medicinal product name

NNC0109-0012

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

NNC0109-0012, 240 mg was administered into either the abdomen or thigh once weekly with NovoPen® 4 by subcutaneous (s.c., under the skin) injection.

Extension-60-60 mg

Arm description

The subjects in this arm who demonstrated 20% or more improvement in tender and swollen joint counts in the main treatment period (at week 24) were eligible to enter the 28 week open-label extension treatment period. Subjects randomised to NNC0109-0012, 60 mg in the main treatment period were to maintain their same dosage regimen during the 28-week extension treatment period.

Arm type

Experimental

Investigational medicinal product name

NNC0109-0012

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

NNC0109-0012, 60 mg was administered into either the abdomen or thigh once weekly with NovoPen® 4 by subcutaneous (s.c., under the skin) injection.

Extension-120-120 mg

Arm description

The subjects in this arm who demonstrated 20% or more improvement in tender and swollen joint counts in the main treatment period (at week 24) were eligible to enter the 28 week open-label extension treatment period. Subjects randomised to NNC0109-0012, 120 mg in the main treatment period were to maintain their same dosage regimen during the 28-week extension treatment period.

Arm type

Experimental

Investigational medicinal product name

NNC0109-0012

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

NNC0109-0012, 120mg was administered into either the abdomen or thigh once weekly with NovoPen® 4 by subcutaneous (s.c., under the skin) injection.

Extension-240-240 mg

Arm description

The subjects in this arm who demonstrated 20% or more improvement in tender and swollen joint counts in the main treatment period (at week 24) were eligible to enter the 28 week open-label extension treatment period. Subjects randomised to NNC0109-0012, 240 mg in the main treatment period were to maintain their same dosage regimen during the 28-week extension treatment period.

Arm type

Experimental

Investigational medicinal product name

NNC0109-0012

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

NNC0109-0012, 240 mg was administered into either the abdomen or thigh once weekly with NovoPen® 4 by subcutaneous (s.c., under the skin) injection.

Number of subjects in period 2 ^[1]	Extension-Placebo-240 mg	Extension-60-60 mg	Extension-120-120 mg	Extension-240-240 mg
Started	28	27	28	29
Completed	5	9	11	9
Not completed	23	18	17	20
Adverse event, serious fatal	1	-	-	-
Adverse event, non-fatal	1	1	-	1
Withdrawal criteria	19	15	17	19
Unclassified	-	1	-	-
Lack of efficacy	2	-	-	-
Protocol deviation	-	1	-	-

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Number of subjects completed the main trial by 24 week : 123 Number of subjects started the open-label extension period : 112 A total of 11 subjects completed the main trial, but did not enter the extension trial due to trial withdrawals as follows: 1 in placebo (adverse event); 4 (all met withdrawal criteria) in main-60 mg; 3 subjects each in main -120 mg and main- 240 mg arms for meeting the withdrawal criteria respectively.

Baseline characteristics

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Reporting group title

Main-Placebo

Reporting group description

All subjects in this arm received NNC0109-0012 placebo once weekly for a period of 24-weeks (double-blinded main treatment period).

Reporting group title

Main-60 mg

Reporting group description

All subjects in this arm received 60 mg of NNC0109-0012, once weekly for a period of 24-weeks (double-blinded main treatment period).

Reporting group title

Main-120 mg

Reporting group description

All subjects in this arm received 120 mg of NNC0109-0012, once weekly for a period of 24-weeks (double-blinded main treatment period).

Reporting group title

Main-240 mg

Reporting group description

All subjects in this arm received 240 mg of NNC0109-0012, once weekly for a period of 24-weeks (double-blinded main treatment period).

Reporting group values	Main-Placebo	Main-60 mg	Main-120 mg	Main-240 mg	Total
Number of subjects	61	61	58	59	239
Age categorical
Units: Subjects
Age continuous
Baseline characteristics for age values were collected and reported for exposed subjects as full analysis set (FAS). Two subjects randomised to the 240 mg group (N=59) were withdrawn before receiving trial product because of inclusion/exclusion criteria violations, however they were not exposed to the active trial product leading to a total number of 57 subjects in 240 mg group.
Units: years
arithmetic mean (standard deviation)	51.1 ( 12 )	51.9 ( 11.6 )	53.2 ( 11.9 )	52.4 ( 11.1 )	-
Gender categorical
Units: Subjects
Female	53	54	49	54	210
Male	8	7	9	5	29
Duration of Rheumatoid Arthritis (RA)
Baseline characteristics for duration of RA data was collected and reported for exposed subjects as full analysis set (FAS). Two subjects randomised to the 240 mg group (N=59) were withdrawn before receiving trial product because of inclusion/exclusion criteria violations, however they were not exposed to the active trial product leading to a total number of 57 subjects in 240 mg group.
Units: Years
arithmetic mean (standard deviation)	10 ( 6.8 )	11.8 ( 8.1 )	12.6 ( 8.8 )	10 ( 6.8 )	-
C-reactive protein (CRP)
Baseline data for CRP was collected and reported for exposed subjects as full analysis set (FAS). Two subjects randomised to the 240 mg group (N=59) were withdrawn before receiving trial product because of inclusion/exclusion criteria violations, however they were not exposed to the active trial product leading to a total number of 57 subjects in 240 mg group.
Units: mg/ L
geometric mean (full range (min-max))	21.4 (2.9 to 299.5)	18.9 (1 to 184.6)	18.2 (0.3 to 123.5)	17 (1.1 to 87.4)	-
Disease activity score in 28 joints (DAS28)
Baseline data for DAS28 was collected and reported for exposed subjects as full analysis set (FAS). Two subjects randomised to the 240 mg group (N=59) were withdrawn before receiving trial product because of inclusion/exclusion criteria violations, however they were not exposed to the active trial product leading to a total number of 57 subjects in 240 mg group.
Units: Number
arithmetic mean (standard deviation)	6.3 ( 0.8 )	6.3 ( 0.8 )	6.5 ( 0.8 )	6.5 ( 0.7 )	-
Tender joint count (TJC) 28
Baseline data for TJC28 was collected and reported for exposed subjects as full analysis set (FAS). Two subjects randomised to the 240 mg group (N=59) were withdrawn before receiving trial product because of inclusion/exclusion criteria violations, however they were not exposed to the active trial product leading to a total number of 57 subjects in 240 mg group.
Units: Number
arithmetic mean (standard deviation)	16.8 ( 6.4 )	16.7 ( 5.8 )	18.7 ( 5.4 )	19.7 ( 6.2 )	-
Swollen joint count (SJC) 28
Baseline data for SJC28 was collected and reported for exposed subjects as full analysis set (FAS). Two subjects randomised to the 240 mg group were withdrawn before receiving trial product because of inclusion/exclusion criteria violations, however they were not exposed to the active trial product leading to total of 57 number of subjects in 240 mg group.
Units: Number
arithmetic mean (standard deviation)	13.5 ( 4.6 )	13.3 ( 5.5 )	13.8 ( 4.8 )	15.7 ( 5.2 )	-
Tender joint count (TJC) 68
Baseline data for TJC68 was collected and reported for exposed subjects as full analysis set (FAS). Two subjects randomised to the 240 mg group (N=59) were withdrawn before receiving trial product because of inclusion/exclusion criteria violations, however they were not exposed to the active trial product leading to a total of 57 number of subjects in 240 mg group.
Units: Number
arithmetic mean (standard deviation)	30.5 ( 15.7 )	29.4 ( 15.5 )	31.1 ( 13.3 )	34.7 ( 15.8 )	-
Swollen joint count (SJC) 66
Baseline data for SJC 66 was collected and reported for exposed subjects as full analysis set (FAS). Two subjects randomised to the 240 mg group (N=59) were withdrawn before receiving trial product because of inclusion/exclusion criteria violations, however they were not exposed to the active trial product leading to a total number of 57 subjects in 240 mg group.
Units: Number
arithmetic mean (standard deviation)	18.4 ( 8.4 )	18.7 ( 10.7 )	18.4 ( 9.2 )	20.7 ( 9.1 )	-
Pain (visual analogue scale [VAS])
Baseline data for pain on VAS was collected and reported for exposed subjects as full analysis set (FAS). Two subjects randomised to the 240 mg group (N=59) were withdrawn before receiving trial product because of inclusion/exclusion criteria violations, however they were not exposed to the active trial product leading to a total number of 57 subjects in 240 mg group.
Units: Centimeter
arithmetic mean (standard deviation)	7 ( 1.9 )	6.7 ( 1.9 )	7.3 ( 2 )	6.5 ( 1.9 )	-
Patient’s Global Assessment of disease activity (PtGA) (VAS)
Baseline data for PtGA was collected and reported for exposed subjects as full analysis set (FAS). Two subjects randomised to the 240 mg group (N=59) were withdrawn before receiving trial product because of inclusion/exclusion criteria violations, however they were not exposed to the active trial product leading to a total number of 57 subjects in 240 mg group.
Units: Centimeter
arithmetic mean (standard deviation)	7 ( 2.2 )	6.9 ( 1.7 )	7.5 ( 1.8 )	6.9 ( 1.7 )	-
Physician’s Global Assessment of disease activity (PhGA) (VAS)
Baseline data for PhGA was collected and reported for exposed subjects as full analysis set (FAS). Two subjects randomised to the 240 mg group (N=59) were withdrawn before receiving trial product because of inclusion/exclusion criteria violations, however they were not exposed to the active trial product leading to a total number of 57 subjects in 240 mg group.
Units: Centimeter
arithmetic mean (standard deviation)	6.7 ( 1.7 )	6.8 ( 1.7 )	7.3 ( 1.5 )	7.1 ( 1.7 )	-
Health Assessment Questionnaire- Disability Index (HAQ-DI)
Baseline data for HAQ-DI was collected and reported for exposed subjects as full analysis set (FAS). Two subjects randomised to the 240 mg group (N=59) were withdrawn before receiving trial product because of inclusion/exclusion criteria violations, however they were not exposed to the active trial product leading to a total number of 57 subjects in 240 mg group.
Units: Points
arithmetic mean (standard deviation)	1.9 ( 0.6 )	1.9 ( 0.6 )	2 ( 0.6 )	2 ( 0.5 )	-

End points

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Reporting group title

Main-Placebo

Reporting group description

All subjects in this arm received NNC0109-0012 placebo once weekly for a period of 24-weeks (double-blinded main treatment period).

Reporting group title

Main-60 mg

Reporting group description

All subjects in this arm received 60 mg of NNC0109-0012, once weekly for a period of 24-weeks (double-blinded main treatment period).

Reporting group title

Main-120 mg

Reporting group description

All subjects in this arm received 120 mg of NNC0109-0012, once weekly for a period of 24-weeks (double-blinded main treatment period).

Reporting group title

Main-240 mg

Reporting group description

All subjects in this arm received 240 mg of NNC0109-0012, once weekly for a period of 24-weeks (double-blinded main treatment period).

Reporting group title

Extension-Placebo-240 mg

Reporting group description

Reporting group title

Extension-60-60 mg

Reporting group description

The subjects in this arm who demonstrated 20% or more improvement in tender and swollen joint counts in the main treatment period (at week 24) were eligible to enter the 28 week open-label extension treatment period. Subjects randomised to NNC0109-0012, 60 mg in the main treatment period were to maintain their same dosage regimen during the 28-week extension treatment period.

Reporting group title

Extension-120-120 mg

Reporting group description

The subjects in this arm who demonstrated 20% or more improvement in tender and swollen joint counts in the main treatment period (at week 24) were eligible to enter the 28 week open-label extension treatment period. Subjects randomised to NNC0109-0012, 120 mg in the main treatment period were to maintain their same dosage regimen during the 28-week extension treatment period.

Reporting group title

Extension-240-240 mg

Reporting group description

The subjects in this arm who demonstrated 20% or more improvement in tender and swollen joint counts in the main treatment period (at week 24) were eligible to enter the 28 week open-label extension treatment period. Subjects randomised to NNC0109-0012, 240 mg in the main treatment period were to maintain their same dosage regimen during the 28-week extension treatment period.

Primary: ACR20 (defined as 20% improvement in American College of Rheumatology criteria measures) (i.e., responder or non-responder)

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End point title

ACR20 (defined as 20% improvement in American College of Rheumatology criteria measures) (i.e., responder or non-responder)

End point description

American College of Rheumatology (ACR) 20 response was assessed at week 12, if there was an improvement equal to or greater than 20% from baseline for the below parameters. 1) Improvement in the SJC (66 out of 68 joints; excludes hips) 2) Improvement in the TJC (68 joints; includes hips) 3) Improvement in at least 3 of the following 5 assessments – Patient’s assessment of pain by visual analogue scale (VAS) – Patient’s Global Assessment of disease activity (PtGA) (VAS) – Physician’s Global Assessment of disease activity (PhGA) (VAS) – Patient’s assessment of physical function as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI, patient reported outcomes(PRO)) – C-reactive protein (CRP) Analysis population: The full analysis set (FAS) included all subjects randomised and exposed to at least one dose of trial product. Missing data were imputed using last observation carried forward (LOCF).

End point type

Primary

End point timeframe

At Week 12.

End point values	Main-Placebo	Main-60 mg	Main-120 mg	Main-240 mg
Number of subjects analysed	61	61	58	57
Units: Percentage of subjects
number (not applicable)
Responder	44.3	47.5	50	50.9
Non-responder	55.7	52.5	50	49.1

Main-240 mg versus main-placebo

Statistical analysis description

The binary endpoint was analysed using a logistic regression model. This model included prior use of anti-TNF biologic therapy and seropositivity strata at screening and treatment as fixed factors, and duration of RA and disease activity score in 28 joints based on C-reactive protein (DAS28-CRP) at baseline as covariates.

Comparison groups

Main-Placebo v Main-240 mg

Number of subjects included in analysis

118

Analysis specification

Pre-specified

Analysis type

other ^[1]

P-value

= 0.4473 ^[2]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.33

Confidence interval

level

95%

sides

2-sided

lower limit

0.64

upper limit

2.76

Notes
[1] - The statistical analyses sought to determine which doses of NNC0109-0012 were effective, and to describe the dose-response relationship for NNC0109-0012. The dose levels of NNC0109-0012 were compared to placebo in a hierarchical manner, starting by comparing the highest dose level of NNC0109-0012 to placebo.
[2] - P values below 0.05 indicate statistical significance for a two-sided test following the testing sequence.

Main-120 mg versus main-placebo

Statistical analysis description

Comparison groups

Main-Placebo v Main-120 mg

Number of subjects included in analysis

119

Analysis specification

Pre-specified

Analysis type

other ^[3]

P-value

= 0.4901 ^[4]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.29

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

2.7

Notes
[3] - The statistical analyses sought to determine which doses of NNC0109-0012 were effective, and to describe the dose-response relationship for NNC0109-0012. The dose levels of NNC0109-0012 were compared to placebo in a hierarchical manner, starting by comparing the highest dose level of NNC0109-0012 to placebo.
[4] - P values below 0.05 indicate statistical significance for a two-sided test following the testing sequence.

Main-60 mg versus main-placebo

Statistical analysis description

Comparison groups

Main-Placebo v Main-60 mg

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

other ^[5]

P-value

= 0.7018 ^[6]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.15

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

2.36

Notes
[5] - The statistical analyses sought to determine which doses of NNC0109-0012 were effective, and to describe the dose-response relationship for NNC0109-0012. The dose levels of NNC0109-0012 were compared to placebo in a hierarchical manner, starting by comparing the highest dose level of NNC0109-0012 to placebo.
[6] - P values below 0.05 indicate statistical significance for a two-sided test following the testing sequence.

Secondary: ACR20

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End point title

ACR20

End point description

ACR 20 response achieved at week 24, if there was an improvement equal to or greater than 20% from baseline for the below parameters. 1) Improvement in the SJC (66 out of 68 joints; excludes hips) 2) Improvement in the TJC (68 joints; includes hips) 3) Improvement in at least 3 of the following 5 assessments – Patient’s assessment of pain by visual analogue scale (VAS) – Patient’s Global Assessment of disease activity (PtGA) (VAS) – Physician’s Global Assessment of disease activity (PhGA) (VAS) – Patient’s assessment of physical function as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI, patient reported outcomes (PRO)) – C-reactive protein (CRP) Analysis population: The FAS included all subjects randomised and exposed to at least one dose of trial product. Missing data were imputed using LOCF.

End point type

Secondary

End point timeframe

At week 24

End point values	Main-Placebo	Main-60 mg	Main-120 mg	Main-240 mg
Number of subjects analysed	61	61	58	57
Units: Percentage of subjects
number (not applicable)
Responder	31.1	36.1	36.2	38.6
Non-responder	68.9	63.9	63.8	61.4

No statistical analyses for this end point

Secondary: ACR50

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End point title

ACR50

End point description

ACR 50 response achieved at week 12, if there was an improvement equal to or greater than 50% from baseline for the below parameters. 1) Improvement in the SJC (66 out of 68 joints; excludes hips) 2) Improvement in the TJC (68 joints; includes hips) 3) Improvement in at least 3 of the following 5 assessments – Patient’s assessment of pain by visual analogue scale (VAS) – Patient’s Global Assessment of disease activity (PtGA) (VAS) – Physician’s Global Assessment of disease activity (PhGA) (VAS) – Patient’s assessment of physical function as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI, patient reported outcomes(PRO)) – C-reactive protein (CRP) Analysis population: The FAS included all subjects randomised and exposed to at least one dose of trial product. Missing data were imputed using LOCF.

End point type

Secondary

End point timeframe

At week 12

End point values	Main-Placebo	Main-60 mg	Main-120 mg	Main-240 mg
Number of subjects analysed	61	61	58	57
Units: Percentage of subjects
number (not applicable)
Responder	19.7	26.2	19	33.3
Non-responder	80.3	73.8	81	66.7

No statistical analyses for this end point

Secondary: ACR20

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End point title

ACR20

End point description

ACR 20 response achieved at week 52, if there was an improvement equal to or greater than 20% from baseline for the below parameters. 1) Improvement in the SJC (66 out of 68 joints; excludes hips) 2) Improvement in the TJC (68 joints; includes hips) 3) Improvement in at least 3 of the following 5 assessments – Patient’s assessment of pain by visual analogue scale (VAS) – Patient’s Global Assessment of disease activity (PtGA) (VAS) – Physician’s Global Assessment of disease activity (PhGA) (VAS) – Patient’s assessment of physical function as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI, patient reported outcomes(PRO)) – C-reactive protein (CRP) Analysis population: The extension trial set (ETS) included all patients who entered the open-label extension from week 25 to 52. The ETS was not defined in the protocol, but was defined before the DBL on 21-Jan-2015. Missing data were imputed using LOCF.

End point type

Secondary

End point timeframe

At week 52

End point values	Extension-Placebo-240 mg	Extension-60-60 mg	Extension-120-120 mg	Extension-240-240 mg
Number of subjects analysed	28	27	28	29
Units: Percentage of subjects
number (not applicable)
Responder	17.9	18.5	25	24.1
Non-responder	82.1	81.5	75	75.9

No statistical analyses for this end point

Secondary: ACR50

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End point title

ACR50

End point description

ACR 50 response achieved at week 24, if there was an improvement equal to or greater than 50% from baseline for the below parameters. 1) Improvement in the SJC (66 out of 68 joints; excludes hips) 2) Improvement in the TJC (68 joints; includes hips) 3) Improvement in at least 3 of the following 5 assessments – Patient’s assessment of pain by visual analogue scale (VAS) – Patient’s Global Assessment of disease activity (PtGA) (VAS) – Physician’s Global Assessment of disease activity (PhGA) (VAS) – Patient’s assessment of physical function as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI, patient reported outcomes(PRO)) – C-reactive protein (CRP) Analysis population: The FAS included all subjects randomised and exposed to at least one dose of trial product. Missing data were imputed using LOCF.

End point type

Secondary

End point timeframe

At week 24

End point values	Main-Placebo	Main-60 mg	Main-120 mg	Main-240 mg
Number of subjects analysed	61	61	58	57
Units: Percentage of subjects
number (not applicable)
Responder	14.8	19.7	19	19.3
Non-responder	85.2	80.3	81	80.7

No statistical analyses for this end point

Secondary: ACR50

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End point title

ACR50

End point description

ACR 50 response achieved at week 52, if there was an improvement equal to or greater than 50% from baseline for the below parameters. 1) Improvement in the SJC (66 out of 68 joints; excludes hips) 2) Improvement in the TJC (68 joints; includes hips) 3) Improvement in at least 3 of the following 5 assessments – Patient’s assessment of pain by visual analogue scale (VAS) – Patient’s Global Assessment of disease activity (PtGA) (VAS) – Physician’s Global Assessment of disease activity (PhGA) (VAS) – Patient’s assessment of physical function as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI, patient reported outcomes(PRO)) – C-reactive protein (CRP) Analysis population: The extension trial set (ETS) included all patients who entered the open-label extension from week 25 to 52. The ETS was not defined in the protocol, but was defined before the DBL on 21-Jan-2015. Missing data were imputed using LOCF.

End point type

Secondary

End point timeframe

At week 52

End point values	Extension-Placebo-240 mg	Extension-60-60 mg	Extension-120-120 mg	Extension-240-240 mg
Number of subjects analysed	28	27	28	29
Units: Percentage of subjects
number (not applicable)
Responder	7.1	0	17.9	13.8
Non-responder	92.9	100	82.1	86.2

No statistical analyses for this end point

Secondary: ACR70

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End point title

ACR70

End point description

ACR 70 response achieved at week 12, if there was an improvement equal to or greater than 70% from baseline for the below parameters. 1) Improvement in the SJC (66 out of 68 joints; excludes hips) 2) Improvement in the TJC (68 joints; includes hips) 3) Improvement in at least 3 of the following 5 assessments – Patient’s assessment of pain by visual analogue scale (VAS) – Patient’s Global Assessment of disease activity (PtGA) (VAS) – Physician’s Global Assessment of disease activity (PhGA) (VAS) – Patient’s assessment of physical function as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI, patient reported outcomes(PRO)) – C-reactive protein (CRP) Analysis population: The FAS included all subjects randomised and exposed to at least one dose of trial product. Missing data were imputed using LOCF.

End point type

Secondary

End point timeframe

At week 12

End point values	Main-Placebo	Main-60 mg	Main-120 mg	Main-240 mg
Number of subjects analysed	61	61	58	57
Units: Percentage of subjects
number (not applicable)
Responder	3.3	1.6	8.6	5.3
Non-responder	96.7	98.4	91.4	94.7

No statistical analyses for this end point

Secondary: ACR70

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End point title

ACR70

End point description

ACR 70 response achieved at week 24, if there was an improvement equal to or greater than 70% from baseline for the below parameters. 1) Improvement in the SJC (66 out of 68 joints; excludes hips) 2) Improvement in the TJC (68 joints; includes hips) 3) Improvement in at least 3 of the following 5 assessments – Patient’s assessment of pain by visual analogue scale (VAS) – Patient’s Global Assessment of disease activity (PtGA) (VAS) – Physician’s Global Assessment of disease activity (PhGA) (VAS) – Patient’s assessment of physical function as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI, patient reported outcomes(PRO)) – C-reactive protein (CRP) Analysis population: The FAS included all subjects randomised and exposed to at least one dose of trial product. Missing data were imputed using LOCF.

End point type

Secondary

End point timeframe

At week 24

End point values	Main-Placebo	Main-60 mg	Main-120 mg	Main-240 mg
Number of subjects analysed	61	61	58	57
Units: Percentage of subjects
number (not applicable)
Responder	6.6	9.8	8.6	5.3
Non-responder	93.4	90.2	91.4	94.7

No statistical analyses for this end point

Secondary: ACR70

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End point title

ACR70

End point description

ACR 70 response achieved at week 52, if there was an improvement equal to or greater than 70% from baseline for the below parameters. 1) Improvement in the SJC (66 out of 68 joints; excludes hips) 2) Improvement in the TJC (68 joints; includes hips) 3) Improvement in at least 3 of the following 5 assessments – Patient’s assessment of pain by visual analogue scale (VAS) – Patient’s Global Assessment of disease activity (PtGA) (VAS) – Physician’s Global Assessment of disease activity (PhGA) (VAS) – Patient’s assessment of physical function as measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI, patient reported outcomes(PRO)) – C-reactive protein (CRP) Analysis population: The extension trial set (ETS) included all patients who entered the open-label extension from week 25 to 52. The ETS was not defined in the protocol, but was defined before the DBL on 21-Jan-2015. Missing data were imputed using LOCF.

End point type

Secondary

End point timeframe

At week 52

End point values	Extension-Placebo-240 mg	Extension-60-60 mg	Extension-120-120 mg	Extension-240-240 mg
Number of subjects analysed	28	27	28	29
Units: Percentage of subjects
number (not applicable)
Responder	0	0	7.1	3.4
Non-responder	100	100	92.9	96.6

No statistical analyses for this end point

Secondary: Change in DAS28-CRP (defined as Disease Activity Score for 28 joints with C-reactive protein measure) from baseline

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End point title

Change in DAS28-CRP (defined as Disease Activity Score for 28 joints with C-reactive protein measure) from baseline

End point description

The 28 joints assessed for this measurement were the proximal interphalangeal (PIP) joints of the fingers, the interphalangeal (IP) joints of the thumbs, the 10 metacarpophalangeal (MCP) joints plus the wrists, elbows, shoulders and knees. In order to calculate the DAS28, each of the 28 joints was to be evaluated for tenderness and swelling. Analysis population: The FAS included all subjects randomised and exposed to at least one dose of trial product. Missing data were imputed using LOCF.

End point type

Secondary

End point timeframe

At weeks 12 and 24

End point values	Main-Placebo	Main-60 mg	Main-120 mg	Main-240 mg
Number of subjects analysed	61	60	57	57
Units: Score
arithmetic mean (standard deviation)
Week 12	-1.3 ( 1.3 )	-1.6 ( 1.3 )	-1.8 ( 1.3 )	-1.7 ( 1.3 )
Week 24	-1.4 ( 1.4 )	-1.7 ( 1.3 )	-1.9 ( 1.1 )	-1.7 ( 1.4 )

No statistical analyses for this end point

Secondary: Simplified Disease Activity Index (SDAI) remission (SDAI of 3.3 or below) At week 12.

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End point title

Simplified Disease Activity Index (SDAI) remission (SDAI of 3.3 or below) At week 12.

End point description

The Simplified Disease Activity Index (SDAI) is the simple sum of the TJC (using 28 joints), SJC (using 28 joints), patient global assessment (PtGA) (0-10 cm scale, recorded on a 100 mm visual analogue scale), physician global assessment (PhGA) (0-10 cm scale, recorded on a 100 mm visual analogue scale), and CRP level (mg/dL). The SDAI was assessed based on the responders (SDAI <= 3.3) and non-responders to the trial product. Analysis population: The FAS included all subjects randomised and exposed to at least one dose of trial product. Missing data were imputed using LOCF.

End point type

Secondary

End point timeframe

At week 12.

End point values	Main-Placebo	Main-60 mg	Main-120 mg	Main-240 mg
Number of subjects analysed	61	60	57	57
Units: Percentage of subjects
number (not applicable)
Responder	0	0	1.7	0
Non-responder	100	100	98.3	100

No statistical analyses for this end point

Secondary: Simplified Disease Activity Index (SDAI) remission (SDAI of 3.3 or below) At week 24.

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End point title

Simplified Disease Activity Index (SDAI) remission (SDAI of 3.3 or below) At week 24.

End point description

The Simplified Disease Activity Index (SDAI) is the simple sum of the TJC (using 28 joints), SJC (using 28 joints), patient global assessment (PtGA) (0-10 cm scale, recorded on a 100 mm visual analogue scale), physician global assessment (PhGA) (0-10 cm scale, recorded on a 100 mm visual analogue scale), and CRP level (mg/dL). The SDAI was analysed at week 24 and assessed based on the responders (SDAI <= 3.3) and non-responders to the trial product. Analysis population: The FAS included all randomised subjects and exposed to at least one dose of trial product. Missing data were imputed using LOCF.

End point type

Secondary

End point timeframe

At week 24

End point values	Main-Placebo	Main-60 mg	Main-120 mg	Main-240 mg
Number of subjects analysed	60	57	58	57
Units: Percentage of subjects
number (not applicable)
Responder	1.6	5	0	0
Non-responder	98.4	95	100	100

No statistical analyses for this end point

Secondary: European League Against Rheumatism (EULAR) criteria response. At week 12

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End point title

European League Against Rheumatism (EULAR) criteria response. At week 12

End point description

The EULAR response criteria was categorised as no response, moderate and good response. The responses were calculated using the present and observed changes in DAS28-CRP. Analysis population: The FAS included all subjects randomised and exposed to at least one dose of trial product. Missing data were imputed using LOCF.

End point type

Secondary

End point timeframe

At week 12

End point values	Main-Placebo	Main-60 mg	Main-120 mg	Main-240 mg
Number of subjects analysed	61	60	57	57
Units: Percentage of subjects
number (not applicable)
No response	47.5	46.7	36.8	43.9
Moderate response	44.3	43.3	49.1	43.9
Good response	8.2	10	14	12.3

No statistical analyses for this end point

Secondary: European League Against Rheumatism (EULAR) criteria response. At week 24.

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End point title

European League Against Rheumatism (EULAR) criteria response. At week 24.

End point description

End point type

Secondary

End point timeframe

At week 24

End point values	Main-Placebo	Main-60 mg	Main-120 mg	Main-240 mg
Number of subjects analysed	61	60	57	57
Units: Percentage of subjects
number (not applicable)
No response	59	61.7	50.9	52.6
Moderate response	32.8	25	40.4	36.8
Good response	8.2	13.3	8.8	10.5

No statistical analyses for this end point

Secondary: Change from baseline in the overall scores of the following PRO measures: Health Assessment Questionnaire – Disability Index (HAQ-DI)

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End point title

Change from baseline in the overall scores of the following PRO measures: Health Assessment Questionnaire – Disability Index (HAQ-DI)

End point description

The HAQ-DI assessed the functional status for performing activities of daily living and included questions of fine movements of the upper extremity, locomotor activities of the lower extremity, and activities that involved both upper and lower extremities. There were 20 questions in 8 categories of functioning which represent dressing, rising, eating walking, hygiene, reach, grip, and usual activities. For each of these categories, the patient reported the amount of difficulty in performing two or three specific activities. The HAQ-DI score ranges from of 0-3 (3=worst functioning) and was calculated according to the HAQ manual based on the 8-category scores and the use of aids/devices and/or help from another person when indicated. Analysis population: The FAS included all subjects randomised and exposed to at least one dose of trial product. Missing data were imputed using LOCF.

End point type

Secondary

End point timeframe

At weeks 12 and 24.

End point values	Main-Placebo	Main-60 mg	Main-120 mg	Main-240 mg
Number of subjects analysed	61	60	57	57
Units: Score
arithmetic mean (standard deviation)
Week 12	-0.26 ( 0.62 )	-0.45 ( 0.56 )	-0.43 ( 0.53 )	-0.42 ( 0.47 )
Week 24	-0.41 ( 0.61 )	-0.43 ( 0.62 )	-0.41 ( 0.57 )	-0.46 ( 0.52 )

No statistical analyses for this end point

Secondary: Change from baseline in the overall scores of Short Form Health Survey (SF-36v2 6D) - Mental Component

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End point title

Change from baseline in the overall scores of Short Form Health Survey (SF-36v2 6D) - Mental Component

End point description

The SF-36v2 Health Survey is a survey which assesses the functional status and well-being of the patient utilising 36 questions covering selected concepts. The concepts covered physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health over the prior 4 weeks. Scores for each concept and overall scores for the physical and the mental components were calculated according to the SF-36 manual. The scores are transformed to a 100-point scale with higher scores indicating a better health state. Analysis population: The FAS included all subjects randomised and exposed to at least one dose of trial product. Missing data were imputed using LOCF.

End point type

Secondary

End point timeframe

At weeks 12 and 24

End point values	Main-Placebo	Main-60 mg	Main-120 mg	Main-240 mg
Number of subjects analysed	60	59	56	57
Units: Score
arithmetic mean (standard deviation)
Week 12	5.5 ( 8.9 )	3.8 ( 10.9 )	5.9 ( 13.2 )	4.2 ( 7.4 )
Week 24	5.1 ( 8.2 )	1.3 ( 12.5 )	6.2 ( 11.8 )	4.3 ( 9 )

No statistical analyses for this end point

Secondary: Change from baseline in the overall scores of Short Form Health Survey (SF-36v2 6D) - Physical Component

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End point title

Change from baseline in the overall scores of Short Form Health Survey (SF-36v2 6D) - Physical Component

End point description

End point type

Secondary

End point timeframe

At weeks 12 and 24.

End point values	Main-Placebo	Main-60 mg	Main-120 mg	Main-240 mg
Number of subjects analysed	60	59	56	57
Units: Score
arithmetic mean (standard deviation)
Week 12	4.1 ( 8.6 )	5.4 ( 7.7 )	4.3 ( 7.9 )	5.3 ( 6.8 )
Week 24	4.8 ( 7.7 )	7.1 ( 9.4 )	4.4 ( 9.1 )	5.7 ( 7.4 )

No statistical analyses for this end point

Secondary: Safety endpoint: Incidence and type of adverse events (AEs) - Up to week 24

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End point title

Safety endpoint: Incidence and type of adverse events (AEs) - Up to week 24

End point description

An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a product, whether or not considered related to the product. A treatment emergent adverse events (TEAEs) was defined as an event that has onset date on or after the first day of dose administration, and no later than the end of the entire trial. All AEs presented in this report are TEAEs. Analysis population: The safety analysis set (SAS) included all patients randomised and exposed to at least one dose of trial product. The AE data was presented for main treatment period (week 0-24) plus the follow-up period (12 weeks) for subjects who withdrew during the main treatment period.

End point type

Secondary

End point timeframe

Up to week 24.

End point values	Main-Placebo	Main-60 mg	Main-120 mg	Main-240 mg
Number of subjects analysed	61	61	58	57
Units: Number of events
All Adverse events	129	116	131	126
Serious adverse events	5	6	2	2
Non-serious adverse events	124	110	129	124

No statistical analyses for this end point

Secondary: Safety endpoint: Incidence and type of adverse events (AEs) - Up to week 52

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End point title

Safety endpoint: Incidence and type of adverse events (AEs) - Up to week 52

End point description

Analysis population: The extension trial set (ETS) consisted of subjects who entered the open-label extension treatment period (week 25-52). For the ETS, the data analyses included measurements starting at week 0 through week 52 plus the 12-week follow-up, and could therefore overlap with AE data reported for the SAS (i.e., for the main treatment period [week 0-24]).

End point type

Secondary

End point timeframe

Up to week 52

End point values	Extension-Placebo-240 mg	Extension-60-60 mg	Extension-120-120 mg	Extension-240-240 mg
Number of subjects analysed	28	27	28	29
Units: Number of events
All adverse events	133	112	159	155
Serious adverse events	4	6	4	3
Non-serious adverse events	129	106	155	152

No statistical analyses for this end point

Secondary: Radiographic assessments - Change from baseline in van der Heijde Sharp score.

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End point title

Radiographic assessments - Change from baseline in van der Heijde Sharp score.

End point description

Radiographic assessment was performed by obtaining posterior anterior projections of hands, wrists and feet and were scored using the van der Heijde (VDH) modified Sharp criteria. Change from baseline in VDH for total erosion score, Joint Space Narrowing (JSN) and modified Total Sharp Score (mTSS) were assessed at week 24. The VDH modified Sharp scoring system assesses the changes in structural damage, assigning scores for erosions of 0–5.0 from 16 areas in the hands and wrists, and from the feet, each side of the 10 metatarsophalangeals (MTPs) and two intraphalangeal joints of the big toe. For JSN, scores of 0–5 were assigned to 15 areas from the hands and wrists and 6 areas from the feet. Analysis population: The FAS included all subjects randomised and exposed to at least one dose of trial product. Missing data were imputed using LOCF. Change from baseline in VDH Sharp score was planned to be analysed only at the pre-planned week 24; hence, no data for week 12 are available.

End point type

Secondary

End point timeframe

At weeks 12 and 24

End point values	Main-Placebo	Main-60 mg	Main-120 mg	Main-240 mg
Number of subjects analysed	45	37	36	42
Units: Score
arithmetic mean (standard deviation)
Total Erosion Score	1.1 ( 2.4 )	0.8 ( 1.5 )	1 ( 4.1 )	0.5 ( 1.3 )
Joint space narrowing (JSN)	0.5 ( 1.1 )	0.3 ( 1.1 )	0.5 ( 2 )	0.5 ( 2.1 )
modified Total Sharp Score (mTSS)	1.6 ( 3.2 )	1.1 ( 2.3 )	1.5 ( 5.9 )	1 ( 3 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

For main trial period: treatment period (week 0-24) + follow-up period (12-week) for subjects who withdrew during the main treatment period. Extension trial period: treatment period (week 25-52) + follow-up period (12-week).

Adverse event reporting additional description

AEs were collected and reported for both safety analysis set (SAS) and extension trial set (ETS). The ETS data analyses included measurements starting at week 0 through week 52 plus the 12-week follow-up, and could therefore overlap with the SAS data analyses reported for main treatment period from week 0-24.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

Main-placebo

Reporting group description

All subjects in this arm recieved NNC0109-0012 placebo once weekly for a period of 24-weeks (double-blinded main treatment period).

Reporting group title

Main-60 mg

Reporting group description

All subjects in this arm recieved 60 mg of NNC0109-0012, once weekly for a period of 24-weeks (double-blinded main treatment period).

Reporting group title

Main-120 mg

Reporting group description

All subjects in this arm recieved 120 mg of NNC0109-0012, once weekly for a period of 24-weeks (double-blinded main treatment period).

Reporting group title

Main-240 mg

Reporting group description

All subjects in this arm recieved 240 mg of NNC0109-0012, once weekly for a period of 24-weeks (double-blinded main treatment period).

Reporting group title

Main-total NNC0109-0012

Reporting group description

This reporting group comprises of all 3 reporting groups: Main-60 mg, Main-120 mg and Main-240 mg for a trial period of 0 to 24-weeks.

Reporting group title

Ext-placebo-240 mg

Reporting group description

Reporting group title

Ext-60-60 mg

Reporting group description

The subjects in this arm who demonstrated 20% or more improvement in tender and swollen joint counts in the main treatment period (at week 24) were eligible to enter the 28 week open-label extension treatment period. Subjects randomised to NNC0109-0012, 60 mg in the main treatment period were to maintain their same dosage regimen during the 28-week extension treatment period.

Reporting group title

Ext-120-120 mg

Reporting group description

The subjects in this arm who demonstrated 20% or more improvement in tender and swollen joint counts in the main treatment period (at week 24) were eligible to enter the 28 week open-label extension treatment period. Subjects randomised to NNC0109-0012, 120 mg in the main treatment period were to maintain their same dosage regimen during the 28-week extension treatment period.

Reporting group title

Ext-240-240 mg

Reporting group description

The subjects in this arm who demonstrated 20% or more improvement in tender and swollen joint counts in the main treatment period (at week 24) were eligible to enter the 28 week open-label extension treatment period. Subjects randomised to NNC0109-0012, 240 mg in the main treatment period were to maintain their same dosage regimen during the 28-week extension treatment period.

Serious adverse events	Main-placebo	Main-60 mg	Main-120 mg	Main-240 mg	Main-total NNC0109-0012	Ext-placebo-240 mg	Ext-60-60 mg	Ext-120-120 mg	Ext-240-240 mg
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 61 (6.56%)	5 / 61 (8.20%)	2 / 58 (3.45%)	1 / 57 (1.75%)	8 / 176 (4.55%)	4 / 28 (14.29%)	5 / 27 (18.52%)	3 / 28 (10.71%)	3 / 29 (10.34%)
number of deaths (all causes)	1	0	1	0	1	2	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	1	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder transitional cell carcinoma
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	0 / 28 (0.00%)	1 / 27 (3.70%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Cholangiocarcinoma
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 176 (0.57%)	0 / 28 (0.00%)	0 / 27 (0.00%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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	0 / 0
Papillary thyroid cancer
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	0 / 28 (0.00%)	0 / 27 (0.00%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0
Investigations
Weight decreased
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	1 / 28 (3.57%)	0 / 27 (0.00%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Patella fracture
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	0 / 28 (0.00%)	0 / 27 (0.00%)	1 / 28 (3.57%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	1 / 28 (3.57%)	0 / 27 (0.00%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	1 / 1	0 / 0	0 / 0	0 / 0
Vascular disorders
Peripheral embolism
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	0 / 28 (0.00%)	0 / 27 (0.00%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	0 / 28 (0.00%)	0 / 27 (0.00%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	1 / 58 (1.72%)	0 / 57 (0.00%)	1 / 176 (0.57%)	0 / 28 (0.00%)	0 / 27 (0.00%)	1 / 28 (3.57%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal hernia
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	0 / 28 (0.00%)	0 / 27 (0.00%)	0 / 28 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer haemorrhage
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	0 / 28 (0.00%)	0 / 27 (0.00%)	1 / 28 (3.57%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	0 / 28 (0.00%)	1 / 27 (3.70%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	1 / 28 (3.57%)	0 / 27 (0.00%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 1	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 176 (0.57%)	0 / 28 (0.00%)	0 / 27 (0.00%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 176 (0.57%)	0 / 28 (0.00%)	0 / 27 (0.00%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	0 / 28 (0.00%)	0 / 27 (0.00%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0
Lung infiltration
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	0 / 28 (0.00%)	1 / 27 (3.70%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Psychiatric disorders
Completed suicide
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	1 / 58 (1.72%)	0 / 57 (0.00%)	1 / 176 (0.57%)	0 / 28 (0.00%)	0 / 27 (0.00%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 176 (0.57%)	0 / 28 (0.00%)	1 / 27 (3.70%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	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	0 / 0
Foot deformity
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	0 / 28 (0.00%)	1 / 27 (3.70%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Muscle spasms
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 176 (0.57%)	0 / 28 (0.00%)	1 / 27 (3.70%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	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	0 / 0
Rotator cuff syndrome
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	0 / 28 (0.00%)	0 / 27 (0.00%)	0 / 28 (0.00%)	1 / 29 (3.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Disseminated tuberculosis
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 176 (0.57%)	0 / 28 (0.00%)	0 / 27 (0.00%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Extradural abscess
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)	1 / 176 (0.57%)	0 / 28 (0.00%)	0 / 27 (0.00%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	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	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)	1 / 176 (0.57%)	0 / 28 (0.00%)	0 / 27 (0.00%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	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	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	0 / 28 (0.00%)	0 / 27 (0.00%)	1 / 28 (3.57%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	1 / 28 (3.57%)	0 / 27 (0.00%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Main-placebo	Main-60 mg	Main-120 mg	Main-240 mg	Main-total NNC0109-0012	Ext-placebo-240 mg	Ext-60-60 mg	Ext-120-120 mg	Ext-240-240 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	27 / 61 (44.26%)	24 / 61 (39.34%)	24 / 58 (41.38%)	27 / 57 (47.37%)	75 / 176 (42.61%)	18 / 28 (64.29%)	17 / 27 (62.96%)	24 / 28 (85.71%)	21 / 29 (72.41%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	2 / 61 (3.28%)	1 / 61 (1.64%)	1 / 58 (1.72%)	1 / 57 (1.75%)	3 / 176 (1.70%)	1 / 28 (3.57%)	0 / 27 (0.00%)	2 / 28 (7.14%)	1 / 29 (3.45%)
occurrences all number	2	1	1	1	3	1	0	2	1
Body temperature increased
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 176 (0.57%)	0 / 28 (0.00%)	2 / 27 (7.41%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences all number	0	1	0	0	1	0	2	0	0
Vascular disorders
Hypertension
subjects affected / exposed	2 / 61 (3.28%)	2 / 61 (3.28%)	2 / 58 (3.45%)	1 / 57 (1.75%)	5 / 176 (2.84%)	1 / 28 (3.57%)	3 / 27 (11.11%)	2 / 28 (7.14%)	2 / 29 (6.90%)
occurrences all number	2	2	2	1	5	1	3	2	2
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	1 / 58 (1.72%)	0 / 57 (0.00%)	1 / 176 (0.57%)	0 / 28 (0.00%)	0 / 27 (0.00%)	2 / 28 (7.14%)	0 / 29 (0.00%)
occurrences all number	0	0	1	0	1	0	0	2	0
Nervous system disorders
Headache
subjects affected / exposed	4 / 61 (6.56%)	2 / 61 (3.28%)	2 / 58 (3.45%)	1 / 57 (1.75%)	5 / 176 (2.84%)	3 / 28 (10.71%)	1 / 27 (3.70%)	2 / 28 (7.14%)	3 / 29 (10.34%)
occurrences all number	4	2	2	2	6	6	1	2	4
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 61 (0.00%)	2 / 61 (3.28%)	3 / 58 (5.17%)	0 / 57 (0.00%)	5 / 176 (2.84%)	0 / 28 (0.00%)	2 / 27 (7.41%)	1 / 28 (3.57%)	0 / 29 (0.00%)
occurrences all number	0	2	3	0	5	0	2	1	0
Injection site erythema
subjects affected / exposed	1 / 61 (1.64%)	1 / 61 (1.64%)	3 / 58 (5.17%)	4 / 57 (7.02%)	8 / 176 (4.55%)	3 / 28 (10.71%)	0 / 27 (0.00%)	3 / 28 (10.71%)	4 / 29 (13.79%)
occurrences all number	1	1	6	19	26	3	0	6	39
Injection site reaction
subjects affected / exposed	2 / 61 (3.28%)	9 / 61 (14.75%)	4 / 58 (6.90%)	3 / 57 (5.26%)	16 / 176 (9.09%)	2 / 28 (7.14%)	7 / 27 (25.93%)	3 / 28 (10.71%)	3 / 29 (10.34%)
occurrences all number	8	16	6	17	39	5	19	4	18
Pyrexia
subjects affected / exposed	0 / 61 (0.00%)	2 / 61 (3.28%)	2 / 58 (3.45%)	2 / 57 (3.51%)	6 / 176 (3.41%)	0 / 28 (0.00%)	3 / 27 (11.11%)	1 / 28 (3.57%)	1 / 29 (3.45%)
occurrences all number	0	2	2	2	6	0	3	1	1
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 176 (0.57%)	1 / 28 (3.57%)	1 / 27 (3.70%)	0 / 28 (0.00%)	2 / 29 (6.90%)
occurrences all number	0	1	0	0	1	1	1	0	2
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	1 / 58 (1.72%)	1 / 57 (1.75%)	2 / 176 (1.14%)	1 / 28 (3.57%)	0 / 27 (0.00%)	2 / 28 (7.14%)	1 / 29 (3.45%)
occurrences all number	1	0	1	1	2	1	0	2	1
Diarrhoea
subjects affected / exposed	3 / 61 (4.92%)	0 / 61 (0.00%)	1 / 58 (1.72%)	3 / 57 (5.26%)	4 / 176 (2.27%)	2 / 28 (7.14%)	1 / 27 (3.70%)	1 / 28 (3.57%)	4 / 29 (13.79%)
occurrences all number	3	0	1	3	4	3	1	1	4
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	2 / 58 (3.45%)	0 / 57 (0.00%)	3 / 176 (1.70%)	0 / 28 (0.00%)	1 / 27 (3.70%)	2 / 28 (7.14%)	0 / 29 (0.00%)
occurrences all number	0	2	3	0	5	0	2	3	0
Nausea
subjects affected / exposed	2 / 61 (3.28%)	3 / 61 (4.92%)	4 / 58 (6.90%)	0 / 57 (0.00%)	7 / 176 (3.98%)	2 / 28 (7.14%)	2 / 27 (7.41%)	4 / 28 (14.29%)	0 / 29 (0.00%)
occurrences all number	2	3	5	0	8	2	2	5	0
Vomiting
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	3 / 58 (5.17%)	1 / 57 (1.75%)	4 / 176 (2.27%)	2 / 28 (7.14%)	0 / 27 (0.00%)	3 / 28 (10.71%)	0 / 29 (0.00%)
occurrences all number	1	0	3	3	6	2	0	3	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 61 (1.64%)	2 / 61 (3.28%)	2 / 58 (3.45%)	1 / 57 (1.75%)	5 / 176 (2.84%)	0 / 28 (0.00%)	2 / 27 (7.41%)	1 / 28 (3.57%)	0 / 29 (0.00%)
occurrences all number	1	2	2	1	5	0	2	2	0
Oropharyngeal pain
subjects affected / exposed	0 / 61 (0.00%)	2 / 61 (3.28%)	0 / 58 (0.00%)	0 / 57 (0.00%)	2 / 176 (1.14%)	0 / 28 (0.00%)	2 / 27 (7.41%)	1 / 28 (3.57%)	0 / 29 (0.00%)
occurrences all number	0	2	0	0	2	0	2	1	0
Productive cough
subjects affected / exposed	0 / 61 (0.00%)	1 / 61 (1.64%)	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 176 (0.57%)	0 / 28 (0.00%)	2 / 27 (7.41%)	0 / 28 (0.00%)	1 / 29 (3.45%)
occurrences all number	0	1	0	0	1	0	2	0	1
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	1 / 58 (1.72%)	0 / 57 (0.00%)	1 / 176 (0.57%)	1 / 28 (3.57%)	0 / 27 (0.00%)	2 / 28 (7.14%)	0 / 29 (0.00%)
occurrences all number	1	0	1	0	1	1	0	2	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	0 / 58 (0.00%)	2 / 57 (3.51%)	2 / 176 (1.14%)	1 / 28 (3.57%)	2 / 27 (7.41%)	2 / 28 (7.14%)	3 / 29 (10.34%)
occurrences all number	1	0	0	2	2	1	2	2	3
Back pain
subjects affected / exposed	2 / 61 (3.28%)	0 / 61 (0.00%)	2 / 58 (3.45%)	0 / 57 (0.00%)	2 / 176 (1.14%)	2 / 28 (7.14%)	0 / 27 (0.00%)	3 / 28 (10.71%)	0 / 29 (0.00%)
occurrences all number	2	0	3	0	3	2	0	4	0
Muscle spasms
subjects affected / exposed	2 / 61 (3.28%)	1 / 61 (1.64%)	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 176 (0.57%)	2 / 28 (7.14%)	2 / 27 (7.41%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences all number	2	1	0	0	1	2	2	0	0
Osteoarthritis
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	2 / 58 (3.45%)	0 / 57 (0.00%)	2 / 176 (1.14%)	0 / 28 (0.00%)	0 / 27 (0.00%)	2 / 28 (7.14%)	0 / 29 (0.00%)
occurrences all number	0	0	2	0	2	0	0	2	0
Pain in extremity
subjects affected / exposed	1 / 61 (1.64%)	1 / 61 (1.64%)	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 176 (0.57%)	1 / 28 (3.57%)	2 / 27 (7.41%)	0 / 28 (0.00%)	0 / 29 (0.00%)
occurrences all number	1	1	0	0	1	1	2	0	0
Rheumatoid arthritis
subjects affected / exposed	2 / 61 (3.28%)	2 / 61 (3.28%)	2 / 58 (3.45%)	1 / 57 (1.75%)	5 / 176 (2.84%)	3 / 28 (10.71%)	2 / 27 (7.41%)	2 / 28 (7.14%)	1 / 29 (3.45%)
occurrences all number	2	5	2	1	8	3	8	3	1
Infections and infestations
Bronchitis
subjects affected / exposed	5 / 61 (8.20%)	2 / 61 (3.28%)	0 / 58 (0.00%)	1 / 57 (1.75%)	3 / 176 (1.70%)	2 / 28 (7.14%)	1 / 27 (3.70%)	2 / 28 (7.14%)	1 / 29 (3.45%)
occurrences all number	5	2	0	1	3	2	1	3	1
Furuncle
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	0 / 28 (0.00%)	0 / 27 (0.00%)	0 / 28 (0.00%)	2 / 29 (6.90%)
occurrences all number	0	0	0	0	0	0	0	0	2
Gastroenteritis
subjects affected / exposed	1 / 61 (1.64%)	0 / 61 (0.00%)	1 / 58 (1.72%)	1 / 57 (1.75%)	2 / 176 (1.14%)	1 / 28 (3.57%)	0 / 27 (0.00%)	5 / 28 (17.86%)	1 / 29 (3.45%)
occurrences all number	2	0	1	1	2	2	0	5	1
Gastroenteritis viral
subjects affected / exposed	1 / 61 (1.64%)	2 / 61 (3.28%)	1 / 58 (1.72%)	0 / 57 (0.00%)	3 / 176 (1.70%)	2 / 28 (7.14%)	2 / 27 (7.41%)	2 / 28 (7.14%)	0 / 29 (0.00%)
occurrences all number	1	2	1	0	3	3	2	2	0
Influenza
subjects affected / exposed	3 / 61 (4.92%)	1 / 61 (1.64%)	3 / 58 (5.17%)	2 / 57 (3.51%)	6 / 176 (3.41%)	3 / 28 (10.71%)	0 / 27 (0.00%)	3 / 28 (10.71%)	1 / 29 (3.45%)
occurrences all number	3	1	3	2	6	3	0	3	1
Nasopharyngitis
subjects affected / exposed	1 / 61 (1.64%)	1 / 61 (1.64%)	0 / 58 (0.00%)	1 / 57 (1.75%)	2 / 176 (1.14%)	1 / 28 (3.57%)	1 / 27 (3.70%)	2 / 28 (7.14%)	0 / 29 (0.00%)
occurrences all number	1	1	0	2	3	1	1	2	0
Pharyngitis
subjects affected / exposed	2 / 61 (3.28%)	1 / 61 (1.64%)	0 / 58 (0.00%)	1 / 57 (1.75%)	2 / 176 (1.14%)	2 / 28 (7.14%)	1 / 27 (3.70%)	1 / 28 (3.57%)	1 / 29 (3.45%)
occurrences all number	2	1	0	1	2	2	1	1	1
Sinusitis
subjects affected / exposed	2 / 61 (3.28%)	2 / 61 (3.28%)	3 / 58 (5.17%)	4 / 57 (7.02%)	9 / 176 (5.11%)	1 / 28 (3.57%)	0 / 27 (0.00%)	3 / 28 (10.71%)	5 / 29 (17.24%)
occurrences all number	2	3	3	5	11	1	0	3	7
Tooth abscess
subjects affected / exposed	0 / 61 (0.00%)	0 / 61 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 176 (0.00%)	0 / 28 (0.00%)	0 / 27 (0.00%)	0 / 28 (0.00%)	2 / 29 (6.90%)
occurrences all number	0	0	0	0	0	0	0	0	2
Upper respiratory tract infection
subjects affected / exposed	3 / 61 (4.92%)	2 / 61 (3.28%)	3 / 58 (5.17%)	1 / 57 (1.75%)	6 / 176 (3.41%)	2 / 28 (7.14%)	4 / 27 (14.81%)	5 / 28 (17.86%)	2 / 29 (6.90%)
occurrences all number	3	2	3	1	6	2	4	6	2
Urinary tract infection
subjects affected / exposed	1 / 61 (1.64%)	2 / 61 (3.28%)	3 / 58 (5.17%)	6 / 57 (10.53%)	11 / 176 (6.25%)	3 / 28 (10.71%)	1 / 27 (3.70%)	5 / 28 (17.86%)	6 / 29 (20.69%)
occurrences all number	1	3	4	7	14	3	1	7	7

More information

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Were there any global substantial amendments to the protocol? Yes

06 Jul 2012

Added definition of highly effective contraception methods; added joint count assessments at V32, V38, V44, and V50; added pregnancy test at V16 and V20; and the correction of other inconsistencies.

30 Jul 2012

Added 1 and 2 hours post-dose Vital Signs to week 24; added Biochemistry, Haematology, Urinalysis and Vital Signs to week 30; reduced frequency of antinuclear antibodies (ANA) testing to Screening visit, week 24 and end-of-trial; increased intra-articular (IA) injection dose from 40 mg/week to 80 mg/week; and the correction of other inconsistencies.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
07 Aug 2014	Novo Nordisk A/S, decided to terminate phase 2b trial NN8226-3612 in rheumatoid arthritis (RA) on 7-Aug-2014 following the failure of the NN8226-3613 trial (EudraCT no: 2012-000610-11) with NNC0109-0012 in RA to achieve its primary efficacy endpoint in a partial database lock (DBL) analysis. The trial failed to demonstrate any statistically significant difference between NNC0109-0012 and placebo on the primary endpoint, ACR20, and showed no effect on disease activity after 12 weeks of treatment in the randomised subjects.	-

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

The trial was terminated prematurely on 07-Aug-2014.

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Clinical trials

Clinical Trial Results: A randomised, double blind, placebo-controlled, multiple dose, phase 2b, 24 week trial followed by an open label extension of NNC0109-0012, an anti-IL-20 biologic, in patients with active rheumatoid arthritis who are inadequate responders to anti-TNFα biologics.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: ACR20 (defined as 20% improvement in American College of Rheumatology criteria measures) (i.e., responder or non-responder)

Primary: ACR20 (defined as 20% improvement in American College of Rheumatology criteria measures) (i.e., responder or non-responder)

Secondary: ACR20

Secondary: ACR20

Secondary: ACR50

Secondary: ACR50

Secondary: ACR20

Secondary: ACR20

Secondary: ACR50

Secondary: ACR50

Secondary: ACR50

Secondary: ACR50

Secondary: ACR70

Secondary: ACR70

Secondary: ACR70

Secondary: ACR70

Secondary: ACR70

Secondary: ACR70

Secondary: Change in DAS28-CRP (defined as Disease Activity Score for 28 joints with C-reactive protein measure) from baseline

Secondary: Change in DAS28-CRP (defined as Disease Activity Score for 28 joints with C-reactive protein measure) from baseline

Secondary: Simplified Disease Activity Index (SDAI) remission (SDAI of 3.3 or below) At week 12.

Secondary: Simplified Disease Activity Index (SDAI) remission (SDAI of 3.3 or below) At week 12.

Secondary: Simplified Disease Activity Index (SDAI) remission (SDAI of 3.3 or below) At week 24.

Secondary: Simplified Disease Activity Index (SDAI) remission (SDAI of 3.3 or below) At week 24.

Secondary: European League Against Rheumatism (EULAR) criteria response. At week 12

Secondary: European League Against Rheumatism (EULAR) criteria response. At week 12

Secondary: European League Against Rheumatism (EULAR) criteria response. At week 24.

Secondary: European League Against Rheumatism (EULAR) criteria response. At week 24.

Secondary: Change from baseline in the overall scores of the following PRO measures: Health Assessment Questionnaire – Disability Index (HAQ-DI)

Secondary: Change from baseline in the overall scores of the following PRO measures: Health Assessment Questionnaire – Disability Index (HAQ-DI)

Secondary: Change from baseline in the overall scores of Short Form Health Survey (SF-36v2 6D) - Mental Component

Secondary: Change from baseline in the overall scores of Short Form Health Survey (SF-36v2 6D) - Mental Component

Secondary: Change from baseline in the overall scores of Short Form Health Survey (SF-36v2 6D) - Physical Component

Secondary: Change from baseline in the overall scores of Short Form Health Survey (SF-36v2 6D) - Physical Component

Secondary: Safety endpoint: Incidence and type of adverse events (AEs) - Up to week 24

Secondary: Safety endpoint: Incidence and type of adverse events (AEs) - Up to week 24

Secondary: Safety endpoint: Incidence and type of adverse events (AEs) - Up to week 52

Secondary: Safety endpoint: Incidence and type of adverse events (AEs) - Up to week 52

Secondary: Radiographic assessments - Change from baseline in van der Heijde Sharp score.

Secondary: Radiographic assessments - Change from baseline in van der Heijde Sharp score.

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A randomised, double blind, placebo-controlled, multiple dose, phase 2b, 24 week trial followed by an open label extension of NNC0109-0012, an anti-IL-20 biologic, in patients with active rheumatoid arthritis who are inadequate responders to anti-TNFα biologics.