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Clinical Trial Results:
A Randomized, Double-blind, Multi-dose, Placebo-controlled Phase 2/3 Study to Evaluate the Efficacy and Safety of Fasinumab in Patients With Moderate to Severe Chronic Low Back Pain

Summary
EudraCT number	2015-003782-28
Trial protocol	DK CZ PL HU
Global end of trial date	12 Sep 2017

Results information
Results version number	v3(current)
This version publication date	24 Jun 2020
First version publication date	30 Sep 2018
Other versions	v1 , v2
Version creation reason

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

R475-PN-1524

ISRCTN number

US NCT number

NCT02620020

WHO universal trial number (UTN)

Sponsor organisation name

Regeneron Pharmaceuticals, Inc.

Sponsor organisation address

777 Old Saw Mill River Rd., Tarrytown, NY, United States, 10591

Public contact

Clinical Trial Administrator, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com

Scientific contact

Clinical Trial Administrator, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.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

17 Aug 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

12 Sep 2017

Was the trial ended prematurely?

Main objective of the trial

To evaluate the efficacy of fasinumab compared to placebo in reducing low back pain (LBP) as measured by the change from baseline to Week 16 in the average daily low back pain intensity (LBPI) numeric rating scale (NRS) score.

Protection of trial subjects

This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

25 Jan 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 92

Country: Number of subjects enrolled

Czech Republic: 63

Country: Number of subjects enrolled

Denmark: 76

Country: Number of subjects enrolled

Estonia: 12

Country: Number of subjects enrolled

Hungary: 31

Country: Number of subjects enrolled

United States: 286

Country: Number of subjects enrolled

Canada: 3

Worldwide total number of subjects

563

EEA total number of subjects

274

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)

414

From 65 to 84 years

147

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 105 sites in the US, CA & EU between 26 Jan 2016 & 13 Sep 2017. Of 1,783 subjects, 563 were randomized in 1:1:1:1 ratio to 1 of 4 treatment groups stratified by baseline LBPI, NRS score (<7, ≥7), duration of chronic LBP (<5 yrs, ≥5yrs) & maximum Kellgren-Lawrence (K-L) score (≤2, >2) at any knee or hip joint at screening.

Screening details

The study consisted of a screening period of up to 30 days & a 7-day pre-randomization period during which pain medication, except study-provided rescue medication, was discontinued. Confirmation of no exclusionary findings on joint on which imaging was performed during screening must have been received before a subject could be randomized.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Placebo SC Q4W and Placebo IV Q8W

Arm description

Subjects randomized to the matching placebo subcutaneously (SC) every four weeks (Q4W) arm received SC placebo in a manner similar to the SC loading dose of the active groups (placebo loading dose) on Day 1 and then an SC injection of placebo at weeks 4, 8, and 12 for a total of 4 doses. Matching placebo intravenously (IV) every 8 weeks (Q8W) was received on Day 1 and at Week 8.

Arm type

Placebo

Investigational medicinal product name

Placebo IV (Matching to Fasinumab)

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received IV infusion of placebo (matching to fasinumab) on Day 1 and at Week 8.

Investigational medicinal product name

Placebo SC (Matching to Fasinumab)

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subject received SC injection of placebo (matching to fasinumab) on Day 1, and at Week 4, 8, 12.

Fasinumab 6 mg SC Q4W and Placebo IV Q8W

Arm description

Subjects randomized to the fasinumab 6 mg SC Q4W arm received fasinumab 12 mg SC on Day 1 (loading dose) and then 6 mg SC (planned maintenance dose) at Weeks 4, 8, and 12 for a total of 4 doses. Matching placebo was received via intravenous (IV) infusion Q8W on Day 1 and at Week 8.

Arm type

Experimental

Investigational medicinal product name

Fasinumab

Investigational medicinal product code

REGN475

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subject received SC injection of fasinumab on Day 1, and at Week 4, 8, 12.

Investigational medicinal product name

Placebo (Matching to Fasinumab)

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received IV infusion of placebo (matching to fasinumab) on Day 1 and at Week 8.

Fasinumab 9 mg SC Q4W and Placebo IV Q8W

Arm description

Subjects randomized to the fasinumab 9 mg SC Q4W arm received 18 mg SC on day 1 (loading dose) and then 9 mg SC (planned maintenance dose) at weeks 4, 8, and 12 for a total of 4 doses. Matching placebo IV Q8W was received on Day 1 and at Week 8.

Arm type

Experimental

Investigational medicinal product name

Fasinumab

Investigational medicinal product code

REGN475

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subject received SC injection of fasinumab on Day 1, and at Week 4, 8, 12.

Investigational medicinal product name

Placebo (Matching to Fasinumab)

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received IV infusion of placebo (matching to fasinumab) on Day 1 and at Week 8.

Fasinumab 9 mg IV Q8W and Placebo SC Q4W

Arm description

Subjects randomized to the fasinumab 9 mg IV Q8W arm received IV infusions of fasinumab 9 mg on Day 1 and Week 8, for a total of 2 doses. Matching placebo SC Q4W was received on day 1 and at weeks 4, 8, and 12.

Arm type

Experimental

Investigational medicinal product name

Placebo (Matching to Fasinumab)

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subject received SC injection of placebo (matching to fasinumab) on Day 1, and at Week 4, 8, 12.

Investigational medicinal product name

Fasinumab

Investigational medicinal product code

REGN475

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Subject received IV infusion of fasinumab on Day 1, and at Week 8.

Number of subjects in period 1	Placebo SC Q4W and Placebo IV Q8W	Fasinumab 6 mg SC Q4W and Placebo IV Q8W	Fasinumab 9 mg SC Q4W and Placebo IV Q8W	Fasinumab 9 mg IV Q8W and Placebo SC Q4W
Started	141	141	140	141
Modified Intent to Treat Set (mITT)	140	139	139	140
Completed	97	106	115	115
Not completed	44	35	25	26
Physician decision	7	4	3	4
Consent withdrawn by subject	20	16	17	12
Death	-	1	-	-
Adverse event	8	4	3	5
Lost to follow-up	4	8	1	4
Protocol deviation	5	2	1	1

Baseline characteristics

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Reporting group title

Placebo SC Q4W and Placebo IV Q8W

Reporting group description

Reporting group title

Fasinumab 6 mg SC Q4W and Placebo IV Q8W

Reporting group description

Reporting group title

Fasinumab 9 mg SC Q4W and Placebo IV Q8W

Reporting group description

Reporting group title

Fasinumab 9 mg IV Q8W and Placebo SC Q4W

Reporting group description

Reporting group values	Placebo SC Q4W and Placebo IV Q8W	Fasinumab 6 mg SC Q4W and Placebo IV Q8W	Fasinumab 9 mg SC Q4W and Placebo IV Q8W	Fasinumab 9 mg IV Q8W and Placebo SC Q4W	Total
Number of subjects	141	141	140	141	563
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	58.1 ± 12.54	58.2 ± 11.29	56.6 ± 10.99	55.4 ± 10.49	-
Gender categorical
Units: Subjects
Female	83	85	84	81	333
Male	58	56	56	60	230
Ethnicity
Units: Subjects
Hispanic or Latino	7	4	4	10	25
Not Hispanic or Latino	134	135	135	131	535
Not Reported	0	2	1	0	3
Race
Units: Subjects
White	127	119	118	116	480
Black or African American	13	19	19	21	72
Asian	1	2	2	1	6
American Indian or Alaska Native	0	1	0	1	2
Native Hawaiian or Other Pacific Islander	0	0	0	1	1
Other	0	0	1	1	2

End points

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Reporting group title

Placebo SC Q4W and Placebo IV Q8W

Reporting group description

Reporting group title

Fasinumab 6 mg SC Q4W and Placebo IV Q8W

Reporting group description

Reporting group title

Fasinumab 9 mg SC Q4W and Placebo IV Q8W

Reporting group description

Reporting group title

Fasinumab 9 mg IV Q8W and Placebo SC Q4W

Reporting group description

Primary: Change From Baseline in the Average Daily Low Back Pain Intensity (LBPI) Score on an 11-point Numerical Rating Scale (NRS) at Week 16

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End point title

Change From Baseline in the Average Daily Low Back Pain Intensity (LBPI) Score on an 11-point Numerical Rating Scale (NRS) at Week 16

End point description

Average daily low back pain was assessed on an 11-point numeric rating scale (NRS) and was defined as the average of the non-missing daily LBPI NRS scores for the 7 days before and including nominal visit. Subjects described their average low back pain during the past 24 hours on a scale ranging from 0 (no pain) to 10 (worst possible pain), where higher scores indicate higher pain. Analysis was performed on modified intent to treat set (mITT) that included all randomized subject per Interactive voice response system (IVRS) who received at least one dose of study drug based on the treatment allocated (as randomized) including data up to 5 weeks after the last dose of study drug. Here, number of subjects analyzed=subjects with available data for specified timepoint.

End point type

Primary

End point timeframe

Baseline to Week 16

End point values	Placebo SC Q4W and Placebo IV Q8W	Fasinumab 6 mg SC Q4W and Placebo IV Q8W	Fasinumab 9 mg SC Q4W and Placebo IV Q8W	Fasinumab 9 mg IV Q8W and Placebo SC Q4W
Number of subjects analysed	49	48	55	56
Units: Units on a scale
least squares mean (standard error)	-1.7 ± 0.23	-2.0 ± 0.23	-2.5 ± 0.22	-2.4 ± 0.22

Fasinumab 6 mg SC Q4W vs Placebo

Statistical analysis description

Analyses are based on mixed-effect model repeated measures (MMRM) model with baseline randomization strata, baseline score, treatment, visit, and treatment-by-visit interaction.

Comparison groups

Placebo SC Q4W and Placebo IV Q8W v Fasinumab 6 mg SC Q4W and Placebo IV Q8W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3876 ^[1]

Method

Mixed-effect model analysis

Parameter type

Least square (LS) mean difference

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.88

upper limit

0.34

Variability estimate

Standard error of the mean

Dispersion value

0.31

Notes
[1] - Nominal p-value

Fasinumab 9 mg SC Q4W vs Placebo

Statistical analysis description

Analyses are based on MMRM model with baseline randomization strata, baseline score, treatment, visit, and treatment-by-visit interaction.

Comparison groups

Fasinumab 9 mg SC Q4W and Placebo IV Q8W v Placebo SC Q4W and Placebo IV Q8W

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.018 ^[2]

Method

Mixed-effect model analysis

Parameter type

LS Mean Difference

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-1.32

upper limit

-0.12

Variability estimate

Standard error of the mean

Dispersion value

0.3

Notes
[2] - Nominal p-value

Fasinumab 9 mg IV Q8W and placebo

Statistical analysis description

Analyses are based on MMRM model with baseline randomization strata, baseline score, treatment, visit, and treatment-by-visit interaction.

Comparison groups

Fasinumab 9 mg IV Q8W and Placebo SC Q4W v Placebo SC Q4W and Placebo IV Q8W

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0288 ^[3]

Method

Mixed-effect model analysis

Parameter type

LS Mean Difference

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-1.26

upper limit

-0.07

Variability estimate

Standard error of the mean

Dispersion value

0.3

Notes
[3] - Nominal p-value

Secondary: Change From Baseline to Weeks 2, 4, 8, and 12 in the Average Low Back Pain Index Numeric Rating Scale Score (LBPI NRS)

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End point title

Change From Baseline to Weeks 2, 4, 8, and 12 in the Average Low Back Pain Index Numeric Rating Scale Score (LBPI NRS)

End point description

Low back pain intensity was assessed on an 11-point numeric rating scale (NRS) and was defined as the average of the non-missing daily LBPI NRS scores for the 7 days before and including nominal visit. Subjects described their average low back pain during the past 24 hours on a scale ranging from 0 (no pain) to 10 (worst possible pain), where higher scores indicate higher pain. Analysis was performed on modified intent to treat set mITT population. Here 'n' signifies number of subjects with available data for specified category.

End point type

Secondary

End point timeframe

Baseline to Week 2, 4, 8, and 12

End point values	Placebo SC Q4W and Placebo IV Q8W	Fasinumab 6 mg SC Q4W and Placebo IV Q8W	Fasinumab 9 mg SC Q4W and Placebo IV Q8W	Fasinumab 9 mg IV Q8W and Placebo SC Q4W
Number of subjects analysed	140	139	139	140
Units: Units on a scale
least squares mean (standard error)
Change to Week 2 (n = 133, 135, 138, 136)	-0.9 ± 0.17	-1.3 ± 0.17	-1.6 ± 0.17	-1.6 ± 0.16
Change to Week 4 (n = 132, 128, 132, 133)	-0.9 ± 0.17	-1.5 ± 0.17	-2.0 ± 0.17	-1.9 ± 0.16
Change to Week 8 (n = 98, 105, 103, 95)	-1.2 ± 0.19	-1.8 ± 0.19	-2.3 ± 0.19	-2.2 ± 0.19
Change to Week 12 (n = 69, 74, 76, 69)	-1.5 ± 0.21	-2.0 ± 0.21	-2.6 ± 0.21	-2.5 ± 0.21

No statistical analyses for this end point

Secondary: Change From Baseline to Week 16 in Roland Morris Disability Questionnaire (RMDQ) Total Score

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End point title

Change From Baseline to Week 16 in Roland Morris Disability Questionnaire (RMDQ) Total Score

End point description

The RMDQ is a self-administered, widely used health status measure for LBP. It measures pain and function, using 24 items describing limitations to everyday life that can be caused by LBP. The score of the RMDQ is the total number of items checked – that is from a minimum of 0 (no disability) to a maximum of 24 (maximum disability), where lower scores indicative of better function. Analysis was performed on mITT population. Here, number of subjects analyzed=subjects with available data for specified timepoint.

End point type

Secondary

End point timeframe

Baseline to Week 16

End point values	Placebo SC Q4W and Placebo IV Q8W	Fasinumab 6 mg SC Q4W and Placebo IV Q8W	Fasinumab 9 mg SC Q4W and Placebo IV Q8W	Fasinumab 9 mg IV Q8W and Placebo SC Q4W
Number of subjects analysed	46	46	55	55
Units: Units on a scale
least squares mean (standard error)	-3.8 ± 0.54	-6.0 ± 0.54	-5.8 ± 0.51	-6.3 ± 0.51

Fasinumab 6 mg SC Q4W vs Placebo

Statistical analysis description

Analyses are based on mixed-effect model repeated measures (MMRM) model with baseline randomization strata, baseline score, treatment, visit, and treatment-by-visit interaction.

Comparison groups

Fasinumab 6 mg SC Q4W and Placebo IV Q8W v Placebo SC Q4W and Placebo IV Q8W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0028 ^[4]

Method

Mixed-effect model analysis

Parameter type

LS mean difference

Point estimate

-2.2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.65

upper limit

-0.77

Variability estimate

Standard error of the mean

Dispersion value

0.73

Notes
[4] - Nominal p-value

Fasinumab 9 mg SC Q4W vs Placebo

Statistical analysis description

Analyses are based on mixed-effect model repeated measures (MMRM) model with baseline randomization strata, baseline score, treatment, visit, and treatment-by-visit interaction.

Comparison groups

Fasinumab 9 mg SC Q4W and Placebo IV Q8W v Placebo SC Q4W and Placebo IV Q8W

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0068 ^[5]

Method

Mixed-effect model analysis

Parameter type

LS Mean Difference

Point estimate

-2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.36

upper limit

-0.54

Variability estimate

Standard error of the mean

Dispersion value

0.72

Notes
[5] - Nominal p-value

Fasinumab 9 mg IV Q8W and placebo

Statistical analysis description

Analyses are based on MMRM model with baseline randomization strata, baseline score, treatment, visit, and treatment-by-visit interaction.

Comparison groups

Fasinumab 9 mg IV Q8W and Placebo SC Q4W v Placebo SC Q4W and Placebo IV Q8W

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0006 ^[6]

Method

Mixed-effect model analysis

Parameter type

LS Mean Difference

Point estimate

-2.5

Confidence interval

level

95%

sides

2-sided

lower limit

-3.88

upper limit

-1.06

Variability estimate

Standard error of the mean

Dispersion value

0.72

Notes
[6] - Nominal p-value

Secondary: Change From Baseline to Week 16 in the Patient Global Assessment (PGA) of Low Back Pain (LBP) Score

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End point title

Change From Baseline to Week 16 in the Patient Global Assessment (PGA) of Low Back Pain (LBP) Score

End point description

The PGA of LBP is a subject assessed 5 point Likert scale of LBP ranging from 0-5 where 1=very well; 2=well; 3=fair; 4=poor; and 5=very poor. Analysis was performed on mITT population. Here, number of subjects analyzed=subjects with available data for specified timepoint.

End point type

Secondary

End point timeframe

Baseline to Week 16

End point values	Placebo SC Q4W and Placebo IV Q8W	Fasinumab 6 mg SC Q4W and Placebo IV Q8W	Fasinumab 9 mg SC Q4W and Placebo IV Q8W	Fasinumab 9 mg IV Q8W and Placebo SC Q4W
Number of subjects analysed	50	48	55	57
Units: Units on a scale
least squares mean (standard error)	-0.7 ± 0.10	-0.9 ± 0.10	-0.8 ± 0.10	-1.0 ± 0.09

Fasinumab 6 mg SC Q4W vs Placebo

Statistical analysis description

Analyses are based on MMRM model with baseline randomization strata, baseline score, treatment, visit, and treatment-by-visit interaction.

Comparison groups

Fasinumab 6 mg SC Q4W and Placebo IV Q8W v Placebo SC Q4W and Placebo IV Q8W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1501 ^[7]

Method

Mixed-effect model analysis

Parameter type

LS Mean Difference

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.46

upper limit

0.07

Variability estimate

Standard error of the mean

Dispersion value

0.14

Notes
[7] - Nominal p-value

Fasinumab 9 mg SC Q4W vs Placebo

Statistical analysis description

Analyses are based on MMRM model with baseline randomization strata, baseline score, treatment, visit, and treatment-by-visit interaction.

Comparison groups

Fasinumab 9 mg SC Q4W and Placebo IV Q8W v Placebo SC Q4W and Placebo IV Q8W

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2603 ^[8]

Method

Mixed-effect model analysis

Parameter type

LS Mean Difference

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.41

upper limit

0.11

Variability estimate

Standard error of the mean

Dispersion value

0.13

Notes
[8] - Nominal p-value

Fasinumab 9 mg IV Q8W and placebo

Statistical analysis description

Analyses are based on MMRM model with baseline randomization strata, baseline score, treatment, visit, and treatment-by-visit interaction.

Comparison groups

Fasinumab 9 mg IV Q8W and Placebo SC Q4W v Placebo SC Q4W and Placebo IV Q8W

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0135 ^[9]

Method

Mixed-effect model analysis

Parameter type

LS Mean Difference

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.59

upper limit

-0.07

Variability estimate

Standard error of the mean

Dispersion value

0.13

Notes
[9] - Nominal p-value

Adverse events

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Timeframe for reporting adverse events

All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Week 36) regardless of seriousness or relationship to investigational product.

Adverse event reporting additional description

Reported AEs and deaths are treatment emergent that is AEs that developed/worsened and deaths that occurred during 'the treatment emergent period’ (from the first dose of study drug up to the 4 weeks after the last dose of SC drug, or 8 weeks after the last dose of IV study drug, whichever is later).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Placebo SC Q4W and Placebo IV Q8W

Reporting group description

Subjects randomized to the matching placebo SC Q4W arm received SC placebo in a manner similar to the SC loading dose of the active groups (placebo loading dose) on Day 1 and then an SC injection of placebo at weeks 4, 8, and 12 for a total of 4 doses. Matching placebo IV Q8W was received on Day 1 and at Week 8.

Reporting group title

Fasinumab 6 mg SC Q4W and Placebo IV Q8W

Reporting group description

Reporting group title

Fasinumab 9 mg SC Q4W and Placebo IV Q8W

Reporting group description

Reporting group title

Fasinumab 9 mg IV Q8W and Placebo SC Q4W

Reporting group description

Serious adverse events	Placebo SC Q4W and Placebo IV Q8W	Fasinumab 6 mg SC Q4W and Placebo IV Q8W	Fasinumab 9 mg SC Q4W and Placebo IV Q8W	Fasinumab 9 mg IV Q8W and Placebo SC Q4W
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 140 (2.86%)	2 / 139 (1.44%)	3 / 139 (2.16%)	5 / 140 (3.57%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events
Investigations
Blood creatine phosphokinase increased
subjects affected / exposed	1 / 140 (0.71%)	0 / 139 (0.00%)	0 / 139 (0.00%)	0 / 140 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	0 / 140 (0.00%)	0 / 139 (0.00%)	0 / 139 (0.00%)	1 / 140 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tongue carcinoma stage iv
subjects affected / exposed	1 / 140 (0.71%)	0 / 139 (0.00%)	0 / 139 (0.00%)	0 / 140 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Concussion
subjects affected / exposed	0 / 140 (0.00%)	1 / 139 (0.72%)	0 / 139 (0.00%)	0 / 140 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Craniocerebral injury
subjects affected / exposed	0 / 140 (0.00%)	1 / 139 (0.72%)	0 / 139 (0.00%)	0 / 140 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye injury
subjects affected / exposed	1 / 140 (0.71%)	0 / 139 (0.00%)	0 / 139 (0.00%)	0 / 140 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 140 (0.00%)	0 / 139 (0.00%)	0 / 139 (0.00%)	1 / 140 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Patella fracture
subjects affected / exposed	0 / 140 (0.00%)	0 / 139 (0.00%)	0 / 139 (0.00%)	1 / 140 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skull fracture
subjects affected / exposed	0 / 140 (0.00%)	1 / 139 (0.72%)	0 / 139 (0.00%)	0 / 140 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 140 (0.00%)	0 / 139 (0.00%)	0 / 139 (0.00%)	1 / 140 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 140 (0.00%)	1 / 139 (0.72%)	0 / 139 (0.00%)	0 / 140 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	1 / 140 (0.71%)	0 / 139 (0.00%)	0 / 139 (0.00%)	0 / 140 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	0 / 140 (0.00%)	0 / 139 (0.00%)	1 / 139 (0.72%)	0 / 140 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 140 (0.00%)	0 / 139 (0.00%)	0 / 139 (0.00%)	1 / 140 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteoarthritis
subjects affected / exposed	0 / 140 (0.00%)	0 / 139 (0.00%)	1 / 139 (0.72%)	0 / 140 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Diverticulitis
subjects affected / exposed	0 / 140 (0.00%)	0 / 139 (0.00%)	1 / 139 (0.72%)	0 / 140 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Placebo SC Q4W and Placebo IV Q8W	Fasinumab 6 mg SC Q4W and Placebo IV Q8W	Fasinumab 9 mg SC Q4W and Placebo IV Q8W	Fasinumab 9 mg IV Q8W and Placebo SC Q4W
Total subjects affected by non serious adverse events
subjects affected / exposed	44 / 140 (31.43%)	35 / 139 (25.18%)	52 / 139 (37.41%)	49 / 140 (35.00%)
Nervous system disorders
Headache
subjects affected / exposed	9 / 140 (6.43%)	9 / 139 (6.47%)	9 / 139 (6.47%)	9 / 140 (6.43%)
occurrences all number	11	9	19	9
Hypoaesthesia
subjects affected / exposed	4 / 140 (2.86%)	4 / 139 (2.88%)	7 / 139 (5.04%)	3 / 140 (2.14%)
occurrences all number	4	4	7	3
Paraesthesia
subjects affected / exposed	4 / 140 (2.86%)	6 / 139 (4.32%)	9 / 139 (6.47%)	9 / 140 (6.43%)
occurrences all number	5	6	10	9
Gastrointestinal disorders
Nausea
subjects affected / exposed	2 / 140 (1.43%)	4 / 139 (2.88%)	7 / 139 (5.04%)	1 / 140 (0.71%)
occurrences all number	4	4	7	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	17 / 140 (12.14%)	15 / 139 (10.79%)	16 / 139 (11.51%)	21 / 140 (15.00%)
occurrences all number	22	26	24	26
Back pain
subjects affected / exposed	7 / 140 (5.00%)	0 / 139 (0.00%)	4 / 139 (2.88%)	5 / 140 (3.57%)
occurrences all number	7	0	4	5
Pain in extremity
subjects affected / exposed	12 / 140 (8.57%)	3 / 139 (2.16%)	5 / 139 (3.60%)	4 / 140 (2.86%)
occurrences all number	14	4	5	7
Infections and infestations
Nasopharyngitis
subjects affected / exposed	8 / 140 (5.71%)	9 / 139 (6.47%)	8 / 139 (5.76%)	10 / 140 (7.14%)
occurrences all number	8	9	9	10

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Were there any global substantial amendments to the protocol? Yes

10 Jan 2016

Following changes were made: - Clarified that the maximum dose of paracetamol/acetaminophen permitted as rescue medication for LBP is 2,600 mg (325 mg x 8) per day in North America, and 2,500 mg (500 mg x 5) per day in Europe, - added confirmed elevated screening ALT or AST > 2.5 x upper limit of normal (ULN) as an exclusion criterion, - added continued noncompliance with protocol-defined maximum paracetamol/acetaminophen use after appropriate counseling as a reason for permanent discontinuation of study drug, - changed the notification requirement for emergency unblinding to “The investigator should promptly document and explain to the sponsor any premature unblinding.” - Made administrative edits.

19 Jan 2016

Following changes were made: - Incorporated revisions to ensure a consistent approach across the fasinumab program, for imaging requirements: added further detail on imaging requirements during the screening period, - specified that radiographs and/or MRI will or must (rather than should) be performed on any joint following report of a clinically significant worsening or exacerbation of pain in that joint, - specified that prior to the pre-randomization visit, - an MRI of the affected joint must be performed and assessed by the central reader for any screening radiographs that are inconclusive for potential joint-related findings and for any knee or hip joint that has a baseline K-L score of ≥3, and specified that, before a subject was randomized, confirmation must be received that there are no exclusionary finding on screening MRIs, - updated the study stopping rules to state that the DMC may recommend temporarily halting the study if the DMC has significant concerns regarding a meaningful imbalance in joint-related AEs, SNS dysfunction, or neurosensory disturbances, - added willingness to consider TJR if necessary as an inclusion criterion, modified exclusion criteria, - added clinically significant sensory and motor neurologic events grade >2 according to Common Terminology Criteria for Adverse Events (CTCAE) v.4 as a new reason for permanent discontinuation of study drug; - specified that sites should use CTCAE v.4 criteria throughout the study for consistency, - added new signs and symptoms indicative of carpal tunnel syndrome as a new reason for permanent discontinuation of study drug, - modified schedule of events, - study visit descriptions and study procedures, - refined and further detail text describing safety reporting, - and monitoring of adverse events of special interest (AESI), - refined and further detail the statistical plan, made minor clarifications and administrative edits.

25 Aug 2016

Following changes were made: - Added additional collection time points for urine to better monitor patient safety, - added creatinine and phosphorous to routine serum and urine chemistry sampling to better monitor patient safety, - updated the terminology from “destructive arthropathy” to “adjudicated arthropathy” to allow for consistency within the program and to allow for a more accurate description of the joint events in the trial, - updated the personnel who have the authorization to approve rescreening, - updated the reporting time for AESIs from 7 days to 24 hours.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
13 Oct 2016	The Food and Drug Administration (FDA) placed the study on partial clinical hold following an adjudicated arthropathy (AA) event that occurred in a subject with chronic low back pain (LBP) and a history of advanced osteoarthritis (OA) (K-L = 3 in the AA joint at screening).	-

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

As a result of the partial clinical hold the Sponsor made a decision not to amend the protocol and consequently randomization and dosing was prematurely discontinued.

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Clinical trials

Clinical Trial Results:
A Randomized, Double-blind, Multi-dose, Placebo-controlled Phase 2/3 Study to Evaluate the Efficacy and Safety of Fasinumab in Patients With Moderate to Severe Chronic Low Back Pain

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in the Average Daily Low Back Pain Intensity (LBPI) Score on an 11-point Numerical Rating Scale (NRS) at Week 16

Primary: Change From Baseline in the Average Daily Low Back Pain Intensity (LBPI) Score on an 11-point Numerical Rating Scale (NRS) at Week 16

Secondary: Change From Baseline to Weeks 2, 4, 8, and 12 in the Average Low Back Pain Index Numeric Rating Scale Score (LBPI NRS)

Secondary: Change From Baseline to Weeks 2, 4, 8, and 12 in the Average Low Back Pain Index Numeric Rating Scale Score (LBPI NRS)

Secondary: Change From Baseline to Week 16 in Roland Morris Disability Questionnaire (RMDQ) Total Score

Secondary: Change From Baseline to Week 16 in Roland Morris Disability Questionnaire (RMDQ) Total Score

Secondary: Change From Baseline to Week 16 in the Patient Global Assessment (PGA) of Low Back Pain (LBP) Score

Secondary: Change From Baseline to Week 16 in the Patient Global Assessment (PGA) of Low Back Pain (LBP) Score

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A Randomized, Double-blind, Multi-dose, Placebo-controlled Phase 2/3 Study to Evaluate the Efficacy and Safety of Fasinumab in Patients With Moderate to Severe Chronic Low Back Pain

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in the Average Daily Low Back Pain Intensity (LBPI) Score on an 11-point Numerical Rating Scale (NRS) at Week 16

Primary: Change From Baseline in the Average Daily Low Back Pain Intensity (LBPI) Score on an 11-point Numerical Rating Scale (NRS) at Week 16

Secondary: Change From Baseline to Weeks 2, 4, 8, and 12 in the Average Low Back Pain Index Numeric Rating Scale Score (LBPI NRS)

Secondary: Change From Baseline to Weeks 2, 4, 8, and 12 in the Average Low Back Pain Index Numeric Rating Scale Score (LBPI NRS)

Secondary: Change From Baseline to Week 16 in Roland Morris Disability Questionnaire (RMDQ) Total Score

Secondary: Change From Baseline to Week 16 in Roland Morris Disability Questionnaire (RMDQ) Total Score

Secondary: Change From Baseline to Week 16 in the Patient Global Assessment (PGA) of Low Back Pain (LBP) Score

Secondary: Change From Baseline to Week 16 in the Patient Global Assessment (PGA) of Low Back Pain (LBP) Score

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Randomized, Double-blind, Multi-dose, Placebo-controlled Phase 2/3 Study to Evaluate the Efficacy and Safety of Fasinumab in Patients With Moderate to Severe Chronic Low Back Pain