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Clinical Trial Results:
A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention

Summary
EudraCT number	2012-005331-90
Trial protocol	DE SE FI NO DK
Global end of trial date	12 Nov 2019

Results information
Results version number	v1(current)
This version publication date	26 Nov 2020
First version publication date	26 Nov 2020
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

20120178

ISRCTN number

US NCT number

NCT01952574

WHO universal trial number (UTN)

Sponsor organisation name

Amgen Inc.

Sponsor organisation address

One Amgen Center Drive, Thousand Oaks, CA, United States, 91320

Public contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Scientific contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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

12 Nov 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

12 Nov 2019

Was the trial ended prematurely?

Main objective of the trial

The primary objective was to evaluate the effect of erenumab (AMG 334) compared to placebo on the change from baseline in monthly migraine days, in subjects with episodic migraine.

Protection of trial subjects

This study was conducted in accordance with relevant country regulations and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. A copy of the protocol, proposed informed consent form, other written subject information, and any proposed advertising materials were submitted to the Independent Ethics Committee (IEC)/Institutional Review Board (IRB) for written approval. A copy of the written approval of the protocol and informed consent form must have been received by Amgen before recruitment of subjects into the study and shipment of investigational product. Before a subject’s participation in the clinical study, the investigator obtained written informed consent from the subject or the subject’s legally acceptable representative after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study and before any protocol-specific screening procedures or any investigational product was administered.

Background therapy

Evidence for comparator

Actual start date of recruitment

06 Aug 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 6

Country: Number of subjects enrolled

Germany: 58

Country: Number of subjects enrolled

Denmark: 26

Country: Number of subjects enrolled

Finland: 42

Country: Number of subjects enrolled

Norway: 56

Country: Number of subjects enrolled

Sweden: 42

Country: Number of subjects enrolled

United States: 253

Worldwide total number of subjects

483

EEA total number of subjects

224

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)

483

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This study was conducted at 59 centers in North America (Canada, USA) and Europe (Denmark, Finland, Germany, Norway, Sweden, and Portugal). The study consisted of a 12-week double-blind treatment phase (DBTP) and a 256-week open-label treatment phase (OLTP) followed by a safety follow-up of 8 to 12 weeks (12 -16 weeks after last dose).

Screening details

Participants were randomized 3:2:2:2 to receive placebo, erenumab 7 mg, erenumab 21 mg, or erenumab 70 mg once a month (QM) in the double-blind phase. Randomization was stratified by region (North America vs. Europe). During the open-label treatment phase, participants in the US could participate in an optional Clinical Home Use (CHU) substudy.

Period 1 title

Double-blind Treatment Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

DBTP: Placebo QM

Arm description

Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.

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

Administered once a month (QM) by subcutaneous injection

DBTP: Erenumab 7 mg QM

Arm description

Participants received erenumab 7 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.

Arm type

Experimental

Investigational medicinal product name

Erenumab

Investigational medicinal product code

AMG 334

Other name

Aimovig™

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Administered once a month (QM) by subcutaneous injection

DBTP: Erenumab 21 mg QM

Arm description

Participants received erenumab 21 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.

Arm type

Experimental

Investigational medicinal product name

Erenumab

Investigational medicinal product code

AMG 334

Other name

Aimovig™

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Administered once a month (QM) by subcutaneous injection

DBTP: Erenumab 70 mg QM

Arm description

Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.

Arm type

Experimental

Investigational medicinal product name

Erenumab

Investigational medicinal product code

AMG 334

Other name

Aimovig™

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Administered once a month (QM) by subcutaneous injection

Number of subjects in period 1	DBTP: Placebo QM	DBTP: Erenumab 7 mg QM	DBTP: Erenumab 21 mg QM	DBTP: Erenumab 70 mg QM
Started	160	108	108	107
Received Study Drug	153	108	105	106
Completed	143	105	99	101
Not completed	17	3	9	6
Consent withdrawn by subject	9	3	3	4
Sponsor Decision	6	-	5	2
Lost to follow-up	2	-	1	-

Period 2 title

Open-label Treatment Phase

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

OLTP: Erenumab 70/140 mg QM

Arm description

Participants received 70 mg erenumab QM from the beginning of the OLTP (week 12). After Protocol Amendment 3, participants still on study had their dose increased to 140 mg QM.

Arm type

Experimental

Investigational medicinal product name

Erenumab

Investigational medicinal product code

AMG 334

Other name

Aimovig™

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Administered once a month (QM) by subcutaneous injection

Number of subjects in period 2 ^[1]	OLTP: Erenumab 70/140 mg QM
Started	383
Received 70 mg Erenumab	383
Received 140 mg Erenumab	250
Completed	221
Not completed	162
Adverse event, serious fatal	1
Consent withdrawn by subject	121
Decision by Sponsor	17
Lost to follow-up	19
Missing	4

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: Participants who were enrolled in Norway did not participate in the OLTP. In addition, 12 subjects who completed the DBTP did not enter the OLTP.

Period 3 title

Clinical Home Use Substudy

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

CHU Substudy: Erenumab 140 mg by Prefilled Syringe

Arm description

Participants in the open-label treatment phase in the United States randomized to self-administer 140 mg erenumab via two 70 mg injections using a prefilled syringe (PFS) on CHU substudy day 1 (under study site supervision), and at home on day 29 (week 4) and day 57 (week 8).

Arm type

Experimental

Investigational medicinal product name

Erenumab

Investigational medicinal product code

AMG 334

Other name

Aimovig™

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Administered once a month (QM) by subcutaneous injection

CHU Substudy: Erenumab 140 mg Autoinjector/Pen

Arm description

Participants in the open-label treatment phase in the United States randomized to self-administer 140 mg erenumab via two 70 mg injections using an autoinjector (AI)/pen on CHU substudy day 1 (under study site supervision), and at home on day 29 (week 4) and day 57 (week 8).

Arm type

Experimental

Investigational medicinal product name

Erenumab

Investigational medicinal product code

AMG 334

Other name

Aimovig™

Pharmaceutical forms

Solution for injection in needle-free injector, Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

Administered once a month (QM) by subcutaneous injection

Number of subjects in period 3 ^[2]	CHU Substudy: Erenumab 140 mg by Prefilled Syringe	CHU Substudy: Erenumab 140 mg Autoinjector/Pen
Started	42	41
Completed	39	40
Not completed	3	1
Consent withdrawn by subject	1	-
Decision by Sponsor	2	1

Notes
[2] - 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: Only participants enrolled in the open-label treatment phase in the United States were eligible to participate in the clinical home use substudy

Baseline characteristics

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Reporting group title

DBTP: Placebo QM

Reporting group description

Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.

Reporting group title

DBTP: Erenumab 7 mg QM

Reporting group description

Participants received erenumab 7 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.

Reporting group title

DBTP: Erenumab 21 mg QM

Reporting group description

Participants received erenumab 21 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.

Reporting group title

DBTP: Erenumab 70 mg QM

Reporting group description

Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.

Reporting group values	DBTP: Placebo QM	DBTP: Erenumab 7 mg QM	DBTP: Erenumab 21 mg QM	DBTP: Erenumab 70 mg QM	Total
Number of subjects	160	108	108	107	483
Age categorical
Units: Subjects
Adults (18-64 years)	160	108	108	107	483
From 65-84 years	0	0	0	0	0
85 years and over	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	41.4 ( 10.0 )	40.3 ( 10.9 )	39.9 ( 12.3 )	42.6 ( 9.9 )	-
Sex: Female, Male
Units: participants
Female	132	88	87	82	389
Male	28	20	21	25	94
Race/Ethnicity, Customized
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0
Asian	2	0	1	1	4
Black or African American	13	10	7	2	32
Native Hawaiian or other Pacific Islander	1	0	0	0	1
White	142	97	100	103	442
Multiple	0	0	0	1	1
Other	2	1	0	0	3
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	11	9	9	1	30
Not Hispanic or Latino	149	99	99	106	453
Region
Region is based on actual data collected at study baseline instead of randomization stratification.
Units: Subjects
North America	85	58	58	58	259
Europe	75	50	50	49	224
Monthly Migraine Days
A migraine day was any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined as a migraine without aura or a migraine with aura. Monthly migraine days were calculated as the number of migraine days in the 4-week baseline phase.
Units: migraine days/month
arithmetic mean (standard deviation)	8.77 ( 2.72 )	8.62 ( 2.79 )	8.93 ( 2.88 )	8.58 ( 2.49 )	-

End points

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Reporting group title

DBTP: Placebo QM

Reporting group description

Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.

Reporting group title

DBTP: Erenumab 7 mg QM

Reporting group description

Participants received erenumab 7 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.

Reporting group title

DBTP: Erenumab 21 mg QM

Reporting group description

Participants received erenumab 21 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.

Reporting group title

DBTP: Erenumab 70 mg QM

Reporting group description

Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.

Reporting group title

OLTP: Erenumab 70/140 mg QM

Reporting group description

Participants received 70 mg erenumab QM from the beginning of the OLTP (week 12). After Protocol Amendment 3, participants still on study had their dose increased to 140 mg QM.

Reporting group title

CHU Substudy: Erenumab 140 mg by Prefilled Syringe

Reporting group description

Reporting group title

CHU Substudy: Erenumab 140 mg Autoinjector/Pen

Reporting group description

Subject analysis set title

OLTP: Erenumab 70 mg QM

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received 70 mg erenumab QM from week 12 until implementation of Protocol Amendment 3 (07 April 2016) in the open-label treatment phase; median duration of exposure was 104 weeks.

Subject analysis set title

OLTP: Erenumab 140 mg QM

Subject analysis set type

Safety analysis

Subject analysis set description

After implementation of Protocol Amendment 3 (07 April 2016), participants still on study received erenumab 140 mg QM up to week 264 in the open-label treatment phase; median duration of exposure was 141 weeks.

Subject analysis set title

Placebo / Erenumab 70/140 mg QM

Subject analysis set type

Safety analysis

Subject analysis set description

Participants randomized to placebo in the double-blind treatment phase received 70 mg erenumab QM from week 12 in the open-label treatment phase. After Protocol Amendment 3, participants still on study had their dose increased to 140 mg QM.

Subject analysis set title

Erenumab 7 mg QM / Erenumab 70/140 mg QM

Subject analysis set type

Safety analysis

Subject analysis set description

Participants randomized to erenumab 7 mg in the double-blind treatment phase received 70 mg erenumab QM from week 12 in the open-label treatment phase. After Protocol Amendment 3, participants still on study had their dose increased to 140 mg QM.

Subject analysis set title

Erenumab 21 mg QM / Erenumab 70/140 mg QM

Subject analysis set type

Safety analysis

Subject analysis set description

Participants randomized to erenumab 21 mg in the double-blind treatment phase received 70 mg erenumab QM from week 12 in the open-label treatment phase. After Protocol Amendment 3, participants still on study had their dose increased to 140 mg QM.

Subject analysis set title

Erenumab 70 mg QM / Erenumab 70/140 mg QM

Subject analysis set type

Safety analysis

Subject analysis set description

Participants randomized to erenumab 70 mg in the double-blind treatment phase received 70 mg erenumab QM from week 12 in the open-label treatment phase. After Protocol Amendment 3, participants still on study had their dose increased to 140 mg QM.

Primary: Change From Baseline in Monthly Migraine Days at Week 12

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End point title

Change From Baseline in Monthly Migraine Days at Week 12

End point description

A migraine day was any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined as a migraine with or without aura. The change from baseline in monthly migraine days was calculated as the number of migraine days during the last 4 weeks of the 12-week double-blind treatment phase – the number of migraine days during the 4-week baseline phase. Data were analyzed in participants who received at least 1 dose of investigational product (IP) and had ≥ 4 migraine days during the 4-week baseline phase (efficacy analysis set), and with at least one change from baseline value in monthly migraine days.

End point type

Primary

End point timeframe

4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase

End point values	DBTP: Placebo QM	DBTP: Erenumab 7 mg QM	DBTP: Erenumab 21 mg QM	DBTP: Erenumab 70 mg QM
Number of subjects analysed	152	107	99	104
Units: migraine days / month
least squares mean (standard error)	-2.28 ( 0.31 )	-2.18 ( 0.36 )	-2.39 ( 0.38 )	-3.40 ( 0.37 )

Analysis of Change in Monthly Migraine Days

Statistical analysis description

The primary analysis utilized a generalized linear mixed model which included treatment, visit, treatment by visit, the stratification factor region, and baseline value as covariates.

Comparison groups

DBTP: Placebo QM v DBTP: Erenumab 70 mg QM

Number of subjects included in analysis

256

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.021

Method

Generalized Linear Mixed Model

Parameter type

LS Mean Difference

Point estimate

-1.12

Confidence interval

level

95%

sides

2-sided

lower limit

-2.06

upper limit

-0.17

Notes
[1] - To maintain the type I error at ≤ 0.05, the pairwise comparison was tested in a sequential testing procedure in the order of erenumab 70 mg vs placebo, 21 mg vs placebo, and 7 mg vs placebo. The lower dose group was only to be tested when the higher dose group was tested as significant.

Analysis of Change in Monthly Migraine Days

Statistical analysis description

The primary analysis utilized a generalized linear mixed model which included treatment, visit, treatment by visit, the stratification factor region, and baseline value as covariates.

Comparison groups

DBTP: Placebo QM v DBTP: Erenumab 21 mg QM

Number of subjects included in analysis

251

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.83

Method

Generalized Linear Mixed Model

Parameter type

LS Mean Difference

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.07

upper limit

0.86

Notes
[2] - To maintain the type I error at ≤ 0.05, the pairwise comparison was tested in a sequential testing procedure in the order of erenumab 70 mg vs placebo, 21 mg vs placebo, and 7 mg vs placebo. The lower dose group was only to be tested when the higher dose group was tested as significant.

Analysis of Change in Monthly Migraine Days

Statistical analysis description

The primary analysis utilized a generalized linear mixed model which included treatment, visit, treatment by visit, the stratification factor region, and baseline value as covariates.

Comparison groups

DBTP: Placebo QM v DBTP: Erenumab 7 mg QM

Number of subjects included in analysis

259

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.82

Method

Generalized Linear Mixed Model

Parameter type

LS Mean Difference

Point estimate

0.11

Confidence interval

level

92%

sides

2-sided

lower limit

-0.83

upper limit

1.05

Notes
[3] - To maintain the type I error at ≤ 0.05, the pairwise comparison was tested in a sequential testing procedure in the order of erenumab 70 mg vs placebo, 21 mg vs placebo, and 7 mg vs placebo. The lower dose group was only to be tested when the higher dose group was tested as significant.

Primary: CHU Substudy: Percentage of Participants Who Self-administered a Full Dose, Partial Dose, or No Dose of Erenumab

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End point title

CHU Substudy: Percentage of Participants Who Self-administered a Full Dose, Partial Dose, or No Dose of Erenumab ^[4]

End point description

To assess participants ability to administer a full dose of erenumab in home-use at day 29 (week 4) and day 57 (week 8), site staff called participants and asked whether the participant administered a full, partial, or no dose of erenumab. A full dose means that the entire volume of both prefilled syringes or autoinjector/pens were injected. Discontinued prior to dosing day indicates participants who had discontinued the investigational product and did not attempt to self-administer on day 29 or 57.

End point type

Primary

End point timeframe

CHU substudy day 29 (week 4) and day 57 (week 8)

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: In the CHU substudy it was hypothesized that users were able to administer a full dose of erenumab comparably using either the prefilled syringe or autoinjector/pen. No formal hypotheses were tested.

End point values	CHU Substudy: Erenumab 140 mg by Prefilled Syringe	CHU Substudy: Erenumab 140 mg Autoinjector/Pen
Number of subjects analysed	42 ^[5]	41 ^[6]
Units: participants
Day 29 (week 4): Full dose	39	41
Day 29 (week 4): Partial dose	1	0
Day 29 (week 4): Discontinued prior to dosing day	2	0
Day 57 (week 8): Full dose	39	39
Day 57 (week 8): Partial dose	0	1
Day 57 (week 8): Discontinued prior to dosing day	3	1

Notes
[5] - Participants enrolled in the CHU substudy who received at least 1 dose of IP in the substudy.
[6] - Participants enrolled in the CHU substudy who received at least 1 dose of IP in the substudy.

No statistical analyses for this end point

Secondary: Percentage of Participants with at Least a 50% Reduction From Baseline in Monthly Migraine Days at Week 12

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End point title

Percentage of Participants with at Least a 50% Reduction From Baseline in Monthly Migraine Days at Week 12

End point description

A migraine day was any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined either as a migraine without aura or a migraine with aura. Monthly migraine days were calculated as the number of migraine days in the 4-week baseline phase and during the last 4 weeks of double-blind treatment. At least a 50% reduction from baseline in monthly migraine days was determined if the change in monthly migraine days from the 4-week baseline phase to the last 4 weeks of the 12-week double-blind treatment phase * 100 / baseline monthly migraine days was less than or equal to -50%. Analyzed in participants who received at least 1 dose of investigational product and had ≥ 4 migraine days during the 4-week baseline phase (efficacy analysis set) with available data at week 12.

End point type

Secondary

End point timeframe

4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase

End point values	DBTP: Placebo QM	DBTP: Erenumab 7 mg QM	DBTP: Erenumab 21 mg QM	DBTP: Erenumab 70 mg QM
Number of subjects analysed	144	104	93	99
Units: percentage of participants
number (not applicable)	22.9	28.8	34.4	46.5

Analysis of Responder Rate

Statistical analysis description

The generalized linear mixed model includes data for all participants in the efficacy analysis set with at least one percent change from baseline value in monthly migraine days (152 participants in the placebo group and 104 in the erenumab 70 mg group)

Comparison groups

DBTP: Placebo QM v DBTP: Erenumab 70 mg QM

Number of subjects included in analysis

243

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.011 ^[7]

Method

Generalised Linear Mixed Model

Parameter type

Odds ratio (OR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

1.17

upper limit

3.42

Notes
[7] - Generalized linear mixed model including treatment, visit, treatment by visit, stratification factor region, and baseline value as covariates.

Analysis of Responder Rate

Statistical analysis description

The generalized linear mixed model includes data for all participants in the efficacy analysis set with at least one change from baseline value in monthly migraine days (152 participants in the placebo group and 99 in the erenumab 21 mg group)

Comparison groups

DBTP: Placebo QM v DBTP: Erenumab 21 mg QM

Number of subjects included in analysis

237

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.44 ^[8]

Method

Generalized Linear Mixed Model

Parameter type

Odds ratio (OR)

Point estimate

1.25

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

2.18

Notes
[8] - Generalized linear mixed model including treatment, visit, treatment by visit, stratification factor region, and baseline value as covariates.

Analysis of Responder Rate

Statistical analysis description

Comparison groups

DBTP: Placebo QM v DBTP: Erenumab 7 mg QM

Number of subjects included in analysis

248

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8 ^[9]

Method

Generalized Linear Mixed Model

Parameter type

Odds ratio (OR)

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

1.63

Notes
[9] - Generalized linear mixed model including treatment, visit, treatment by visit, stratification factor region, and baseline value as covariates.

Secondary: Change From Baseline in Monthly Migraine Attacks at Week 12

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End point title

Change From Baseline in Monthly Migraine Attacks at Week 12

End point description

A migraine attack is an episode of any qualified migraine headache or migraine specific medication intakes for aura only. A migraine attack that was interrupted by sleep or that temporarily remits and then recurs within 48 hours or an attack treated successfully with medication but that relapses within 48 hours was considered to be one attack. The change from baseline in monthly migraine attacks was calculated as the number of migraine attacks during the last 4 weeks of the 12-week double-blind treatment phase – the number of migraine attacks during the 4-week baseline phase. Analyzed in participants who received at least 1 dose of investigational product and had ≥ 4 migraine days during the 4-week baseline phase (efficacy analysis set), and with at least one change from baseline value in monthly migraine attacks.

End point type

Secondary

End point timeframe

4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase

End point values	DBTP: Placebo QM	DBTP: Erenumab 7 mg QM	DBTP: Erenumab 21 mg QM	DBTP: Erenumab 70 mg QM
Number of subjects analysed	152	107	99	104
Units: migraine attacks/month
least squares mean (standard error)	-1.44 ( 0.17 )	-1.07 ( 0.20 )	-1.42 ( 0.21 )	-1.84 ( 0.20 )

Analysis of Change in Monthly Migraine Attacks

Comparison groups

DBTP: Placebo QM v DBTP: Erenumab 70 mg QM

Number of subjects included in analysis

256

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.13 ^[10]

Method

Generalized Linear Mixed Model

Parameter type

LS Mean Difference

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.92

upper limit

0.12

Notes
[10] - Generalized linear mixed model including treatment, visit, treatment by visit, the stratification factor region, and baseline value as covariates.

Analysis of Change in Monthly Migraine Attacks

Comparison groups

DBTP: Placebo QM v DBTP: Erenumab 21 mg QM

Number of subjects included in analysis

251

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.95 ^[11]

Method

Generalized Linear Mixed Model

Parameter type

LS Mean Difference

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.51

upper limit

0.54

Notes
[11] - Generalized linear mixed model including treatment, visit, treatment by visit, the stratification factor region, and baseline value as covariates.

Analysis of Change in Monthly Migraine Attacks

Comparison groups

DBTP: Placebo QM v DBTP: Erenumab 7 mg QM

Number of subjects included in analysis

259

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.16 ^[12]

Method

Generalized Linear Mixed Model

Parameter type

LS Mean Difference

Point estimate

0.37

Confidence interval

level

95%

sides

2-sided

lower limit

-0.14

upper limit

0.87

Notes
[12] - Generalized linear mixed model including treatment, visit, treatment by visit, the stratification factor region, and baseline value as covariates.

Secondary: Number of Participants with Treatment-emergent Adverse Events in the Double-blind Treatment Phase

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End point title

Number of Participants with Treatment-emergent Adverse Events in the Double-blind Treatment Phase

End point description

An adverse event (AE) is any untoward medical occurrence in a clinical trial subject, including worsening of a pre-existing medical condition and laboratory value changes that require treatment or adjustment in current therapy. AEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03: 1 Mild; asymptomatic or mild symptoms 2 Moderate; minimal, local or noninvasive intervention indicated; limiting daily activities 3 Severe or medically significant but not immediately life-threatening; hospitalization indicated; disabling; limiting self-care 4 Life-threatening consequences; urgent intervention indicated 5 Death related to AE A serious adverse event is an AE that meets at least 1 of the following criteria: • fatal • life threatening • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • congenital anomaly/birth defect • other medically important serious event

End point type

Secondary

End point timeframe

From first dose of study drug in the double-blind treatment phase until the first dose of study drug in the open-label treatment phase (12 weeks) or up to 12 weeks after last dose for participants who did not enter the open-label treatment phase.

End point values	DBTP: Placebo QM	DBTP: Erenumab 7 mg QM	DBTP: Erenumab 21 mg QM	DBTP: Erenumab 70 mg QM
Number of subjects analysed	153 ^[13]	108 ^[14]	105 ^[15]	106 ^[16]
Units: participants
Any adverse event (AE)	81	57	55	57
Serious adverse events (SAEs)	1	1	0	1
AE leading to discontinuation of IP	2	2	2	3
AE Grade ≥ 2	36	31	25	23
AE Grade ≥ 3	3	3	3	3
AE Grade ≥ 4	0	0	0	0
Fatal adverse events	0	0	0	0

Notes
[13] - Safety analysis set
[14] - Safety analysis set
[15] - Safety analysis set
[16] - Safety analysis set

No statistical analyses for this end point

Secondary: Number of Participants with Treatment-emergent Adverse Events in the Open-label Treatment Phase

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End point title

Number of Participants with Treatment-emergent Adverse Events in the Open-label Treatment Phase

End point description

End point type

Secondary

End point timeframe

From first dose in the open-label treatment phase up to 12 weeks (participants receiving 70 mg only) or 16 weeks (participants with dose increased to 140 mg) after the last dose; a maximum of 268 weeks.

End point values	OLTP: Erenumab 70/140 mg QM	OLTP: Erenumab 70 mg QM	OLTP: Erenumab 140 mg QM
Number of subjects analysed	383	383	250
Units: participants
Any adverse event (AE)	340	323	216
Serious adverse events (SAEs)	49	30	25
AE leading to discontinuation of IP	18	16	2
AE Grade ≥ 2	286	249	180
AE Grade ≥ 3	83	55	40
AE Grade ≥ 4	4	1	3
Fatal adverse events	2	1	1

No statistical analyses for this end point

Secondary: CHU Substudy: Number of Participants with Treatment-emergent Adverse Events During the CHU Substudy

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End point title

CHU Substudy: Number of Participants with Treatment-emergent Adverse Events During the CHU Substudy

End point description

AEs were graded using the CTCAE version 4.03: 1 Mild; asymptomatic or mild symptoms 2 Moderate; minimal, local or noninvasive intervention indicated; limiting daily activities 3 Severe or medically significant but not immediately life-threatening; hospitalization indicated; disabling; limiting self-care 4 Life-threatening consequences; urgent intervention indicated 5 Death related to AE A serious adverse event is an AE that meets at least 1 of the following criteria: • fatal • life threatening • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • congenital anomaly/birth defect • other medically important serious event An adverse device effect is any AE related to the use of a medical device, including AEs resulting from insufficient or inadequate instructions for use, any malfunction of the device, or use error or from intentional misuse of the device.

End point type

Secondary

End point timeframe

From first dose in the CHU substudy to end of substudy (up to 12 weeks)

End point values	CHU Substudy: Erenumab 140 mg by Prefilled Syringe	CHU Substudy: Erenumab 140 mg Autoinjector/Pen
Number of subjects analysed	42 ^[17]	41 ^[18]
Units: participants
Any adverse event	13	17
AE Grade ≥ 2	7	10
AE Grade ≥ 3	1	2
AE Grade ≥ 4	0	0
Serious adverse events	0	0
Leading to discontinuation of IP	0	0
Fatal adverse events	0	0
Injection site reactions	4	2
Adverse device effects	2	2

Notes
[17] - Participants enrolled in the CHU substudy who received at least 1 dose of IP in the substudy
[18] - Participants enrolled in the CHU substudy who received at least 1 dose of IP in the substudy

No statistical analyses for this end point

Secondary: Number of Participants who Developed Anti-erenumab Antibodies During the Double-blind Treatment Phase

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End point title

Number of Participants who Developed Anti-erenumab Antibodies During the Double-blind Treatment Phase

End point description

Two validated assays were used to detect the presence of anti-erenumab antibodies. First, an electrochemiluminescent bridging immunoassay was used to detect binding antibodies (screening assay) and confirm antibodies (confirmatory assay) capable of binding erenumab. Second, a cell-based bioassay was used to test positive binding antibody samples for neutralizing activity against erenumab. Participants who developed anti-erenumab antibodies are participants who were negative or had no result at baseline but positive at any time postbaseline during the DBTP. If a sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the participant was defined as positive for neutralizing antibodies.

End point type

Secondary

End point timeframe

12 weeks

End point values	DBTP: Placebo QM	DBTP: Erenumab 7 mg QM	DBTP: Erenumab 21 mg QM	DBTP: Erenumab 70 mg QM
Number of subjects analysed	149 ^[19]	107 ^[20]	104 ^[21]	106 ^[22]
Units: participants
Developed binding antibodies	0	13	12	8
Developed neutralizing antibodies	0	5	3	1

Notes
[19] - Participants who received at least 1 dose of IP and with valid postbaseline antibody testing results
[20] - Participants who received at least 1 dose of IP and with valid postbaseline antibody testing results
[21] - Participants who received at least 1 dose of IP and with valid postbaseline antibody testing results
[22] - Participants who received at least 1 dose of IP and with valid postbaseline antibody testing results

No statistical analyses for this end point

Secondary: Number of Participants who Developed Anti-erenumab Antibodies During the Open-label Treatment Phase

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End point title

Number of Participants who Developed Anti-erenumab Antibodies During the Open-label Treatment Phase

End point description

Two validated assays were used to detect the presence of anti-erenumab antibodies. First, an electrochemiluminescent bridging immunoassay was used to detect binding antibodies (screening assay) and confirm antibodies (confirmatory assay) capable of binding erenumab. Second, a cell-based bioassay was used to test positive binding antibody samples for neutralizing activity against erenumab. Participants who developed anti-erenumab antibodies are participants who were negative prior to the first OLTP dose but positive at any time during the OLTP, or participants with no data prior to first dose in OLTP with any post-baseline positive results. If a sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the participant was defined as positive for neutralizing antibodies.

End point type

Secondary

End point timeframe

From week 12 up to 12 weeks (participants receiving 70 mg only) or 16 weeks (participants with dose increased to 140 mg) after the last dose; maximum 268 weeks.

End point values	Placebo / Erenumab 70/140 mg QM	Erenumab 7 mg QM / Erenumab 70/140 mg QM	Erenumab 21 mg QM / Erenumab 70/140 mg QM	Erenumab 70 mg QM / Erenumab 70/140 mg QM
Number of subjects analysed	119 ^[23]	88 ^[24]	87 ^[25]	86 ^[26]
Units: participants
Developed binding antibodies	12	8	6	5
Developed neutralizing antibodies	1	0	1	0

Notes
[23] - Subjects who received at least 1 dose of IP in the OLTP with valid antibody results during the OLTP
[24] - Subjects who received at least 1 dose of IP in the OLTP with valid antibody results during the OLTP
[25] - Subjects who received at least 1 dose of IP in the OLTP with valid antibody results during the OLTP
[26] - Subjects who received at least 1 dose of IP in the OLTP with valid antibody results during the OLTP

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

DBTP: From first dose of IP in the DBTP until the first dose of IP in the OLTP (12 weeks). OLTP: From first dose in the OLTP up to 12 weeks or 16 weeks (70 mg and 140 mg doses respectively) after the last dose; up to 268 weeks. CHU substudy: 12 weeks

Adverse event reporting additional description

Participants who did not enter the OLTP were followed for up to 12 weeks after last dose in the DBTP. In the OLTP participants were followed for up to 12 weeks (participants receiving 70 mg only) or 16 weeks (participants with dose increased to 140 mg) after last dose.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

DBTP: Placebo QM

Reporting group description

Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.

Reporting group title

DBTP: Erenumab 7 mg QM

Reporting group description

Participants received erenumab 7 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.

Reporting group title

DBTP: Erenumab 21 mg QM

Reporting group description

Participants received erenumab 21 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.

Reporting group title

DBTP: Erenumab 70 mg QM

Reporting group description

Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.

Reporting group title

OpLTP: Erenumab 70 mg QM

Reporting group description

Participants received 70 mg erenumab QM from week 12 until implementation of Protocol Amendment 3 (07 April 2016) in the open-label treatment phase; median duration of exposure was 104 weeks.

Reporting group title

OLTP: Erenumab 140 mg QM

Reporting group description

Reporting group title

OLTP: Erenumab 70/140 mg QM

Reporting group description

Participants received 70 mg erenumab QM from week 12 to week 264 (last dose). After Protocol Amendment 3, participants still on study had their dose increased to 140 mg QM. The overall median duration of exposure was 255 weeks.

Reporting group title

CHU Substudy: Erenumab 140 mg PFS

Reporting group description

Participants in the open-label treatment phase in the United States self-administered 140 mg erenumab via two 70 mg injections using a prefilled syringe (PFS) on CHU substudy day 1 (under study site supervision), and at home on day 29 (week 4) and day 57 (week 8).

Reporting group title

CHU Substudy: Erenumab 140 mg AI/Pen

Reporting group description

Participants in the open-label treatment phase in the United States self-administered 140 mg erenumab via two 70 mg injections using an autoinjector/pen (AI)/pen) on CHU substudy day 1 (under study site supervision), and at home on day 29 (week 4) and day 57 (week 8).

Reporting group title

CHU Substudy: Total

Reporting group description

Participants in the open-label treatment phase in the United States self-administered 140 mg erenumab via two 70 mg injections using a prefilled syringe or autoinjector/pen on CHU substudy day 1 (under study site supervision), and at home on day 29 (week 4) and day 57 (week 8).

Serious adverse events	DBTP: Placebo QM	DBTP: Erenumab 7 mg QM	DBTP: Erenumab 21 mg QM	DBTP: Erenumab 70 mg QM	OpLTP: Erenumab 70 mg QM	OLTP: Erenumab 140 mg QM	OLTP: Erenumab 70/140 mg QM	CHU Substudy: Erenumab 140 mg PFS	CHU Substudy: Erenumab 140 mg AI/Pen	CHU Substudy: Total
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 153 (0.65%)	1 / 108 (0.93%)	0 / 105 (0.00%)	1 / 106 (0.94%)	30 / 383 (7.83%)	25 / 250 (10.00%)	49 / 383 (12.79%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
number of deaths (all causes)	0	0	0	0	1	1	2	0	0	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of the cervix
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Breast cancer
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	2 / 383 (0.52%)	0 / 250 (0.00%)	2 / 383 (0.52%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2	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	0 / 0
Invasive lobular breast carcinoma
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Lipoma
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Lung adenocarcinoma stage III
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Prostate cancer
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Uterine leiomyoma
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	1 / 250 (0.40%)	2 / 383 (0.52%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2	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	0 / 0
Vascular disorders
Arteriosclerosis
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	1 / 250 (0.40%)	2 / 383 (0.52%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2	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	0 / 0
Thrombosis
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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 / 1	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Reproductive system and breast disorders
Ovarian cyst ruptured
subjects affected / exposed	0 / 153 (0.00%)	1 / 108 (0.93%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	0 / 250 (0.00%)	0 / 383 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Adnexa uteri cyst
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Menorrhagia
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Ovarian cyst
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Psychiatric disorders
Adjustment disorder
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	1 / 250 (0.40%)	2 / 383 (0.52%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2	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	0 / 0
Suicide attempt
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Injury, poisoning and procedural complications
Ligament rupture
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	2 / 250 (0.80%)	3 / 383 (0.78%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 3	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	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Congenital, familial and genetic disorders
Developmental hip dysplasia
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Cardiac disorders
Coronary artery stenosis
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Hypertensive heart disease
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Migraine
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	1 / 106 (0.94%)	0 / 383 (0.00%)	0 / 250 (0.00%)	0 / 383 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Cauda equina syndrome
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Cervicobrachial syndrome
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Headache
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Lumbar radiculopathy
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Optic neuritis
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Syncope
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	2 / 383 (0.52%)	0 / 250 (0.00%)	2 / 383 (0.52%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2	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	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	1 / 106 (0.94%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	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	0 / 0
Eye disorders
Visual impairment
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Gastrointestinal disorders
Abdominal adhesions
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Abdominal hernia
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Appendicitis noninfective
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Colitis ischaemic
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Crohn's disease
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Diverticulum
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Faecaloma
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Intra-abdominal haematoma
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Pancreatic cyst
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Peritoneal haemorrhage
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Rectal prolapse
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Hepatic cyst
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Renal and urinary disorders
Bladder prolapse
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Pelvi-ureteric obstruction
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Endocrine disorders
Primary hyperaldosteronism
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Metatarsalgia
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	1 / 250 (0.40%)	2 / 383 (0.52%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2	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	0 / 0
Infections and infestations
Abdominal abscess
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Appendicitis
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	2 / 250 (0.80%)	2 / 383 (0.52%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2	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	0 / 0
Cellulitis
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Diverticulitis
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	1 / 383 (0.26%)	0 / 250 (0.00%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Pneumonia klebsiella
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Tubo-ovarian abscess
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 153 (0.65%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	0 / 250 (0.00%)	0 / 383 (0.00%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (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	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	0 / 0
Metabolism and nutrition disorders
Hypoglycaemia
subjects affected / exposed	0 / 153 (0.00%)	0 / 108 (0.00%)	0 / 105 (0.00%)	0 / 106 (0.00%)	0 / 383 (0.00%)	1 / 250 (0.40%)	1 / 383 (0.26%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0

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

Non-serious adverse events	DBTP: Placebo QM	DBTP: Erenumab 7 mg QM	DBTP: Erenumab 21 mg QM	DBTP: Erenumab 70 mg QM	OpLTP: Erenumab 70 mg QM	OLTP: Erenumab 140 mg QM	OLTP: Erenumab 70/140 mg QM	CHU Substudy: Erenumab 140 mg PFS	CHU Substudy: Erenumab 140 mg AI/Pen	CHU Substudy: Total
Total subjects affected by non serious adverse events
subjects affected / exposed	45 / 153 (29.41%)	27 / 108 (25.00%)	24 / 105 (22.86%)	31 / 106 (29.25%)	220 / 383 (57.44%)	172 / 250 (68.80%)	264 / 383 (68.93%)	7 / 42 (16.67%)	9 / 41 (21.95%)	16 / 83 (19.28%)
Vascular disorders
Hypertension
subjects affected / exposed	2 / 153 (1.31%)	1 / 108 (0.93%)	0 / 105 (0.00%)	2 / 106 (1.89%)	14 / 383 (3.66%)	11 / 250 (4.40%)	25 / 383 (6.53%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences all number	2	1	0	2	14	12	26	0	0	0
Nervous system disorders
Headache
subjects affected / exposed	1 / 153 (0.65%)	4 / 108 (3.70%)	1 / 105 (0.95%)	3 / 106 (2.83%)	10 / 383 (2.61%)	11 / 250 (4.40%)	21 / 383 (5.48%)	1 / 42 (2.38%)	0 / 41 (0.00%)	1 / 83 (1.20%)
occurrences all number	1	5	1	5	11	13	24	1	0	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	3 / 153 (1.96%)	5 / 108 (4.63%)	2 / 105 (1.90%)	4 / 106 (3.77%)	19 / 383 (4.96%)	11 / 250 (4.40%)	29 / 383 (7.57%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences all number	3	8	3	4	25	12	37	0	0	0
Gastrointestinal disorders
Constipation
subjects affected / exposed	1 / 153 (0.65%)	0 / 108 (0.00%)	1 / 105 (0.95%)	3 / 106 (2.83%)	9 / 383 (2.35%)	15 / 250 (6.00%)	24 / 383 (6.27%)	1 / 42 (2.38%)	0 / 41 (0.00%)	1 / 83 (1.20%)
occurrences all number	1	0	1	3	9	16	25	1	0	1
Nausea
subjects affected / exposed	2 / 153 (1.31%)	3 / 108 (2.78%)	1 / 105 (0.95%)	3 / 106 (2.83%)	13 / 383 (3.39%)	18 / 250 (7.20%)	29 / 383 (7.57%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences all number	2	4	1	3	14	18	32	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 153 (1.96%)	2 / 108 (1.85%)	1 / 105 (0.95%)	0 / 106 (0.00%)	15 / 383 (3.92%)	14 / 250 (5.60%)	27 / 383 (7.05%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences all number	3	2	1	0	17	18	35	0	0	0
Oropharyngeal pain
subjects affected / exposed	1 / 153 (0.65%)	1 / 108 (0.93%)	2 / 105 (1.90%)	2 / 106 (1.89%)	15 / 383 (3.92%)	7 / 250 (2.80%)	20 / 383 (5.22%)	1 / 42 (2.38%)	0 / 41 (0.00%)	1 / 83 (1.20%)
occurrences all number	1	1	2	2	18	7	25	1	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	5 / 153 (3.27%)	1 / 108 (0.93%)	0 / 105 (0.00%)	1 / 106 (0.94%)	26 / 383 (6.79%)	13 / 250 (5.20%)	37 / 383 (9.66%)	0 / 42 (0.00%)	1 / 41 (2.44%)	1 / 83 (1.20%)
occurrences all number	6	1	0	1	35	15	50	0	1	1
Back pain
subjects affected / exposed	4 / 153 (2.61%)	2 / 108 (1.85%)	4 / 105 (3.81%)	2 / 106 (1.89%)	30 / 383 (7.83%)	21 / 250 (8.40%)	48 / 383 (12.53%)	0 / 42 (0.00%)	1 / 41 (2.44%)	1 / 83 (1.20%)
occurrences all number	4	2	4	2	40	24	64	0	1	1
Pain in extremity
subjects affected / exposed	1 / 153 (0.65%)	1 / 108 (0.93%)	2 / 105 (1.90%)	2 / 106 (1.89%)	16 / 383 (4.18%)	11 / 250 (4.40%)	25 / 383 (6.53%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences all number	1	1	2	3	18	11	29	0	0	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	12 / 153 (7.84%)	10 / 108 (9.26%)	6 / 105 (5.71%)	6 / 106 (5.66%)	82 / 383 (21.41%)	59 / 250 (23.60%)	111 / 383 (28.98%)	0 / 42 (0.00%)	2 / 41 (4.88%)	2 / 83 (2.41%)
occurrences all number	13	10	8	6	145	106	251	0	2	2
Bronchitis
subjects affected / exposed	1 / 153 (0.65%)	0 / 108 (0.00%)	0 / 105 (0.00%)	1 / 106 (0.94%)	17 / 383 (4.44%)	14 / 250 (5.60%)	31 / 383 (8.09%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences all number	1	0	0	1	18	15	33	0	0	0
Influenza
subjects affected / exposed	5 / 153 (3.27%)	1 / 108 (0.93%)	4 / 105 (3.81%)	1 / 106 (0.94%)	36 / 383 (9.40%)	31 / 250 (12.40%)	56 / 383 (14.62%)	0 / 42 (0.00%)	1 / 41 (2.44%)	1 / 83 (1.20%)
occurrences all number	5	1	4	1	46	39	85	0	1	1
Pneumonia
subjects affected / exposed	1 / 153 (0.65%)	0 / 108 (0.00%)	0 / 105 (0.00%)	1 / 106 (0.94%)	11 / 383 (2.87%)	11 / 250 (4.40%)	22 / 383 (5.74%)	0 / 42 (0.00%)	0 / 41 (0.00%)	0 / 83 (0.00%)
occurrences all number	1	0	0	1	13	12	25	0	0	0
Sinusitis
subjects affected / exposed	2 / 153 (1.31%)	2 / 108 (1.85%)	1 / 105 (0.95%)	2 / 106 (1.89%)	30 / 383 (7.83%)	26 / 250 (10.40%)	53 / 383 (13.84%)	1 / 42 (2.38%)	1 / 41 (2.44%)	2 / 83 (2.41%)
occurrences all number	2	2	1	2	40	33	73	1	1	2
Upper respiratory tract infection
subjects affected / exposed	3 / 153 (1.96%)	1 / 108 (0.93%)	2 / 105 (1.90%)	2 / 106 (1.89%)	52 / 383 (13.58%)	53 / 250 (21.20%)	78 / 383 (20.37%)	3 / 42 (7.14%)	2 / 41 (4.88%)	5 / 83 (6.02%)
occurrences all number	3	1	2	2	81	98	179	3	2	5
Urinary tract infection
subjects affected / exposed	1 / 153 (0.65%)	0 / 108 (0.00%)	1 / 105 (0.95%)	1 / 106 (0.94%)	23 / 383 (6.01%)	23 / 250 (9.20%)	41 / 383 (10.70%)	0 / 42 (0.00%)	1 / 41 (2.44%)	1 / 83 (1.20%)
occurrences all number	1	0	1	2	25	32	57	0	1	1

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Were there any global substantial amendments to the protocol? Yes

15 Nov 2013

- Exploratory objective and endpoint regarding change from baseline in monthly average severity of migraine-related symptoms was added. - Removed saliva collection procedures and the associated objective and endpoint. - Modified inclusion and exclusion criteria to remove the exclusion of basilar-type migraine, modified contraception eligibility criterion, adjusted the definition of poorly controlled hypertension, and removed the exception for Gilbert¡'s syndrome in the exclusion criteria. - Added hepatitis reflexive polymerase chain reaction to confirm viral status for hepatitis B and C. - Added chemistry and hematology laboratory assessments at the week 2 study visit. - Added anti-AMG 334 antibody sampling (and associated PK testing) at weeks 2, 4, 8, and 36 study visits and clarified the communication process for antibody results to maintain blinding. - Modified the list of medications excluded during the study and modified the list of medications for which eligible subjects must not have failed due to lack of efficacy in migraine prophylaxis. - Updated AMG 334 background information. - Changed the visit window for the day 1 study visit from ± 3 days to + 7 days. - Removed several limitations for re-screening subjects. - Added details from the Investigational Product Instruction Manual related to the number of investigational product injections and acceptable injection locations. - A closed testing procedure was incorporated to control the family-wise error rate at 0.05 for the primary endpoint. - Implemented minor text clarifications and corrections.

09 Jul 2014

- To allow for the collection of long-term safety, tolerability, and efficacy data beyond 1 year, the open-label treatment phase was extended from 40 weeks to up to 256 weeks. Appropriate changes were made throughout the protocol to reflect this change in duration of the open-label treatment phase. - ECG and laboratory assessments were added in the open-label treatment phase. - A formal interim analysis was added at week 64, to occur once all subjects completed the week 64 study visit. - An Event Adjudication Committee was added for the overall AMG 334 clinical development program to provide a thorough and systematic review and classification of all cardiovascular and cerebrovascular events that may have occurred during the study. - Clarified the testing procedure to be utilized (ie, sequential) to control the family-wise error rate at 0.05 for the primary endpoint. - Certain protocol text was clarified and minor text errors were corrected.

07 Apr 2016

- Increased the dose of erenumab to 140 mg during the open-label phase. - Added a 12-week safety follow-up (16 weeks after the last dose of investigational product). - Added that HIT-6 will be collected every 4 weeks for 52 weeks after dose increase. - Added that laboratory, vital sign, and anti-erenumab antibody data would be collected 12 weeks after the dose increase.

23 May 2017

- Allowed subjects at all sites globally to participate in a single-injection clinical home use substudy.

19 Sep 2017

- Removed the clinical home use substudy as the substudy was no longer necessary. - Added collection of clinical outcomes assessments and patient-reported outcomes up to week 268 to evaluate long-term efficacy. Previously eDiary collection stopped at week 64. Monthly clinical outcome assessments were collected every 24 weeks beginning at the week 188 visit. - Added new packaging of erenumab as prefilled syringes containing 1 mL of 70 mg/mL or 140 mg/mL erenumab. - Added serum pregnancy testing to the safety follow-up visit in the Schedule of Assessment to be consistent with the rest of the protocol. - Clarified language in Section 10.4.4 Final Analysis and Section 10.5.4 Safety Analyses.

08 Mar 2019

- Clarified that commercial erenumab may be used during the safety follow-up period. - Aligned end of study and primary completion language with the current template. - Removed retired language related to self-evident corrections.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results:
A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in Monthly Migraine Days at Week 12

Primary: Change From Baseline in Monthly Migraine Days at Week 12

Primary: CHU Substudy: Percentage of Participants Who Self-administered a Full Dose, Partial Dose, or No Dose of Erenumab

Primary: CHU Substudy: Percentage of Participants Who Self-administered a Full Dose, Partial Dose, or No Dose of Erenumab

Secondary: Percentage of Participants with at Least a 50% Reduction From Baseline in Monthly Migraine Days at Week 12

Secondary: Percentage of Participants with at Least a 50% Reduction From Baseline in Monthly Migraine Days at Week 12

Secondary: Change From Baseline in Monthly Migraine Attacks at Week 12

Secondary: Change From Baseline in Monthly Migraine Attacks at Week 12

Secondary: Number of Participants with Treatment-emergent Adverse Events in the Double-blind Treatment Phase

Secondary: Number of Participants with Treatment-emergent Adverse Events in the Double-blind Treatment Phase

Secondary: Number of Participants with Treatment-emergent Adverse Events in the Open-label Treatment Phase

Secondary: Number of Participants with Treatment-emergent Adverse Events in the Open-label Treatment Phase

Secondary: CHU Substudy: Number of Participants with Treatment-emergent Adverse Events During the CHU Substudy

Secondary: CHU Substudy: Number of Participants with Treatment-emergent Adverse Events During the CHU Substudy

Secondary: Number of Participants who Developed Anti-erenumab Antibodies During the Double-blind Treatment Phase

Secondary: Number of Participants who Developed Anti-erenumab Antibodies During the Double-blind Treatment Phase

Secondary: Number of Participants who Developed Anti-erenumab Antibodies During the Open-label Treatment Phase

Secondary: Number of Participants who Developed Anti-erenumab Antibodies During the Open-label Treatment Phase

Adverse events

Adverse events

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Substantial protocol amendments (globally)

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Clinical trials

Clinical Trial Results: A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in Monthly Migraine Days at Week 12

Primary: Change From Baseline in Monthly Migraine Days at Week 12

Primary: CHU Substudy: Percentage of Participants Who Self-administered a Full Dose, Partial Dose, or No Dose of Erenumab

Primary: CHU Substudy: Percentage of Participants Who Self-administered a Full Dose, Partial Dose, or No Dose of Erenumab

Secondary: Percentage of Participants with at Least a 50% Reduction From Baseline in Monthly Migraine Days at Week 12

Secondary: Percentage of Participants with at Least a 50% Reduction From Baseline in Monthly Migraine Days at Week 12

Secondary: Change From Baseline in Monthly Migraine Attacks at Week 12

Secondary: Change From Baseline in Monthly Migraine Attacks at Week 12

Secondary: Number of Participants with Treatment-emergent Adverse Events in the Double-blind Treatment Phase

Secondary: Number of Participants with Treatment-emergent Adverse Events in the Double-blind Treatment Phase

Secondary: Number of Participants with Treatment-emergent Adverse Events in the Open-label Treatment Phase

Secondary: Number of Participants with Treatment-emergent Adverse Events in the Open-label Treatment Phase

Secondary: CHU Substudy: Number of Participants with Treatment-emergent Adverse Events During the CHU Substudy

Secondary: CHU Substudy: Number of Participants with Treatment-emergent Adverse Events During the CHU Substudy

Secondary: Number of Participants who Developed Anti-erenumab Antibodies During the Double-blind Treatment Phase

Secondary: Number of Participants who Developed Anti-erenumab Antibodies During the Double-blind Treatment Phase

Secondary: Number of Participants who Developed Anti-erenumab Antibodies During the Open-label Treatment Phase

Secondary: Number of Participants who Developed Anti-erenumab Antibodies During the Open-label Treatment Phase

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention