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Clinical Trial Results:
A Phase 4, Randomized, Double-blind, Multicenter, Parallel-group, Active-controlled, Forced-dose Titration, Safety and Efficacy Study of SPD489 (VYVANSE®) Compared With OROS-MPH (CONCERTA®) With a Placebo Reference Arm, in Adolescents Aged 13-17 Years With Attention-deficit/Hyperactivity Disorder (ADHD)

Summary
EudraCT number	2011-005452-34
Trial protocol	DE IT HU SE
Global end of trial date	22 May 2014

Results information
Results version number	v1(current)
This version publication date	04 Sep 2018
First version publication date	20 Mar 2015
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

SPD489-406

ISRCTN number

US NCT number

NCT01552902

WHO universal trial number (UTN)

Sponsor organisation name

Shire Development LLC

Sponsor organisation address

725 Chesterbrook Boulevard, Wayne, Pennsylvania, United States, 19087

Public contact

Medical Communications, Shire Pharmaceutical Development Ltd., +44 8000556614, medinfoglobal@shire.com

Scientific contact

Medical Communications, Shire Pharmaceutical Development Ltd., +44 8000556614, medinfoglobal@shire.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?

Yes

Analysis stage

Final

Date of interim/final analysis

27 Jun 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

22 May 2014

Was the trial ended prematurely?

Main objective of the trial

To evaluate the efficacy of lisdexamfetamine dimesylate 70 milligram (mg) compared with osmotic controlled oral release delivery system-methylphenidate (OROS-MPH) 72 mg in adolescents (13-17 years of age, inclusive) with ADHD.

Protection of trial subjects

This study was conducted in accordance with International Conference on Harmonisation of Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

03 Apr 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 493

Country: Number of subjects enrolled

Canada: 25

Country: Number of subjects enrolled

European Union: 31

Worldwide total number of subjects

549

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

549

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 77 sites in the United States, Canada, and Europe.

Screening details

Of the 778 screened subjects, 229 were screen failures and 549 were randomized to treatment. A total of 547 subjects were treated and the reasons for 2 'randomized but not treated' subjects included withdrawal by 1 subject in the Methylphenidate group and 1 subject with a protocol violation in the Lisdexamfetamine group.

Period 1 title

Overall trial (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

Arm description

2 placebo over encapsulated capsules once daily orally for 6 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

2 placebo over encapsulated capsules once daily orally for 6 weeks.

Lisdexamfetamine dimesylate

Arm description

Lisdexamfetamine dimesylate (LDX, Vyvanse®, SPD489) 30 to 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 4 weeks (forced dose titration), followed by LDX 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 2 weeks (dose maintenance).

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

2 placebo over encapsulated capsules once daily orally for 6 weeks.

Investigational medicinal product name

Lisdexamfetamine dimesylate

Investigational medicinal product code

SPD489

Other name

Elvanse, Tyvense, Vyvanse, LDX

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Methylphenidate

Arm description

Methylphenidate (Concerta, OROS-MPH) 18 to 72 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule (no placebo administered when methylphenidate 72 mg [2*36 mg capsules] was administered) for 4 weeks (forced dose titration), followed by methylphenidate 72 mg (2*36 mg capsules) over encapsulated capsule once daily orally for 2 weeks (dose maintenance).

Arm type

Active comparator

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

2 placebo over encapsulated capsules once daily orally for 6 weeks.

Investigational medicinal product name

Methylphenidate

Investigational medicinal product code

Other name

Concerta, OROS-MPH

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1 ^[1]	Placebo	Lisdexamfetamine dimesylate	Methylphenidate
Started	110	218	219
Completed	97	181	186
Not completed	13	37	33
Consent withdrawn by subject	1	9	6
Protocol violation	3	3	3
Adverse event	1	15	14
Unspecified	3	4	3
Lost to follow-up	1	3	6
Lack of efficacy	4	3	1

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Not all enrolled subjects were treated with study drugs. Since baseline period included only treated subjects, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

2 placebo over encapsulated capsules once daily orally for 6 weeks.

Reporting group title

Lisdexamfetamine dimesylate

Reporting group description

Reporting group title

Methylphenidate

Reporting group description

Reporting group values	Placebo	Lisdexamfetamine dimesylate	Methylphenidate	Total
Number of subjects	110	218	219	547
Age categorical
Age was calculated as the difference between date of birth and date of informed consent. The Safety set consisted of all subjects in the Randomized set (all screened subjects for whom a randomization number was generated) who took at least 1 dose of investigational product.
Units: Subjects
Less Than or Equal to 18 Years	110	218	219	547
Between 18 and 65 Years	0	0	0	0
Greater Than or Equal to 65 Years	0	0	0	0
Age continuous
Age was calculated as the difference between date of birth and date of informed consent. Safety set.
Units: years
arithmetic mean (standard deviation)	14.7 ( 1.37 )	14.6 ( 1.38 )	14.7 ( 1.42 )	-
Gender categorical
Safety set.
Units: Subjects
Female	34	83	69	186
Male	76	135	150	361
ADHD Subtype
Safety set.
Units: Subjects
Predominantly Inattentive	40	70	71	181
Predominantly Hyperactive/Impulsive	2	2	4	8
Combined Subtype	68	146	144	358
Clinical Global Impressions – Severity of Illness (CGI-S)
The Clinical Global Impressions Scale permits a global evaluation of the subject’s severity of illness and improvement over time. The scale includes a severity of illness item and a global improvement item. The investigator performed the CGI-S to rate the severity of a subject’s condition on a 7-point scale (1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; or 7=extremely ill). Safety set.
Units: Subjects
Borderline mentally ill	1	0	0	1
Mildly ill	2	4	1	7
Moderately ill	60	93	115	268
Markedly ill	41	106	90	237
Severely ill	6	15	13	34
Attention-deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) Total Score
The ADHD-RS-IV was developed to measure the behaviors of children with ADHD and is commonly used in clinical studies of ADHD. The ADHD-RS-IV consisted of 18 items designed to reflect current symptomatology of ADHD based on Diagnostic and Statistical Manual of Mental Disorders, 4th Edition-Text Revision (DSM-IV-TR) criteria. Each item was scored on a 4-point scale ranging from 0 (reflecting no symptoms) to 3 (reflecting severe symptoms) with total scores ranging from 0-54, Higher score = more severe symptoms. Safety set.
Units: Units on a scale
arithmetic mean (standard deviation)	36.1 ( 5.91 )	37.2 ( 6.46 )	36.9 ( 6.42 )	-

End points

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Reporting group title

Placebo

Reporting group description

2 placebo over encapsulated capsules once daily orally for 6 weeks.

Reporting group title

Lisdexamfetamine dimesylate

Reporting group description

Reporting group title

Methylphenidate

Reporting group description

Subject analysis set title

Full analysis set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

FAS consisted of a total of 532 subjects (106 in placebo, 210 in Lisdexamfetamine dimesylate, and 216 in Methylphenidate) which was defined as all subjects in the Safety set who had at least 1 post-baseline measurement of the ADHD-RS-IV.

Primary: Change From Baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale, Fourth Edition (ADHD-RS-IV) Total Score at Week 6

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End point title

Change From Baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale, Fourth Edition (ADHD-RS-IV) Total Score at Week 6

End point description

The ADHD-RS-IV was developed to measure the behaviors of children with ADHD and is commonly used in clinical studies of ADHD. The ADHD-RS-IV consisted of 18 items designed to reflect current symptomatology of ADHD based on Diagnostic and Statistical Manual of Mental Disorders, 4th Edition-Text Revision (DSM-IV-TR) criteria. Each item was scored on a 4-point scale ranging from 0 (reflecting no symptoms) to 3 (reflecting severe symptoms) with total scores ranging from 0-54, Higher score = more severe symptoms. FAS.

End point type

Primary

End point timeframe

Baseline, Week 6

End point values	Placebo	Lisdexamfetamine dimesylate	Methylphenidate
Number of subjects analysed	93 ^[1]	175 ^[2]	181 ^[3]
Units: Units on a scale
least squares mean (standard error)	-17 ( 1.03 )	-25.4 ( 0.74 )	-22.1 ( 0.73 )

Notes
[1] - Not all FAS subjects were evaluable for this endpoint.
[2] - Not all FAS subjects were evaluable for this endpoint.
[3] - Not all FAS subjects were evaluable for this endpoint.

Lisdexamfetamine versus Methylphenidate

Statistical analysis description

The least squares mean (LSM), the difference in LSM and its 95% confidence interval (CI), and the p-value were from a mixed effects model for repeated measures that included treatment group, visit, interaction of the treatment group with the visit as factors, baseline score as a covariate, and an adjustment for the interaction of the baseline score with the visit. The model was based on Restricted maximum likelihood (REML) method of estimation and utilized an unstructured covariance.

Comparison groups

Lisdexamfetamine dimesylate v Methylphenidate

Number of subjects included in analysis

356

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0013

Method

Mixed models analysis

Parameter type

Difference in LSM

Point estimate

-3.4

Confidence interval

level

95%

sides

2-sided

lower limit

-5.4

upper limit

-1.3

Methylphenidate versus Placebo

Statistical analysis description

The LSM, the difference in LSM and its 95% CI, and the p-value were from a mixed effects model for repeated measures that includes treatment group, visit, interaction of the treatment group with the visit as factors, baseline score as a covariate, and an adjustment for the interaction of the baseline score with the visit. The model was based on REML method of estimation and utilized an unstructured covariance.

Comparison groups

Methylphenidate v Placebo

Number of subjects included in analysis

274

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Difference in LSM

Point estimate

-5.1

Confidence interval

level

95%

sides

2-sided

lower limit

-7.6

upper limit

-2.6

Lisdexamfetamine versus Placebo

Statistical analysis description

The LSM, the difference in LSM and its 95% CI, and the p-value were from a mixed effects model for repeated measures that included treatment group, visit, interaction of the treatment group with the visit as factors, baseline score as a covariate, and an adjustment for the interaction of the baseline score with the visit. The model was based on REML method of estimation and utilized an unstructured covariance.

Comparison groups

Lisdexamfetamine dimesylate v Placebo

Number of subjects included in analysis

268

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Difference in LSM

Point estimate

-8.5

Confidence interval

level

95%

sides

2-sided

lower limit

-11

upper limit

-6

Secondary: Percentage of Subjects With an Improved Measurement in the Clinical Global Impression - Global Improvement (CGI-I) at Week 6

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End point title

Percentage of Subjects With an Improved Measurement in the Clinical Global Impression - Global Improvement (CGI-I) at Week 6

End point description

The Clinical Global Impressions Scale permits a global evaluation of the subject’s severity of illness and improvement over time. The scale included a severity of illness item and a global improvement item. The investigator performed the CGI-I to rate the improvement of a subject’s ADHD symptoms based on a 7-point scale (1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; or 7=very much worse.). Percentage of subjects with an improved measurement (response of very much improved and much improved) is reported. FAS.

End point type

Secondary

End point timeframe

Week 6

End point values	Placebo	Lisdexamfetamine dimesylate	Methylphenidate
Number of subjects analysed	106	210	216
Units: Percentage of subjects
number (not applicable)	50	81.4	71.3

No statistical analyses for this end point

Other pre-specified: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs

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End point title

Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs

End point description

An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation subject administered as a pharmaceutical product that did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were events between first dose of double-blind investigational product and up to 3 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Safety set.

End point type

Other pre-specified

End point timeframe

Baseline up to 3 days after last dose (last dose at Week 6)

End point values	Placebo	Lisdexamfetamine dimesylate	Methylphenidate
Number of subjects analysed	110	218	219
Units: Subjects
Subjects with TEAEs	49	145	129
Subjects with serious TEAEs	1	1	1

No statistical analyses for this end point

Other pre-specified: Change From Baseline in Blood Pressure at Week 6

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End point title

Change From Baseline in Blood Pressure at Week 6

End point description

Safety set.

End point type

Other pre-specified

End point timeframe

Baseline, Week 6

End point values	Placebo	Lisdexamfetamine dimesylate	Methylphenidate
Number of subjects analysed	93 ^[4]	175 ^[5]	181 ^[6]
Units: millimeter of mercury (mmHg)
arithmetic mean (standard deviation)
Systolic blood pressure	-1 ( 9.88 )	1.5 ( 9.56 )	2.4 ( 9.97 )
Diastolic blood pressure	-0.1 ( 8.1 )	3.4 ( 8.15 )	3.5 ( 8.59 )

Notes
[4] - Not all Safety set subjects were evaluable for this endpoint.
[5] - Not all Safety set subjects were evaluable for this endpoint.
[6] - Not all Safety set subjects were evaluable for this endpoint.

No statistical analyses for this end point

Other pre-specified: Change from Baseline in Pulse Rate at Week 6

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End point title

Change from Baseline in Pulse Rate at Week 6

End point description

Safety set.

End point type

Other pre-specified

End point timeframe

Baseline, Week 6

End point values	Placebo	Lisdexamfetamine dimesylate	Methylphenidate
Number of subjects analysed	93 ^[7]	175 ^[8]	181 ^[9]
Units: Beats per minute
arithmetic mean (standard deviation)	2.4 ( 10.81 )	6.7 ( 12.46 )	8.2 ( 12.7 )

Notes
[7] - Not all Safety set subjects were evaluable for this endpoint.
[8] - Not all Safety set subjects were evaluable for this endpoint.
[9] - Not all Safety set subjects were evaluable for this endpoint.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to 3 days after last dose (last dose at Week 6)

Adverse event reporting additional description

AEs occurred during the double-blind evaluation phase were considered as TEAEs if AEs had a start date on or after the first dose of double-blind study drug or a start date before the date of the first dose of double-blind study drug, but increased in severity on or after the date of the first dose of double-blind study drug. Safety set.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.0

Reporting group title

Placebo

Reporting group description

2 placebo over encapsulated capsules once daily orally for 6 weeks.

Reporting group title

Methylphenidate

Reporting group description

Reporting group title

Lisdexamfetamine dimesylate

Reporting group description

Serious adverse events	Placebo	Methylphenidate	Lisdexamfetamine dimesylate
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 110 (0.91%)	1 / 219 (0.46%)	1 / 218 (0.46%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events
Psychiatric disorders
Suicidal ideation
subjects affected / exposed	0 / 110 (0.00%)	0 / 219 (0.00%)	1 / 218 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychotic episode
subjects affected / exposed	1 / 110 (0.91%)	0 / 219 (0.00%)	0 / 218 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 110 (0.00%)	1 / 219 (0.46%)	0 / 218 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Placebo	Methylphenidate	Lisdexamfetamine dimesylate
Total subjects affected by non serious adverse events
subjects affected / exposed	32 / 110 (29.09%)	99 / 219 (45.21%)	113 / 218 (51.83%)
Investigations
Weight decreased
subjects affected / exposed	0 / 110 (0.00%)	11 / 219 (5.02%)	23 / 218 (10.55%)
occurrences all number	0	11	23
Nervous system disorders
Headache
subjects affected / exposed	9 / 110 (8.18%)	35 / 219 (15.98%)	33 / 218 (15.14%)
occurrences all number	13	40	45
Dizziness
subjects affected / exposed	0 / 110 (0.00%)	11 / 219 (5.02%)	12 / 218 (5.50%)
occurrences all number	0	11	12
General disorders and administration site conditions
Irritability
subjects affected / exposed	7 / 110 (6.36%)	15 / 219 (6.85%)	11 / 218 (5.05%)
occurrences all number	7	16	11
Gastrointestinal disorders
Dry mouth
subjects affected / exposed	1 / 110 (0.91%)	7 / 219 (3.20%)	16 / 218 (7.34%)
occurrences all number	1	7	18
Nausea
subjects affected / exposed	3 / 110 (2.73%)	11 / 219 (5.02%)	11 / 218 (5.05%)
occurrences all number	3	11	12
Abdominal pain upper
subjects affected / exposed	2 / 110 (1.82%)	8 / 219 (3.65%)	11 / 218 (5.05%)
occurrences all number	2	8	11
Psychiatric disorders
Insomnia
subjects affected / exposed	3 / 110 (2.73%)	17 / 219 (7.76%)	17 / 218 (7.80%)
occurrences all number	3	20	17
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	11 / 110 (10.00%)	51 / 219 (23.29%)	69 / 218 (31.65%)
occurrences all number	11	52	74

More information

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Were there any global substantial amendments to the protocol? Yes

15 Mar 2012

Revision of Inclusion Criterion at the request of the Institutional Review Board to indicate that blood pressure measurements should not exceed the 90th percentile.

26 Aug 2012

1. Increased number of sites from 55 to approximately 65 to support study recruitment 2. Replaced World Health Organization body mass index (BMI) values with Centers for Disease Control and Prevention (CDC) BMI values 3. Revision of reporting instructions for the treatment assignment to be unblinded as soon as possible after the investigator was unblinded 4. Changed the start of the screening and washout phase from 7-28 days to 3-28 days prior to the baseline visit (Visit 0) to address day of enrolment for subjects who did not require a medication washout 5. Clarification that the washout telephone call was applicable to all subjects. Modified washout telephone call procedures 6. Modification that subjects accepted to participate in the pharmacogenomic substudy signed the pharmacogenomic informed consent and assent 7. Revision to include provision for additional care of subjects after the study.

04 Jan 2013

1. Addition of Europe and Canada to support study recruitment 2. Addition of text indicating randomization would be stratified by geographic region 3. Revision of text regarding Shire’s serious adverse event (SAE) reporting information 4. Clarification that timeframe for reporting SAEs was 24 hours (rather than 1 business day) to comply with Medicines and Healthcare Products Regulatory Agency (United Kingdom) 5. Addition of Inclusion Criterion to allow subjects not completely satisfied with aspects of their current ADHD therapy to participate in the study 6. Removal of Exclusion Criterion that disqualified subjects who were well-controlled on their current ADHD medication with acceptable tolerability 7. Increased the number of sites from 65 to approximately 80 to account for the addition of Europe and Canada 8. Inclusion of updated information regarding the definition, period of observation, and recording of AEs 9. Addition of text to indicate that a change in a vital sign or ECG value could represent an AE if clinically relevant 10. Specification of information related to inpatient hospitalization or prolongation of existing hospitalization for SAEs.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale, Fourth Edition (ADHD-RS-IV) Total Score at Week 6

Primary: Change From Baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale, Fourth Edition (ADHD-RS-IV) Total Score at Week 6

Secondary: Percentage of Subjects With an Improved Measurement in the Clinical Global Impression - Global Improvement (CGI-I) at Week 6

Secondary: Percentage of Subjects With an Improved Measurement in the Clinical Global Impression - Global Improvement (CGI-I) at Week 6

Other pre-specified: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs

Other pre-specified: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs

Other pre-specified: Change From Baseline in Blood Pressure at Week 6

Other pre-specified: Change From Baseline in Blood Pressure at Week 6

Other pre-specified: Change from Baseline in Pulse Rate at Week 6

Other pre-specified: Change from Baseline in Pulse Rate at Week 6

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA