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Clinical Trial Results:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-Center Trial to Evaluate the Efficacy and Safety of a Single Treatment of DaxibotulinumtoxinA for Injection in Adults with Isolated Cervical Dystonia (ASPEN-1)

Summary
EudraCT number	2018-000446-19
Trial protocol	AT FR GB IT
Global end of trial date	16 Jun 2020

Results information
Results version number	v1(current)
This version publication date	04 May 2023
First version publication date	04 May 2023
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

1720302

ISRCTN number

US NCT number

NCT03608397

WHO universal trial number (UTN)

Sponsor organisation name

Revance Therapeutics Inc

Sponsor organisation address

7555 Gateway Blvd. Newark, CA, United States, 94560

Public contact

Regulatory Affairs Manager, Revance Therapeutics Inc, +1 5107423557, jlintao@revance.com

Scientific contact

Domenico Vitarella, Sr. Director, Clinical Development, Revance Therapeutics Inc, +1 510-742-3400, dvitarella@revance.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

16 Jun 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

16 Jun 2020

Was the trial ended prematurely?

Main objective of the trial

To compare the efficacy of a high and low dose of daxibotulinumtoxinA (DAXI) for injection (250 unit [botulinum toxin] [U]; 125 U) relative to placebo, and to each other, in adults with moderate to severe, isolated cervical dystonia (CD).

Protection of trial subjects

This study was conducted in accordance with the accepted version of the Declaration of Helsinki, in compliance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, and according to the appropriate regulatory requirements in the countries where the study was conducted.

Background therapy

Evidence for comparator

Actual start date of recruitment

20 Jun 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 61

Country: Number of subjects enrolled

United Kingdom: 4

Country: Number of subjects enrolled

Austria: 2

Country: Number of subjects enrolled

Czechia: 20

Country: Number of subjects enrolled

France: 7

Country: Number of subjects enrolled

Germany: 10

Country: Number of subjects enrolled

Canada: 1

Country: Number of subjects enrolled

United States: 186

Country: Number of subjects enrolled

Spain: 10

Worldwide total number of subjects

301

EEA total number of subjects

110

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)

206

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This study was conducted at total of 60 sites in 9 countries from 20 June 2018 to 16 June 2020.

Screening details

A total of the 444 subjects were screened for this study, of which 301 were randomised and received study drug.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm description

Subjects received placebo matched to DAXI 125 U, intramuscular (IM) injection, once on Day 1.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Placebo, 2.5 mL of reconstituted clear, colorless solution injection, administered via IM route.

DAXI 125 U

Arm description

Subjects received DAXI 125 U, IM injection, once on Day 1.

Arm type

Experimental

Investigational medicinal product name

DAXI 125 U

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

DAXI 125 U, 2.5 mL of reconstituted clear, colorless solution injection, administered via IM route.

DAXI 250 U

Arm description

Subjects received DAXI 250 U, IM injection, once on Day 1.

Arm type

Experimental

Investigational medicinal product name

DAXI 250 U

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

DAXI 250 U, 2.5 mL of reconstituted clear, colorless solution injection, administered via IM route.

Number of subjects in period 1	Placebo	DAXI 125 U	DAXI 250 U
Started	46	125	130
Completed	45	120	126
Not completed	1	5	4
Consent withdrawn by subject	1	3	2
Adverse event, non-fatal	-	-	1
Death	-	1	-
Unspecified	-	-	1
Other-Unspecified	-	1	-

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Subjects received placebo matched to DAXI 125 U, intramuscular (IM) injection, once on Day 1.

Reporting group title

DAXI 125 U

Reporting group description

Subjects received DAXI 125 U, IM injection, once on Day 1.

Reporting group title

DAXI 250 U

Reporting group description

Subjects received DAXI 250 U, IM injection, once on Day 1.

Reporting group values	Placebo	DAXI 125 U	DAXI 250 U	Total
Number of subjects	46	125	130	301
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	34	82	90	206
From 65-84 years	12	43	40	95
85 years and over	0	0	0	0
Age continuous
Units: years
arithmetic mean (full range (min-max))	56.5 (29.0 to 80.0)	57.4 (18.0 to 80.0)	58.5 (30.0 to 79.0)	-
Gender categorical
Units: Subjects
Female	29	87	79	195
Male	17	38	51	106
Race
Units: Subjects
White	43	118	126	287
Black	2	3	1	6
Asian	1	1	1	3
American Indian or Alaska Native	0	0	1	1
Native Hawaiian or Other Pacific Islander	0	1	0	1
Other	0	2	1	3
Ethnicity
Units: Subjects
Hispanic or Latino	4	4	7	15
Not Hispanic or Latino	41	119	123	283
Not Provided	1	2	0	3

End points

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Reporting group title

Placebo

Reporting group description

Subjects received placebo matched to DAXI 125 U, intramuscular (IM) injection, once on Day 1.

Reporting group title

DAXI 125 U

Reporting group description

Subjects received DAXI 125 U, IM injection, once on Day 1.

Reporting group title

DAXI 250 U

Reporting group description

Subjects received DAXI 250 U, IM injection, once on Day 1.

Primary: Average Change From Baseline in Total Score of Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) at Weeks 4 and 6

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End point title

Average Change From Baseline in Total Score of Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) at Weeks 4 and 6

End point description

The TWSTRS is a composite assessment scale that covers different features of CD. The scale evaluates the severity of dystonia, patient-perceived disability from dystonia, and pain. The TWSTRS total score is the sum of the TWSTRS severity score (0–35), the TWSTRS disability score (0–30), and the TWSTRS pain score (0–20), and ranges from 0 to 85. The higher score indicates worst outcomes, and a negative change indicates better outcomes. The ITT population was defined as all subjects who were randomised and received study injections in this study. Here, "number of subjects analysed" signifies those subjects who were evaluable for this endpoint. Average change from baseline data of Weeks 4 and 6 were presented.

End point type

Primary

End point timeframe

Baseline, Weeks 4 and 6

End point values	Placebo	DAXI 125 U	DAXI 250 U
Number of subjects analysed	46	125	130
Units: score on a scale
least squares mean (standard error)	-4.3 ( 1.82 )	-12.7 ( 1.30 )	-10.9 ( 1.25 )

DAXI 125 U vs. Placebo

Statistical analysis description

Statistical data of average change from baseline of Weeks 4 and 6 were reported.

Comparison groups

Placebo v DAXI 125 U

Number of subjects included in analysis

171

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001 ^[1]

Method

ANCOVA

Parameter type

Least Square Mean (LSM) Difference

Point estimate

-8.5

Confidence interval

level

95%

sides

2-sided

lower limit

-12.3

upper limit

-4.7

Variability estimate

Standard error of the mean

Dispersion value

1.93

Notes
[1] - p-value was based on average change from baseline of weeks 4 and 6 were as per ANCOVA model with terms for treatment.

DAXI 250 U vs. Placebo

Statistical analysis description

Statistical data of average change from baseline of Weeks 4 and 6 were reported.

Comparison groups

Placebo v DAXI 250 U

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0006 ^[2]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-6.6

Confidence interval

level

95%

sides

2-sided

lower limit

-10.4

upper limit

-2.9

Variability estimate

Standard error of the mean

Dispersion value

1.92

Notes
[2] - p-value was based on average change from baseline of weeks 4 and 6 were as per ANCOVA model with terms for treatment.

DAXI 250 U vs. DAXI 125 U

Comparison groups

DAXI 125 U v DAXI 250 U

Number of subjects included in analysis

255

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1902 ^[3]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

4.6

Variability estimate

Standard error of the mean

Dispersion value

1.4

Notes
[3] - p-value was based on average change from baseline of weeks 4 and 6 were as per ANCOVA model with terms for treatment.

Secondary: Change From Baseline in Total Score of TWSTRS at Weeks 2, 4, 6, 12, 16, 20, 24,28, 32 and 36

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End point title

Change From Baseline in Total Score of TWSTRS at Weeks 2, 4, 6, 12, 16, 20, 24,28, 32 and 36

End point description

The TWSTRS is a composite assessment scale that covers different features of cervical dystonia (CD). The scale evaluates the severity of dystonia, patient-perceived disability from dystonia, and pain. The TWSTRS total score is the sum of the TWSTRS severity score (0–35), the TWSTRS disability score (0–30), and the TWSTRS pain score (0–20), and ranges from 0 to 85. The higher score indicates worst outcomes and a negative change indicates better outcomes. The ITT population was defined as all subjects who were randomised and received study injections in this study. Here, "number of subjects analysed" signifies those subjects who were evaluable for this endpoint and "n" refer to number of subjects who were subjects evaluable for given timepoints.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 6, 12, 16, 20, 24, 28, 32 and 36

End point values	Placebo	DAXI 125 U	DAXI 250 U
Number of subjects analysed	46	123	128
Units: score on a scale
arithmetic mean (standard deviation)
Week 2 (n=46, 123, 127)	-5.97 ( 8.442 )	-11.14 ( 10.325 )	-8.01 ( 8.849 )
Week 4 (n=46, 123, 127)	-5.63 ( 9.226 )	-13.67 ( 11.960 )	-11.54 ( 10.921 )
Week 6 (n=46, 123, 128)	-5.02 ( 11.450 )	-13.16 ( 12.533 )	-11.19 ( 12.295 )
Week 12 (n=21, 91, 94)	-11.05 ( 10.323 )	-13.53 ( 10.935 )	-10.85 ( 9.630 )
Week 16 (n=15, 65, 60)	-8.53 ( 8.404 )	-14.24 ( 9.902 )	-10.76 ( 11.606 )
Week 20 (n=11, 47, 41)	-8.17 ( 8.695 )	-12.96 ( 11.230 )	-10.92 ( 10.624 )
Week 24 (n=7, 28, 23)	-5.89 ( 7.738 )	-13.77 ( 10.963 )	-9.41 ( 13.630 )
Week 28 (n=4, 19, 15)	-8.68 ( 4.460 )	-15.38 ( 10.048 )	-9.68 ( 15.921 )
Week 32 (n=4, 13, 7)	-8.05 ( 5.645 )	-16.81 ( 10.651 )	-16.99 ( 12.936 )
Week 36 (n=3, 11, 4)	-7.60 ( 6.643 )	-13.59 ( 7.702 )	-16.40 ( 10.072 )

No statistical analyses for this end point

Secondary: Duration of Effect

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End point title

Duration of Effect

End point description

Duration of effect was defined as time in weeks from treatment to loss of at least 80 percent (%) of the peak treatment effect achieved at Weeks 4 and 6 (that is, the target TWSTRS score). The TWSTRS-total score that was consistent with loss of at least 80% of the peak treatment effect called the target TWSTRS score. The ITT population was defined as all subjects who were randomised and received study injections in this study. Here, "number of subjects analysed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline up to Week 36

End point values	Placebo	DAXI 125 U	DAXI 250 U
Number of subjects analysed	16	43	62
Units: weeks
median (confidence interval 95%)	20.1 (16.1 to 24.4)	24.0 (20.3 to 29.1)	20.3 (16.7 to 24.0)

No statistical analyses for this end point

Secondary: Percentage of Subjects With at Least 2-point Improvement on Clinical Global Impression of Change (CGIC) Scale at Week 4 or 6

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End point title

Percentage of Subjects With at Least 2-point Improvement on Clinical Global Impression of Change (CGIC) Scale at Week 4 or 6

End point description

Improvement is defined as a response of moderately better (+2) or very much better (+3) at Week 4 or Week 6. The CGIC is a questionnaire that captures the clinician’s overall impression of the subject’s response to study treatment. The clinician’s selected response maps to a 7-point scale: negative (-) 3 (very much worse), 0 (about the same), to positive (+) 3 (very much better). The higher score indicates better outcomes. The ITT population was defined as all subjects who were randomised and received study injections in this study. Here, "number of subjects analysed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

At Week 4 or 6

End point values	Placebo	DAXI 125 U	DAXI 250 U
Number of subjects analysed	46	124	130
Units: percentage of subjects
number (confidence interval 95%)	28.3 (15.2 to 41.3)	60.8 (52.7 to 69.9)	56.9 (48.4 to 65.4)

DAXI 125 U vs. Placebo

Comparison groups

Placebo v DAXI 125 U

Number of subjects included in analysis

170

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0001

Method

Cochran-Mantel-Haenszel

Confidence interval

DAXI 250 U vs. Placebo

Comparison groups

Placebo v DAXI 250 U

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0009

Method

Cochran-Mantel-Haenszel

Confidence interval

DAXI 250 U vs. DAXI 125 U

Comparison groups

DAXI 125 U v DAXI 250 U

Number of subjects included in analysis

254

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.4801

Method

Cochran-Mantel-Haenszel

Confidence interval

Secondary: Percentage of Subjects With at Least 2-point Improvement on Patient Global Impression of Change (PGIC) at Week 4 or 6

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End point title

Percentage of Subjects With at Least 2-point Improvement on Patient Global Impression of Change (PGIC) at Week 4 or 6

End point description

Improvement is defined as a response of moderately better (+2) or very much better (+3) at Week 4 or Week 6. The PGIC is a questionnaire that captures the subject’s overall impression of their response to study treatment. The subject’s selected response maps to a 7-point scale: -3 (very much worse), 0 (about the same), to +3 (very much better). A higher score indicates better outcomes. The ITT population was defined as all subjects who were randomised and received study injections in this study. Here, "number of subjects analysed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

At Week 4 or 6

End point values	Placebo	DAXI 125 U	DAXI 250 U
Number of subjects analysed	46	124	130
Units: percentage of subjects
number (confidence interval 95%)	21.7 (9.8 to 33.7)	53.6 (45.3 to 62.8)	50.8 (42.2 to 59.4)

DAXI 125 U vs. Placebo

Comparison groups

Placebo v DAXI 125 U

Number of subjects included in analysis

170

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0002

Method

Cochran-Mantel-Haenszel

Confidence interval

DAXI 250 U vs. Placebo

Comparison groups

Placebo v DAXI 250 U

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0007

Method

Cochran-Mantel-Haenszel

Confidence interval

DAXI 250 U vs. DAXI 125 U

Comparison groups

DAXI 125 U v DAXI 250 U

Number of subjects included in analysis

254

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.6034

Method

Cochran-Mantel-Haenszel

Confidence interval

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

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End point title

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

End point description

A TEAE was any untoward medical occurrence (example, sign, symptom, disease, syndrome, intercurrent illness, clinically significant abnormal laboratory finding, injury, or accident) that emerged or worsened following administration of study drug and until end of study participation. The untoward medical occurrence might not necessarily have a causal relationship to the administration of the investigational product. SAE: event resulted in any of following: Death; life-threatening; persistent or significant disability/incapacity or substantial disruption of the subject’s ability to carry out normal life functions; required in-patient hospitalisation or prolonged hospitalisation; congenital anomaly/birth defect; did not meet any of above serious criteria, but based upon appropriate clinical judgment could have jeopardised subject or required medical or surgical intervention to prevent one of outcomes listed above. Safety population: All randomised subjects who received study injections.

End point type

Secondary

End point timeframe

Baseline up to Week 36

End point values	Placebo	DAXI 125 U	DAXI 250 U
Number of subjects analysed	46	125	130
Units: subjects
TEAEs	18	74	64
SAE	0	5	3

No statistical analyses for this end point

Secondary: Number of Subjects With Serum Neutralizing Antibodies for DAXI

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End point title

Number of Subjects With Serum Neutralizing Antibodies for DAXI

End point description

Positive neutralising antibodies for DAXI were reported in this endpoint. The safety population was defined as all randomised subjects who received study injections. Here, "number of subjects analysed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline up to Week 36

End point values	Placebo	DAXI 125 U	DAXI 250 U
Number of subjects analysed	46	125	130
Units: subjects	0	0	1

No statistical analyses for this end point

Secondary: Number of Subjects With Clinically Significant Changes in Pulmonary Function by Spirometry

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End point title

Number of Subjects With Clinically Significant Changes in Pulmonary Function by Spirometry

End point description

The safety population was defined as all randomized subjects who received study injections.

End point type

Secondary

End point timeframe

Baseline up to Week 36

End point values	Placebo	DAXI 125 U	DAXI 250 U
Number of subjects analysed	46	125	130
Units: subjects	0	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to Week 36

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Placebo

Reporting group description

Subjects received placebo matched to DAXI 125 U, IM injection, once on Day 1.

Reporting group title

DAXI 125 U

Reporting group description

Subjects received DAXI 125 U, IM injection, once on Day 1.

Reporting group title

DAXI 250 U

Reporting group description

Subjects received DAXI 250 U, IM injection, once on Day 1.

Serious adverse events	Placebo	DAXI 125 U	DAXI 250 U
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 46 (0.00%)	5 / 125 (4.00%)	3 / 130 (2.31%)
number of deaths (all causes)	0	1	0
number of deaths resulting from adverse events	0	0	0
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 46 (0.00%)	0 / 125 (0.00%)	1 / 130 (0.77%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular extrasystoles
subjects affected / exposed	0 / 46 (0.00%)	0 / 125 (0.00%)	1 / 130 (0.77%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Transient global amnesia
subjects affected / exposed	0 / 46 (0.00%)	0 / 125 (0.00%)	1 / 130 (0.77%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 46 (0.00%)	0 / 125 (0.00%)	1 / 130 (0.77%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 46 (0.00%)	1 / 125 (0.80%)	0 / 130 (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
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 46 (0.00%)	1 / 125 (0.80%)	0 / 130 (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
Psychiatric disorders
Depression
subjects affected / exposed	0 / 46 (0.00%)	1 / 125 (0.80%)	0 / 130 (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
Renal and urinary disorders
Renal tubular injury
subjects affected / exposed	0 / 46 (0.00%)	1 / 125 (0.80%)	0 / 130 (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
Infections and infestations
Urinary tract infection
subjects affected / exposed	0 / 46 (0.00%)	1 / 125 (0.80%)	0 / 130 (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: 3%

Non-serious adverse events	Placebo	DAXI 125 U	DAXI 250 U
Total subjects affected by non serious adverse events
subjects affected / exposed	10 / 46 (21.74%)	42 / 125 (33.60%)	41 / 130 (31.54%)
Nervous system disorders
Headache
subjects affected / exposed	1 / 46 (2.17%)	11 / 125 (8.80%)	9 / 130 (6.92%)
occurrences all number	1	11	10
General disorders and administration site conditions
Injection site pain
subjects affected / exposed	2 / 46 (4.35%)	10 / 125 (8.00%)	7 / 130 (5.38%)
occurrences all number	2	12	9
Injection site erythema
subjects affected / exposed	1 / 46 (2.17%)	6 / 125 (4.80%)	3 / 130 (2.31%)
occurrences all number	1	6	3
Gastrointestinal disorders
Dysphagia
subjects affected / exposed	0 / 46 (0.00%)	2 / 125 (1.60%)	5 / 130 (3.85%)
occurrences all number	0	2	6
Nausea
subjects affected / exposed	2 / 46 (4.35%)	1 / 125 (0.80%)	1 / 130 (0.77%)
occurrences all number	2	1	1
Musculoskeletal and connective tissue disorders
Musculoskeletal pain
subjects affected / exposed	0 / 46 (0.00%)	5 / 125 (4.00%)	5 / 130 (3.85%)
occurrences all number	0	5	5
Muscular weakness
subjects affected / exposed	0 / 46 (0.00%)	6 / 125 (4.80%)	3 / 130 (2.31%)
occurrences all number	0	6	3
Neck pain
subjects affected / exposed	2 / 46 (4.35%)	5 / 125 (4.00%)	4 / 130 (3.08%)
occurrences all number	2	6	4
Spinal pain
subjects affected / exposed	1 / 46 (2.17%)	3 / 125 (2.40%)	4 / 130 (3.08%)
occurrences all number	1	3	6
Back pain
subjects affected / exposed	2 / 46 (4.35%)	1 / 125 (0.80%)	2 / 130 (1.54%)
occurrences all number	2	1	2
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	2 / 46 (4.35%)	2 / 125 (1.60%)	7 / 130 (5.38%)
occurrences all number	2	2	7
Nasopharyngitis
subjects affected / exposed	0 / 46 (0.00%)	4 / 125 (3.20%)	3 / 130 (2.31%)
occurrences all number	0	4	3

More information

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Were there any global substantial amendments to the protocol? Yes

02 Feb 2018

Modified the protocol title. • Changed the medical monitor. • Modified the study design: o Changed sample size from 180 to 301 subjects. o Expanded participating countries to include Europe. • Changed the number of planned sites from 50 to approximately 80 sites. • Modified the study objectives. • Modified the primary, secondary, and exploratory endpoints. • Changed the number of scheduled visits from 17 to 12 visits. • Modified the screening period from 2 to 3 weeks. • Modified the schedule of assessments. • Modified the PGIC and CGIC scales from 9-point to 7-point scales. • Updated safety evaluations (added spirometry and DSS). • Modified and updated inclusion and exclusion criteria. • Limited the dose of drug to be injected into each targeted muscle to minimum and maximum ranges; modified the Injectable Muscles and Injection Volume by Muscle Table. • Modified the scientific rationale and dose justification to match updates. • Updated the list of prohibited medications. • Added the Cervical Dystonia Impact Profile (CDIP)-58, Treatment Satisfaction Questionnaire (TSQ), Work Productivity and Activity Impairment (WPAI) questionnaire, and Short Form-36 Survey (SF-36) survey.

26 Mar 2018

• Clarified inclusion and exclusion criteria; added 1 exclusion criterion. • Clarified sections describing study intervention. • Updated secondary and exploratory endpoints. • Clarified study assessment sections and moved some examples and scales to the appendices. • Reorganized the statistical analysis section to align with headings of ICHe9 guidance. • Added prior treatment experience, age, and gender as sub-analyses to the primary endpoint as exploratory endpoints. • Made wording changes to endpoints and sample size justification for clarification. • Clarified muscles for injections. • Clarified BoNT and BoNTA and made global terminology changes for clarification: DAXI to DAXI for injection, total TWSTRS score to TWSTRS-total score, medical judgment to clinical judgment.

16 May 2018

• Added more information about Study RT002-CL005 to the introduction. • Added dysphagia as a known potential risk. • Updated study design section for clarification. • Clarified Inclusion Criterion #2. • Updated Exclusion Criteria #6, #8, #10, #14, #17, and #20. • Updated text about allowed concomitant medications; for focal dystonia treatments, amended time for stable dose requirement from 3 months to 4 weeks. • Amended recruitment and retention strategies section. • Clarified study intervention sections. • Amended pregnancy section. • Updated UPs section to align with guidance from regulatory authorities and added suspected unexpected serious adverse reaction (SUSAR) information. • Clarified sections about end-of-study (EOS), TWSTRS, AE expectedness, follow-up of non-SAEs, and follow-up of post-study SAEs. • In the statistical analysis section, added objectives with endpoints and clarified secondary efficacy endpoints. • Updated information for key study personnel. • Clarified instructions for injecting muscles.

27 Jun 2018

• Clarified inclusion criteria. • Clarified that a subject who had no reduction or an increase from baseline in the average TWSTRS-total score at Weeks 4 and 6 was the same as a subject who had a lack of efficacy. • Added information to the justification for dosing, randomization, blinding sections for clarification. • Added the TWSTRS rater certification examination. • Added information to the sample size justification. • Updated information for key study personnel.

10 Jul 2019

• Added National Clinical Trial Identified Number: NCT03608397. • Added a blood sample for antibody testing at Week 2 and Week 4. • Updated Medical Monitor’s information.

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 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-Center Trial to Evaluate the Efficacy and Safety of a Single Treatment of DaxibotulinumtoxinA for Injection in Adults with Isolated Cervical Dystonia (ASPEN-1)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Average Change From Baseline in Total Score of Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) at Weeks 4 and 6

Primary: Average Change From Baseline in Total Score of Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) at Weeks 4 and 6

Secondary: Change From Baseline in Total Score of TWSTRS at Weeks 2, 4, 6, 12, 16, 20, 24,28, 32 and 36

Secondary: Change From Baseline in Total Score of TWSTRS at Weeks 2, 4, 6, 12, 16, 20, 24,28, 32 and 36

Secondary: Duration of Effect

Secondary: Duration of Effect

Secondary: Percentage of Subjects With at Least 2-point Improvement on Clinical Global Impression of Change (CGIC) Scale at Week 4 or 6

Secondary: Percentage of Subjects With at Least 2-point Improvement on Clinical Global Impression of Change (CGIC) Scale at Week 4 or 6

Secondary: Percentage of Subjects With at Least 2-point Improvement on Patient Global Impression of Change (PGIC) at Week 4 or 6

Secondary: Percentage of Subjects With at Least 2-point Improvement on Patient Global Impression of Change (PGIC) at Week 4 or 6

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

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

Secondary: Number of Subjects With Serum Neutralizing Antibodies for DAXI

Secondary: Number of Subjects With Serum Neutralizing Antibodies for DAXI

Secondary: Number of Subjects With Clinically Significant Changes in Pulmonary Function by Spirometry

Secondary: Number of Subjects With Clinically Significant Changes in Pulmonary Function by Spirometry

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Outside EU/EEA

Clinical trials

Clinical Trial Results: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-Center Trial to Evaluate the Efficacy and Safety of a Single Treatment of DaxibotulinumtoxinA for Injection in Adults with Isolated Cervical Dystonia (ASPEN-1)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Average Change From Baseline in Total Score of Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) at Weeks 4 and 6

Primary: Average Change From Baseline in Total Score of Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) at Weeks 4 and 6

Secondary: Change From Baseline in Total Score of TWSTRS at Weeks 2, 4, 6, 12, 16, 20, 24,28, 32 and 36

Secondary: Change From Baseline in Total Score of TWSTRS at Weeks 2, 4, 6, 12, 16, 20, 24,28, 32 and 36

Secondary: Duration of Effect

Secondary: Duration of Effect

Secondary: Percentage of Subjects With at Least 2-point Improvement on Clinical Global Impression of Change (CGIC) Scale at Week 4 or 6

Secondary: Percentage of Subjects With at Least 2-point Improvement on Clinical Global Impression of Change (CGIC) Scale at Week 4 or 6

Secondary: Percentage of Subjects With at Least 2-point Improvement on Patient Global Impression of Change (PGIC) at Week 4 or 6

Secondary: Percentage of Subjects With at Least 2-point Improvement on Patient Global Impression of Change (PGIC) at Week 4 or 6

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

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

Secondary: Number of Subjects With Serum Neutralizing Antibodies for DAXI

Secondary: Number of Subjects With Serum Neutralizing Antibodies for DAXI

Secondary: Number of Subjects With Clinically Significant Changes in Pulmonary Function by Spirometry

Secondary: Number of Subjects With Clinically Significant Changes in Pulmonary Function by Spirometry

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-Center Trial to Evaluate the Efficacy and Safety of a Single Treatment of DaxibotulinumtoxinA for Injection in Adults with Isolated Cervical Dystonia (ASPEN-1)