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Clinical Trial Results:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Investigating the Efficacy and Safety of CVT-301 (Levodopa Inhalation Powder) in Parkinson?s Disease Patients With Motor Response Fluctuations (OFF Phenomena) (SPAN-PD?)

Summary
EudraCT number	2015-005067-17
Trial protocol	CZ ES
Global end of trial date	06 Dec 2016

Results information
Results version number	v1(current)
This version publication date	28 Feb 2018
First version publication date	28 Feb 2018
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

CVT-301-004

ISRCTN number

US NCT number

NCT02240030

WHO universal trial number (UTN)

Sponsor organisation name

Acorda Therapeutics

Sponsor organisation address

420 Saw Mill River Road, Ardsley, United States, 10502

Public contact

Regulatory Affairs, INC Research, 44 1276481000, SM_Regaffairs_eu_ap@incresearch.com

Scientific contact

Regulatory Affairs, INC Research, 44 1276481000, SM_Regaffairs_eu_ap@incresearch.com

Sponsor organisation name

Acorda Therapeutics

Sponsor organisation address

420 Saw Mill River Road, Ardsley, United States, 10502

Public contact

Acorda Therapeutics, Acorda Therapeutics, 914 326-5827, rrifelli@acorda.com

Scientific contact

Acorda Therapeutics, Acorda Therapeutics, 914 326-5827, rrifelli@acorda.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

06 Dec 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

06 Dec 2016

Global end of trial reached?

Yes

Global end of trial date

06 Dec 2016

Was the trial ended prematurely?

Main objective of the trial

To compare the effects of CVT-301 versus placebo on the change from pre-dose in Unified Parkinson?s Disease Rating Scale (UPDRS) Part 3 motor score at 30 minutes following treatment of patients experiencing an OFF episode at Treatment Visit 4 (TV4) (Week 12).

Protection of trial subjects

Conduct of the study must be approved by an appropriately constituted IRB or IEC. Approval is required for the study protocol, investigational drug brochure, protocol amendments, informed consent forms, patient information sheets, and advertising materials. For each study patient, written informed consent will be obtained prior to any protocol-related activities. As part of this procedure, the principal investigator or one of his/her associates must explain orally and in writing the nature, duration, and purpose of the study, and the action of the drug in such a manner that the patient is aware of the potential risks, inconveniences, or adverse effects that may occur. The patient should be informed that he/she may withdraw from the study at any time, and the patient will receive all information that is required by local regulations and ICH guidelines. The principal investigator will provide the Sponsor or its representative with a copy of the IRB/IEC-approved informed consent form prior to the start of the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

03 Nov 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 66

Country: Number of subjects enrolled

Spain: 5

Country: Number of subjects enrolled

United States: 248

Country: Number of subjects enrolled

Canada: 20

Worldwide total number of subjects

339

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

167

From 65 to 84 years

172

85 years and over

Subject disposition

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Recruitment details

Patients were screened at 70 sites in the United States (US), Canada, and Europe. From this total, 65 sites enrolled patients in the study: 52 sites in the US, 4 sites in Canada, 8 sites in Poland, and 1 site in Spain.

Screening details

* Idiophathic PD, aged 30-85 years * Modified Hoehn and Yahr scale 1-3 (ON state) * Daily OFF time > 2 hours/day (excluding morning OFF) * On a stabel DDI/LD regimen * Other PD medications stable >4 weeks prior to screening * UPDRS Part III >25% increase between ON and OFF at screening * Mini Mental Status Examination Score >25

Period 1 title

12 week (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

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

Are arms mutually exclusive

Yes

CVT-301 High Dose

Arm description

Capsules of levodopa inhalational powder used up to 5 times/day for OFF episodes for 3 months duration CVT-301

Arm type

Experimental

Investigational medicinal product name

Levodopa

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Inhalation of two capsules up to 5 times daily.

CVT-301 Low Dose

Arm description

Capsules of levodopa inhalational powder used up to 5 times/day for OFF episodes for 3 months duration

Arm type

Experimental

Investigational medicinal product name

CVT-301 Low Dose

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Inhalation of two capsules up to 5 times daily

Placebo

Arm description

Capsules of inhalation-grade lactose used up to 5 times/day for OFF episodes for 3 months duration.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, hard capsule

Routes of administration

Inhalation use

Dosage and administration details

Inhalation of two capsules up to 5 times daily.

Number of subjects in period 1	CVT-301 High Dose	CVT-301 Low Dose	Placebo
Started	114	113	112
Completed	97	96	97
Not completed	17	17	15
Consent withdrawn by subject	9	9	10
Adverse event, non-fatal	6	3	3
Other	1	2	2
Lost to follow-up	-	2	-
Lack of efficacy	1	1	-

Baseline characteristics

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Reporting group title

CVT-301 High Dose

Reporting group description

Capsules of levodopa inhalational powder used up to 5 times/day for OFF episodes for 3 months duration CVT-301

Reporting group title

CVT-301 Low Dose

Reporting group description

Capsules of levodopa inhalational powder used up to 5 times/day for OFF episodes for 3 months duration

Reporting group title

Placebo

Reporting group description

Capsules of inhalation-grade lactose used up to 5 times/day for OFF episodes for 3 months duration.

Reporting group values	CVT-301 High Dose	CVT-301 Low Dose	Placebo	Total
Number of subjects	114	113	112	339
Age categorical
Participants 339
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)	58	54	55	167
From 65-84 years	56	59	57	172
85 years and over	0	0	0	0
Age continuous
Idiopathic, PD aged 30-85
Units: years
log mean (standard deviation)	63.5 ( 7.97 )	63.9 ( 9.24 )	62.6 ( 8.83 )	-
Gender categorical
Female and Male
Units: Subjects
Female	31	33	26	90
Male	83	80	86	249

End points

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Reporting group title

CVT-301 High Dose

Reporting group description

Capsules of levodopa inhalational powder used up to 5 times/day for OFF episodes for 3 months duration CVT-301

Reporting group title

CVT-301 Low Dose

Reporting group description

Capsules of levodopa inhalational powder used up to 5 times/day for OFF episodes for 3 months duration

Reporting group title

Placebo

Reporting group description

Capsules of inhalation-grade lactose used up to 5 times/day for OFF episodes for 3 months duration.

Primary: Unified Parkinson’s Disease Rating Scale (UPDRS) Part III

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End point title

Unified Parkinson’s Disease Rating Scale (UPDRS) Part III

End point description

Primary Efficacy Analysis: Change from Predose in the UPDRS Part 3 Score at 30 Minutes Postdose at Treatment Visit 4 for CVT-301 DL2 versus Placebo (ITT Population)

End point type

Primary

End point timeframe

at week 12

End point values	CVT-301 High Dose	CVT-301 Low Dose	Placebo
Number of subjects analysed	114	113	112
Units: Units on Scale
least squares mean (standard deviation)	-9.83 ( 1.506 )	0 ( 0 )	-5.91 ( 1.500 )

Primary Efficacy Endpoint

Statistical analysis description

The statistical hypothesis to be tested for the primary efficacy variable was the following: H0: μa = μp versus Ha: μa ≠ μp μ = mean change from predose in UPDRS Part 3 score at 30 minutes postdose a = active treatment group (CVT-301 DL2, CVT-301 DL1) p = placebo treatment group

Comparison groups

Placebo v CVT-301 High Dose

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Mixed models analysis

Confidence interval

Secondary: Proportion of Patients Achieving Resolution of an OFF to an ON State within 60 Minutes

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End point title

Proportion of Patients Achieving Resolution of an OFF to an ON State within 60 Minutes

End point description

Examiner-assessed observation - Subject Achieving Resolution of an OFF to and ON state within 60 Minutes at TV4 - Observed

End point type

Secondary

End point timeframe

12-Weeks

End point values	CVT-301 High Dose	CVT-301 Low Dose	Placebo
Number of subjects analysed	114	113	112
Units: Participants
number (not applicable)	56	55	35

No statistical analyses for this end point

Secondary: UPDRS Part III motor score at 20 minutes

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End point title

UPDRS Part III motor score at 20 minutes

End point description

Change in UPDRS Part III (motor) score at 20 minutes from pre to post -dose with CVT-301 vs placebo at week 12

End point type

Secondary

End point timeframe

12-Weeks

End point values	CVT-301 High Dose	CVT-301 Low Dose	Placebo
Number of subjects analysed	95	97	95
Units: Dispersion/Precision
least squares mean (confidence interval 97.5%)	-9.04 (-11.70 to -6.37)	-8.47 (-11.11 to -5.82)	-6.49 (-9.15 to -3.83)

No statistical analyses for this end point

Secondary: Proportion of subjects who improved PGIC with CVT-301 vs. Placebo at week 12

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End point title

Proportion of subjects who improved PGIC with CVT-301 vs. Placebo at week 12

End point description

Patient Global impression of change at treatment visit 4 by improvement category

End point type

Secondary

End point timeframe

12-Weeks

End point values	CVT-301 High Dose	CVT-301 Low Dose	Placebo
Number of subjects analysed	98	99	97
Units: Participants	70	61	45

No statistical analyses for this end point

Secondary: UPDRS Part III at 10 min.

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End point title

UPDRS Part III at 10 min.

End point description

Change in UPDRS Part III (motor) score at 10 min from pre- to post-dose with CVT-301 vs Placebo at week 12

End point type

Secondary

End point timeframe

12-Weeks

End point values	CVT-301 High Dose	CVT-301 Low Dose	Placebo
Number of subjects analysed	95	97	95
Units: Dispersion/Precision
least squares mean (confidence interval 95%)	-6.45 (-8.62 to -4.27)	-5.16 (-7.31 to -3.00)	-4.18 (-6.35 to -2.01)

No statistical analyses for this end point

Secondary: PD Patient Diary

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End point title

PD Patient Diary

End point description

Change from baseline in total daily OFF times for consecutive days prior to week 12 visit

End point type

Secondary

End point timeframe

post week 12

End point values	CVT-301 High Dose	CVT-301 Low Dose	Placebo
Number of subjects analysed	95	96	97
Units: Dispersion/Precision
least squares mean (confidence interval 95%)	-0.47 (-1.02 to 0.09)	-0.58 (-1.13 to -0.03)	-0.48 (-1.03 to 0.08)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

12 Week Study

Adverse event reporting additional description

Of 339 patients, 179 (52.8%) experienced at least 1 TEAE during the study: 49 patients (43.8%) reported at least 1 TEAE while on placebo and 64 (56.6%) and 66 (57.9%) patients reported at least 1 TEAE while on CVT-301 DL1 and CVT-301 DL2, respectively.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

10.0

Reporting group title

CVT-301 High Dose

Reporting group description

Capsules of levodopa inhalational powder used up to 5 times/day for OFF episodes for 3 months duration

Reporting group title

CVT-301 Low Dose

Reporting group description

Capsules of levodopa inhalational powder used up to 5 times/day for OFF episodes for 3 months duration

Reporting group title

Placebo

Reporting group description

Capsules of inhalation-grade lactose used up to 5 times/day for OFF episodes for 3 months duration.

Serious adverse events	CVT-301 High Dose	CVT-301 Low Dose	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 114 (1.75%)	6 / 113 (5.31%)	3 / 112 (2.68%)
number of deaths (all causes)	0	1	0
number of deaths resulting from adverse events
Cardiac disorders
Chest Pains
Additional description: Two subjects reported chest pain in the 60-mg group.
subjects affected / exposed	0 / 114 (0.00%)	2 / 113 (1.77%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 114 (0.00%)	1 / 113 (0.88%)	0 / 112 (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
Atrial fibrillation
subjects affected / exposed	1 / 114 (0.88%)	1 / 113 (0.88%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 114 (0.00%)	1 / 113 (0.88%)	0 / 112 (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
Coronary artery disease
subjects affected / exposed	0 / 114 (0.00%)	0 / 113 (0.00%)	1 / 112 (0.89%)
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
Syncope
subjects affected / exposed	0 / 114 (0.00%)	1 / 113 (0.88%)	0 / 112 (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
Gastrointestinal disorders
Pancreatitis acute
subjects affected / exposed	0 / 114 (0.00%)	0 / 113 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Lumbar spinal stenosis
subjects affected / exposed	1 / 114 (0.88%)	0 / 113 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 4%

Non-serious adverse events	CVT-301 High Dose	CVT-301 Low Dose	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	66 / 114 (57.89%)	64 / 113 (56.64%)	49 / 112 (43.75%)
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	3 / 114 (2.63%)	5 / 113 (4.42%)	2 / 112 (1.79%)
occurrences all number	3	5	2
Nervous system disorders
Dyskinesia
subjects affected / exposed	4 / 114 (3.51%)	5 / 113 (4.42%)	0 / 112 (0.00%)
occurrences all number	4	5	0
Dizziness
subjects affected / exposed	1 / 114 (0.88%)	2 / 113 (1.77%)	5 / 112 (4.46%)
occurrences all number	1	2	5
Gastrointestinal disorders
Nausea
subjects affected / exposed	6 / 114 (5.26%)	0 / 113 (0.00%)	3 / 112 (2.68%)
occurrences all number	6	0	4
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	17 / 114 (14.91%)	17 / 113 (15.04%)	2 / 112 (1.79%)
occurrences all number	18	20	2
Throat Irritation
subjects affected / exposed	1 / 114 (0.88%)	8 / 113 (7.08%)	0 / 112 (0.00%)
occurrences all number	1	8	0
Sputum discoloured
subjects affected / exposed	6 / 114 (5.26%)	0 / 113 (0.00%)	0 / 112 (0.00%)
occurrences all number	6	0	0
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	7 / 114 (6.14%)	2 / 113 (1.77%)	3 / 112 (2.68%)
occurrences all number	7	2	3

More information

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Were there any global substantial amendments to the protocol? Yes

10 Jul 2015

Protocol Versions 2.0 and 3.0 (dated 22 October 2014 and 26 November 2014, respectively) were not implemented at the sites because of administrative oversight. Protocol Version 4.0, dated 10 July 2015, incorporated recommendations in the US Food and Drug Administration (FDA) Type B End-of-Phase 2 Meeting Minutes dated 07 Aug 2014 to reduce the number of secondary outcome measures in the hierarchy and reorder the objectives according to clinical relevance, taking statistical power into account.

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.

N/A

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Clinical trials

Clinical Trial Results:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Investigating the Efficacy and Safety of CVT-301 (Levodopa Inhalation Powder) in Parkinson?s Disease Patients With Motor Response Fluctuations (OFF Phenomena) (SPAN-PD?)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Unified Parkinson’s Disease Rating Scale (UPDRS) Part III

Primary: Unified Parkinson’s Disease Rating Scale (UPDRS) Part III

Secondary: Proportion of Patients Achieving Resolution of an OFF to an ON State within 60 Minutes

Secondary: Proportion of Patients Achieving Resolution of an OFF to an ON State within 60 Minutes

Secondary: UPDRS Part III motor score at 20 minutes

Secondary: UPDRS Part III motor score at 20 minutes

Secondary: Proportion of subjects who improved PGIC with CVT-301 vs. Placebo at week 12

Secondary: Proportion of subjects who improved PGIC with CVT-301 vs. Placebo at week 12

Secondary: UPDRS Part III at 10 min.

Secondary: UPDRS Part III at 10 min.

Secondary: PD Patient Diary

Secondary: PD Patient Diary

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Investigating the Efficacy and Safety of CVT-301 (Levodopa Inhalation Powder) in Parkinson?s Disease Patients With Motor Response Fluctuations (OFF Phenomena) (SPAN-PD?)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Unified Parkinson’s Disease Rating Scale (UPDRS) Part III

Primary: Unified Parkinson’s Disease Rating Scale (UPDRS) Part III

Secondary: Proportion of Patients Achieving Resolution of an OFF to an ON State within 60 Minutes

Secondary: Proportion of Patients Achieving Resolution of an OFF to an ON State within 60 Minutes

Secondary: UPDRS Part III motor score at 20 minutes

Secondary: UPDRS Part III motor score at 20 minutes

Secondary: Proportion of subjects who improved PGIC with CVT-301 vs. Placebo at week 12

Secondary: Proportion of subjects who improved PGIC with CVT-301 vs. Placebo at week 12

Secondary: UPDRS Part III at 10 min.

Secondary: UPDRS Part III at 10 min.

Secondary: PD Patient Diary

Secondary: PD Patient Diary

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 Study Investigating the Efficacy and Safety of CVT-301 (Levodopa Inhalation Powder) in Parkinson?s Disease Patients With Motor Response Fluctuations (OFF Phenomena) (SPAN-PD?)