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    Clinical Trial Results:
    A 12 Month, Dose-Level Blinded Study Investigating the Safety and Efficacy of CVT-301 (Levodopa Inhalation Powder) in Parkinson's Disease Patients With Motor Response Fluctuations (OFF Phenomena)

    Summary
    EudraCT number
    		 2015-005626-19
    Trial protocol
    		 CZ   ES  
    Global end of trial date
    23 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jun 2019
    First version publication date
    13 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CVT-301-004E
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02242487
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Acorda Therapeutics
    Sponsor organisation address
    420 Saw Mill River Road, Ardsley, United States, 10502
    Public contact
    Charles Oh Senior Vice President Clinical Development, Acorda Therapeutics 420 Saw Mill River Road Ardsley, NY 10502, 011 914-326-5455, coh@acorda.com
    Scientific contact
    Charles Oh Senior Vice President Clinical Development, Acorda Therapeutics 420 Saw Mill River Road Ardsley, NY 10502, 011 914-326-5455, coh@acorda.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To characterize the effects of CVT-301 on pulmonary safety, as assessed by spirometry (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and FEV1/FVC ratio) over a 12-month period.
    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
    01 Jan 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 84
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    United States: 201
    Worldwide total number of subjects
    312
    EEA total number of subjects
    103
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    151
    From 65 to 84 years
    161
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Three hundred and twenty-five patients were randomized in study CVT-301-004E. Of these 325 patients, 237 were rollover patients from CVT-301-004, 43 were CVT- 301 naïve patients who were not previously enrolled in CVT-301 studies, 30 were rollover patients from the Observational Cohort in CVT-301-005, 9 were rollover patients from CVT-301-009.

    Pre-assignment
    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
    Period 1 title
    12-month (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CVT-301 Low Dose
    Arm description
    		 60 mg of Levodopa
    Arm type
    		 Experimental

    Investigational medicinal product name
    CVT-301
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    60 mg (two capsules of 30 mg each) of Levodopa up to 5 times a day.

    Arm title
    		 CVT-301 High Dose
    Arm description
    		 84 mg of Levodopa
    Arm type
    		 Experimental

    Investigational medicinal product name
    CVT-301
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    84 mg (two capsules of 42 mg each) up to 5 times a day.

    Number of subjects in period 1
    		CVT-301 Low Dose CVT-301 High Dose
    Started
    153
    159
    Completed
    99
    117
    Not completed
    54
    42
         Consent withdrawn by subject
    29
    14
         Adverse event, non-fatal
    13
    15
         Lost to follow-up
    2
    1
         miscellaneous
    4
    6
         Lack of efficacy
    4
    6
         Protocol deviation
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CVT-301 Low Dose
    Reporting group description
    		 60 mg of Levodopa

    Reporting group title
    CVT-301 High Dose
    Reporting group description
    		 84 mg of Levodopa

    Reporting group values
    		 CVT-301 Low Dose CVT-301 High Dose Total
    Number of subjects
    		 153 159 312
    Age categorical
    There were 312 patients in the Safety Population. The mean age (SD) was 63.4 (8.55) years.
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 71 80 151
        From 65-84 years
    		 82 79 161
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 43 40 83
        Male
    		 110 119 229
    Subject analysis sets

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Of the 325 randomized patients, 312 patients were in the Safety population. There was approximately the same number of patients in each dose group.

    Subject analysis set title
    ITT Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Of the 325 randomized patients, 297 patients were in the ITT Population. There was approximately the same number of patients in each dose group.

    Subject analysis sets values
    		 Safety Population ITT Population
    Number of subjects
    312
    297
    Age categorical
    There were 312 patients in the Safety Population. The mean age (SD) was 63.4 (8.55) years.
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    151
    143
        From 65-84 years
    161
    154
        85 years and over
    0
    0
    Age continuous
    Units:
        
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    229
    83
        Male
    83
    214

    End points

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    End points reporting groups
    Reporting group title
    CVT-301 Low Dose
    Reporting group description
    		 60 mg of Levodopa

    Reporting group title
    CVT-301 High Dose
    Reporting group description
    		 84 mg of Levodopa

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Of the 325 randomized patients, 312 patients were in the Safety population. There was approximately the same number of patients in each dose group.

    Subject analysis set title
    ITT Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Of the 325 randomized patients, 297 patients were in the ITT Population. There was approximately the same number of patients in each dose group.

    Primary: Pulmonary safety of CVT-301 change from baseline for FEV1

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    End point title
    		 Pulmonary safety of CVT-301 change from baseline for FEV1 [1]
    End point description
    To characterize the effects of CVT-301 on pulmonary safety, as assessed by spirometry FEV1 (forced expiratory volume in 1 second) by treatment group and visit (TV). This study was a 12-month, dose-level blinded, multicenter study of 2 inhaled dose levels of CVT-301 for the treatment of up to 5 OFF periods per day in PD (Parkinson's Disease) patients experiencing motor fluctuations (OFF periods). Baseline is defined as the last non-missing assessment before the first dose of CVT-301 in study CVT-301-004 for the patients who received CVT-301 in CVT-301-004 and as the last non-missing assessment before the first dose of CVT-301 in CVT-301-004E for the rest of the patients.
    End point type
    Primary
    End point timeframe
    Change from baseline at 52 weeks
    Notes
    [1] - 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: This was a Safety study and therefore reporting of pulmonary outcomes was descriptive.
    End point values
    		 CVT-301 Low Dose CVT-301 High Dose
    Number of subjects analysed
    153
    159
    Units: liter
    log mean (standard deviation)
        Baseline (N=153 LD - 159 HD)
    2.957 ± 0.6995
    3.117 ± 0.7735
        TV3 (N=141 LD - 149 HD)
    -0.059 ± 0.2321
    -0.078 ± 0.2108
        TV4 (N=119 LD - 136 HD)
    -0.057 ± 0.1999
    -0.058 ± 0.2136
        TV5 (N=112 LD - 125 HD)
    -0.076 ± 0.2155
    -0.052 ± 0.2096
        TV6 (N=105 LD - 115 HD)
    -0.086 ± 0.2238
    -0.097 ± 0.2230
    No statistical analyses for this end point

    Primary: Pulmonary Safety for CVT-301 change from baseline for FVC

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    End point title
    		 Pulmonary Safety for CVT-301 change from baseline for FVC [2]
    End point description
    To characterize the effects of CVT-301 on pulmonary safety, as assessed by spirometry FVC, (forced vital capacity ratio) by treatment group and visit (TV). This study was a 12-month, dose-level blinded, multicenter study of 2 inhaled dose levels of CVT-301 for the treatment of up to 5 OFF periods per day in PD patients experiencing motor fluctuations (OFF periods). Baseline is defined as the last non-missing assessment before the first dose of CVT-301 in study CVT-301-004 for the patients who received CVT-301 in CVT-301-004 and as the last non-missing assessment before the first dose of CVT-301 in CVT-301-004E for the rest of the patients.
    End point type
    Primary
    End point timeframe
    Change from baseline at 52 weeks.
    Notes
    [2] - 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: This was a Safety study and therefore reporting of pulmonary outcomes was descriptive.
    End point values
    		 CVT-301 Low Dose CVT-301 High Dose
    Number of subjects analysed
    153
    159
    Units: Liter
    log mean (standard deviation)
        Baseline (N=153 LD - 159 HD)
    3.840 ± 0.9047
    4.045 ± 0.9811
        TV3 (N=141 LD - 149 HD)
    -0.064 ± 0.2575
    -0.086 ± 0.2667
        TV4 (N=119 LD - 136 HD)
    -0.053 ± 0.2710
    -0.062 ± 0.2688
        TV5 (N=112 LD - 125 HD)
    -0.089 ± 0.3051
    -0.050 ± 0.2659
        TV6 (N=105 LD - 115 HD)
    -0.106 ± 0.2866
    -0.089 ± 0.2747
    No statistical analyses for this end point

    Primary: Pulmonary Safety for CVT-301 change from baseline for (FEV1/FVC)

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    End point title
    		 Pulmonary Safety for CVT-301 change from baseline for (FEV1/FVC) [3]
    End point description
    To characterize the effects of CVT-301 on pulmonary safety, as assessed by spirometry FEV1/FVC (FEV1 forced expiratory volume in 1 second and (FVC) forced vital capacity ratio). This study was a 12-month, dose-level blinded, multicenter study of 2 inhaled dose levels of CVT-301 for the treatment of up to 5 OFF periods per day in PD patients experiencing motor fluctuations (OFF periods). Baseline is defined as the last non-missing assessment before the first dose of CVT-301 in study CVT-301-004 for the patients who received CVT-301 in CVT-301-004 and as the last non-missing assessment before the first dose of CVT-301 in CVT-301-004E for the rest of the patients.
    End point type
    Primary
    End point timeframe
    Change from baseline at 52 weeks
    Notes
    [3] - 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: This was a Safety study and therefore reporting of pulmonary outcomes was descriptive.
    End point values
    		 CVT-301 Low Dose CVT-301 High Dose
    Number of subjects analysed
    153
    159
    Units: Ratio %
    log mean (standard deviation)
        Baseline (N=153 LD - 159 HD)
    77.2 ± 5.24
    77.2 ± 6.00
        TV3 (N=141 LD - 149 HD)
    -0.2 ± 3.35
    -0.3 ± 2.89
        TV4 (N=119 LD - 136 HD)
    -0.3 ± 3.64
    -0.3 ± 3.02
        TV5 (N=112 LD - 125 HD)
    -0.3 ± 2.75
    -0.3 ± 3.02
        TV6 (N=105 LD - 115 HD)
    -0.2 ± 3.36
    -0.7 ± 3.51
    No statistical analyses for this end point

    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
    Proportion of patients achieving resolution of an OFF to an ON state within 60 minutes after study drug is administered in the clinic, and maintaining the ON state at 60 minutes after study drug administration (per the examiner’s subjective assessment).
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    		 CVT-301 Low Dose CVT-301 High Dose
    Number of subjects analysed
    144
    153
    Units: Participants
    98
    128
    No statistical analyses for this end point

    Secondary: Change from baseline in OFF time.

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    End point title
    		 Change from baseline in OFF time.
    End point description
    Patient reported total daily OFF time and was assessed by the patient and recorded in the patient Diary. An “OFF state” is defined as the time when medication is not providing benefit with respect to mobility, slowness, and stiffness. OFF episodes may be heralded by non-motor symptoms (e.g., pain, anxiety) prior to the appearance of motor symptoms. Patients will record their ON and OFF states in their diaries at home. TV = Treatment group and visit.
    End point type
    Secondary
    End point timeframe
    Change from baseline through 12 months duration of outpatient use.
    End point values
    		 CVT-301 Low Dose CVT-301 High Dose
    Number of subjects analysed
    144
    153
    Units: Hours
    least squares mean (standard error)
        TV2 (Week 4) (N=137 LD - 143HD)
    -0.33 ± 0.221
    -0.55 ± 0.217
        TV3 (Week 12) (N=133 LD - 139 HD)
    -0.23 ± 0.232
    -0.38 ± 0.227
        TV4 (Week 24) (N=114 LD - 130 HD)
    -0.65 ± 0.235
    -0.73 ± 0.227
        TV5 (Week 36) (N=102 LD - 116 HD)
    -0.49 ± 0.238
    -0.92 ± 0.230
        TV6 (Week 52) (N=94 LD - 110 HD)
    -0.70 ± 0.239
    -0.88 ± 0.229
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12-month period
    Adverse event reporting additional description
    218 patients experienced at least 1 TEAE. There were 35 patients who experienced a serious TEAE, 26 patients who experienced a TEAE that led to study withdrawal, 30 patients that led to study drug discontinuation, 10 led to drug dose reduction, 31 experienced severe TEAE. No death occurred during this study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    CVT-301 Low Dose
    Reporting group description
    		 Capsules of 60 mg of levodopa inhalational powder used up to 5 times/day for OFF episodes for 12 months duration.

    Reporting group title
    CVT-301 High Dose
    Reporting group description
    		 Capsules of 84 mg of levodopa inhalational powder used up to 5 times/day for OFF episodes for 12 months duration.

    Serious adverse events
    		 CVT-301 Low Dose CVT-301 High Dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 153 (14.38%)
    13 / 159 (8.18%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostrate cancer
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostrate cancer metastatic
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Bone graft
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Impulse-control disorder
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide threat
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device connection tissue
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 153 (0.65%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 153 (0.65%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycocardial infarction
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Central nervous system lesion
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic encephalaopathy
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Megacolon
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal achalasia
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    3 / 153 (1.96%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 153 (0.65%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile immunisation
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising soft tissue infection
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneuomonia
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CVT-301 Low Dose CVT-301 High Dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    103 / 153 (67.32%)
    115 / 159 (72.33%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    24 / 153 (15.69%)
    17 / 159 (10.69%)
         occurrences all number
    26
    22
    Nervous system disorders
    Dyskinesia
         subjects affected / exposed
    6 / 153 (3.92%)
    10 / 159 (6.29%)
         occurrences all number
    6
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    25 / 153 (16.34%)
    23 / 159 (14.47%)
         occurrences all number
    28
    27
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 153 (5.23%)
    3 / 159 (1.89%)
         occurrences all number
    9
    4
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 153 (6.54%)
    12 / 159 (7.55%)
         occurrences all number
    10
    13
    Nasopharyngitis
         subjects affected / exposed
    8 / 153 (5.23%)
    4 / 159 (2.52%)
         occurrences all number
    8
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Sep 2014
    In the USA, the original protocol CVT-301-004E Version 1.0 was submitted to the FDA on 25 August 2014 in Investigational New Drug application 115750, Sequence 0018; however, it was not activated and was never provided to any study sites. The protocol was subsequently amended to Version 1.1, which included minor administrative changes and clarifications that did not impact the study design or patient safety. Version 1.1 was provided to all study sites in the USA and Canada. The protocol was amended to Version 2.0 that also contained minor clarifications that did not impact the study design or patient safety and 3.0 was submitted to the FDA on 12 December 2014 in Investigational New Drug application 115750, Sequence 0024. It should be noted that Version 2.0 was never activated nor implemented at any study sites, and Version 3.0 was implemented only in Canada. Version 4.0 replaced Version 1.1 at all study sites in the USA; in Canada, Version 4.0 replaced Version 3.0. Version 4.0 was a major amendment that included, among other updates: • Removal of pulmonary assessments from the neurology sites to a dedicated pulmonary function facility after TV1. Removal of post-Screening UPDRS Part 3; simplified objectives to ensure consistency with study CVT-301-004. • Addition of 2 efficacy scales (PHQ-9 and Impact of Parkinson’s OFF Episodes Patient Survey) for consistency with the core study, CVT-301-004. • Enrollment opened to patients from the observational arm of CVT-301-005 and from study CVT-301-009. • Enrollment closed to former patients from the CVT-301-003 study as patients may have developed tolerability for CVT-301. • Expanded the study to sites in Europe to align with the core study, CVT-301-004. Version 5.0 included the recommendations by the Agency to assess withdrawal and rebound including the Movement Disorder Society-UPDRS parts 1B and 2 during 28 days when completing withdrawal assessments at home.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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