E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 15.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10034007 |
E.1.2 | Term | Parkinson's disease NOS |
E.1.2 | System Organ Class | 100000004852 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main objective of the trial is to compare the effects of CVT-301 Dose Level 2 (DL2; high dose) and placebo on the mean change from pre-dose in average UPDRS Part 3 motor score at 10 to 60 minutes following treatment of patients experiencing an OFF episode at the end-of-treatment (EOT) visit (Visit 6). |
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E.2.2 | Secondary objectives of the trial |
- Compare the effects of CVT-301 and placebo on the mean time to resolution of an OFF episode to an ON state at each dose level
- Characterize the effects of CVT-301 and placebo on daily ON time with and without troublesome dyskinesia
- Characterize the safety and tolerability of CVT-301 when used chronically to provide relief from OFF episodes overall and at each dose level
- Compare the effects of CVT-301 DL1 and placebo on the mean change from pre-dose in the average UPDRS Part 3 motor score at 10 to 60 minutes
- Compare the effects of CVT-301 and placebo on the mean change from pre-dose in the UPDRS Part 3 motor score at specified time points following observed treatment of patients experiencing an OFF episode at each visit at each dose level
- Characterize the effects of CVT-301 on safety, including acute and chronic pulmonary safety using spirometry, electrocardiograms, vital signs, and clinical laboratory tests overall |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
In order to be eligible to enter the study, patients must meet all of the following criteria:
1.Has signed and dated an IRB/IEC-approved informed consent form before any protocol-specific screening procedures are performed.
2.Has a clinical diagnosis of idiopathic PD (i.e., not induced by drugs or other diseases) as defined by fulfilling Steps 1 and 2 of the UK Brain Bank criteria, diagnosed after the age of 30 years.
3.Is a male or female aged 30 to 80 years, inclusive. Women of child-bearing potential must use protocol-defined contraceptive measures (see Section 11.1.5) and must have a negative serum human chorionic gonadotropin (hCG) test at screening. These patients must be willing to remain on their current form of contraception for the duration of the study.
4.Is classified as Stage 1 to 3 (in the ON state) on the modified Hoehn and Yahr scale for staging of PD severity.
5.Is LD-responsive (as documented by the investigator) with a PD medication regimen that includes a LD/DDI-containing regimen at least 4 times during the waking day. LD-containing regimens must be stable for at least 2 weeks prior to screening.
6.Has normal cognition as confirmed by a score of ≥25 on the Mini Mental State Examination (MMSE).
7.Has a difference in UPDRS Part 3 scores of ≥25% between ON and OFF states during screening.
8.If treated with dopamine agonists, COMT inhibitors, MAO-B inhibitors, or other non-LD-containing PD medications, must be on a stable dose for at least 4 weeks prior to screening and must remain stable throughout the study.
9.Has not received apomorphine for at least 4 weeks prior to screening and agrees not to be treated with apomorphine for the duration of the study.
10.Experiences motor fluctuations with recognizable and predictable OFF episodes and has an average of at least 2 hours of OFF time per waking day, exclusive of early morning OFF time (by self-report and confirmed by diary). Patients should be able to recognize their “wearing off” symptoms and verify that they usually improve after their next dose of PD medication.
11.Is willing and able to complete all study assessments and procedures.
12.If a current smoker, is able to comply with the following guidelines: agrees not to smoke for the entire clinic visit days (including screening visits, in-clinic treatment visits, and follow-up visit) until completion of all study procedures.
13.If the patient is a current or former smoker, has no history of, nor has ever been treated for any smoking-related pulmonary condition (e.g., chronic bronchitis, emphysema, chronic obstructive pulmonary disease [COPD]) or asthma, and has no evidence of obstructive lung disease by spirometry assessment. Patient must agree to abstain from smoking on the day of each in-clinic visit from waking through completion of all assessments for that visit day.
14.Has a screening FEV1 greater than 60% of predicted for race, age, sex, and height, and FEV1/FVC ratio greater than or equal to 75%, in the ON state.
15.If taking anti-depressant medication, the anti-depressant dose must be stable for at least 4 weeks prior to screening.
16.Understands (with or without caregiver assistance) his/her daily PD medications.
17.Is able (with or without caregiver assistance) to attend all study visits. |
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E.4 | Principal exclusion criteria |
Patients meeting any of the following exclusion criteria at screening will not be enrolled in the study:
1.Is a pregnant or lactating woman.
2.Has dyskinesia of a severity that might significantly interfere with the patient’s ability to perform study procedures and assessments.
3.Has a current history of symptomatic orthostatic hypotension despite adequate treatment.
4.Has any known contraindication to the use of LD, including a history of malignant melanoma or a history of narrow-angle glaucoma.
5.Has any condition that in the investigator’s opinion would make the patient unsuitable for participation in the study and/or medical condition that, in the opinion of the investigator, would interfere with participation in this study.
6.Has a history of COPD, asthma, or other chronic respiratory diseases within the last 5 years, or is currently receiving treatment for any of these conditions.
7.Has any contraindication to performing routine spirometry (see Appendix 12 for a list of contraindications).
8.Has used reserpine or catecholaminergic blocking agents within the last 3 months.
9.Has a history of psychotic symptoms requiring treatment with an antipsychotic medication within the past 12 months; however, in regions where they are approved, certain low-dose atypical antipsychotic agents (which may be prescribed for conditions other than psychosis) are allowed if the dose has been stable for at least 8 weeks prior to screening (quetiapine ≤50 mg/day, risperidone ≤1 mg/day, and olanzipine ≤2.5 mg/day).
10.Has received dopamine agonist blocking agents and/or non-specific monoamine oxidase inhibitors (MAOIs) within the last 3 months; however, in regions where it is approved, use of domperidone is permitted if the maximum daily dose does not exceed 60 mg and if the dose has been stable for at least 4 weeks prior to screening.
11.Has a history of suicidal ideation or suicide attempt within the past 12 months.
12.Has had previous stereotactic surgery or is planning surgery during the study period.
13.In the opinion of the investigator (or caregiver, as applicable), has signs/symptoms suggestive of clinically significant cognitive impairment that would interfere with the ability to comply with study procedures.
14.Has a history of any primary malignancy, with the exception of basal cell or successfully treated squamous cell carcinomas of the skin, cervical carcinoma in situ, or prostatic carcinoma in situ; or other malignancies curatively treated and with no evidence of disease recurrence for at least 3 years.
15.Has a history within 12 months prior to screening of substance-related disorders (with the exception of caffeine-related and nicotine-related disorders) as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR).
16.Has any clinically significant abnormality following review of screening laboratory data, previous medical history or intercurrent illness, and physical examination data that, in the investigator’s opinion, may compromise the safety of the patient in the study.
17.Has been treated with an investigational drug within 4 weeks or 5 half-lives (whichever is longer) prior to the beginning of the screening period (this includes investigational formulations of marketed products).
18.Has had any prior exposure to CVT-301.
Note: An active or recent (within 3 days) respiratory infection will not disqualify a patient from enrolling in the study. However, all symptoms should be resolved for at least 3 days prior to the baseline visit (the screening period may be extended for up to 4 weeks to accommodate this recovery). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoints:
The primary endpoint of the study is the mean change from pre-dose in the average UPDRS Part 3 score at 10 to 60 minutes post-dose. The differences between CVT 301 DL2 and placebo at the EOT visit (Visit 6) in the primary endpoint will be estimated using a Mixed Model for Repeated Measurements (MMRM).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
10 to 60 minutes following treatment
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E.5.2 | Secondary end point(s) |
At-Home Objectives:
To compare the effects of CVT-301 and placebo on the mean
time to resolution of an OFF episode to an ON state during the 2-week at-home period at each dose level.
To compare the effects of CVT-301 and placebo on the
proportion of treated OFF episodes that resolve to an ON state
overall and at pre-specified categorical time intervals following
completion of CVT-301 and placebo inhalation during the 2-week
at-home period at each dose level.
To characterize the effects of CVT-301 and placebo on daily ON
time with and without troublesome dyskinesia and the total daily
OFF time from diaries with data collected for 3 days immediately
prior to each visit at each dose level.
To characterize the safety and tolerability of CVT-301 when
used chronically to provide relief from OFF episodes overall and
during the 2-week at-home period at each dose level.
In-Clinic Objectives:
To compare the effects of CVT-301 Dose Level 1 (DL1; low
dose) and placebo on the mean change from pre-dose in the average
UPDRS Part 3 motor score at 10 to 60 minutes following treatment
of patients experiencing an OFF episode at the end of 1 week of
treatment (Visit 4).
To compare the effects of CVT-301 and placebo on the mean
change from pre-dose in the UPDRS Part 3 motor score at specified
time points following observed treatment of patients experiencing an
OFF episode at each visit at each dose level.
To compare the effects of CVT-301 and placebo on the time to
objective motor response, defined as a ≥30% reduction from pre-
dose in the UPDRS Part 3 motor score at each visit at each dose
level.
To compare the effects of CVT-301 and placebo on the number
and proportion of patients achieving an objective motor response at
each visit at each dose level.
To compare the effects of CVT-301 and placebo on examiner-rated time to an ON state following observed treatment of patients
experiencing an OFF episode at each visit at each dose level.
To assess the occurrence, duration, and severity of dyskinesia
following study treatment at each visit at each dose level.
To characterize the effects of CVT-301 on safety, including
acute and chronic pulmonary safety using spirometry,
electrocardiograms (ECGs), vital signs (blood pressure, heart rate,
respiratory rate), and clinical laboratory tests overall and at each visit (when assessed) at each dose level.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary endpoints are evaluated during the study conduct as mentioned above |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Italy |
Serbia |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of the trial is the last visit of the last patient globally. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |