| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Parkinson's Disease With Motor Response Fluctuations (OFF Phenomena) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Parkinson's Disease With Periods of Prolonged Immobility or Freezing |
|
| 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 | 20.0 |
| 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 |
|
| 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 |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
• Proportion of patients achieving resolution of an OFF to an ON state within 60 minutes after study drug is administered in the clinic, maintaining the ON state at 60 minutes after study drug administration (per examiner’s subjective assessment)
Patient-reported total daily OFF time, total daily ON time without dyskinesia, total daily ON time with non-troublesome dyskinesia, and total daily ON time with troublesome dyskinesia, assessed by the patient and recorded in the patient diary
• Change from baseline visit 39-Item PD Questionnaire (PDQ-39)
• Proportion of patients who improved based on the Patient Global Impression of Change (PGI-C) rating scale measured pre-dose
• Change from baseline visit Schwab and England (S&E) Activities of Daily Living (ADL) score
• Change from baseline visit 9-Item Patient Health
Questionnaire (PHQ-9)
• Change from baseline visit Impact of Parkinson’s OFF Episodes Patient Survey
• Change from baseline visit UPDRS Part 2 score |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria (not assessed for the CVT-301-004 study
patients):
• Has signed and dated an IRB/IEC-approved informed
consent form before any protocol-specific screening
procedures are performed.
• Is a male or female aged 30 to 86 years, inclusive. Women
of child-bearing potential must use protocol-defined
contraceptive measures 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.
• Patients who have idiopathic PD (i.e., not induced by drugs
or other diseases) as defined by fulfilling Steps 1 and 2 of
the United Kingdom (UK) Brain Bank criteria, diagnosed
after the age of 30 years.
• Patients who are classified as Stage 1 to 3 (in the ON state)
on the modified Hoehn and Yahr scale for staging of PD
severity.
• Patients who have experienced motor fluctuations for a
minimum of 2 hours of average daily OFF time per waking
day (excluding early morning OFF time) by self-report and
confirmed by the PD Diary (on 3 consecutive days) during
the screening period.
• Patients who are on a LD-containing therapy, not including
Rytary (or equivalent), must be stable on oral LD-containing
therapy for at least 2 weeks prior to SV1 with a
LD/dopamine decarboxylase inhibitor (DDI)-containing
regimen.
• Patients who are on a LD-containing therapy, when
including Rytary (or equivalent), should be on a stable dose
for at least 6 weeks prior to SV1
• The frequency of L-dopa administrations must be at least 3
times during the waking day and a total daily LD dose of ≤
1600 mg
• Patients should be stable on other PD medications for at
least 4 weeks prior to SV1.
• Patients must have a ≥25% difference between UPDRS Part
3 scores recorded in their ON and OFF states at screening.
• Patients must have normal cognition as confirmed by a score
of ≥25 on the MMSE (in the ON state).
• Patients must be able to perform a spirometry maneuver in
the ON and OFF states and must have a screening FEV1 ≥
50% of predicted, and an FEV1/FVC ratio > 60% in the ON
state at screening. (A pulmonologist will review the
spirometry tracings/morphology of any patients with an
FEV1 that is ≥ 50% to < 60% of predicted or an FEV1/FVC
ratio that is >60% to <70% in order to determine eligibility.
Patients with an FEV1/FVC ratio that is >60% to <70% will
complete spirometry before and after the administration of a
bronchodilator in a pulmonary function laboratory. Testing
will be performed in accordance with the 2005
ATS/European Respiratory Society [ERS] criteria prior to
randomization. The results of the bronchodilator challenge
will be reviewed by a pulmonologist prior to potential
randomization.) |
|
| E.4 | Principal exclusion criteria |
• Patients who have dyskinesia of a severity that would
significantly interfere with their ability to participate or
perform study procedures.
• Pregnant or lactating females or females wishing to become
pregnant.
• Patients who have any known contraindication to the use of
LD, including a history of malignant melanoma or a history
of narrow-angle glaucoma.
• Patients who have had previous surgery for PD (including
but not limited to cell transplantation) or plan to have
stereotactic surgery during the study period. Patients who
have had deep brain stimulation [DBS] will also be excluded
unless the procedure was performed more than 6 months
prior to study enrollment.
• Patients with a history of psychotic symptoms requiring
treatment, or suicidal ideation or attempt within the prior
12 months.
• Patients who have cancer with the exception of the
following: basal cell carcinoma or successfully treated
squamous cell carcinoma of the skin; cervical carcinoma in
situ; prostatic carcinoma in situ; or other malignancies
curatively treated and with no evidence of disease recurrence
for at least 3 years.
• Patients taking certain prohibited medications.
• Patients with a history of drug or alcohol abuse within the
prior 12 months.
• Patients with chronic obstructive pulmonary disease
(COPD), asthma, or other chronic respiratory disease within
the last 5 years
• Patients with any contraindication to performing routine
spirometry or who are unable to perform a spirometry
maneuver.
• Patients with a current history of symptomatic orthostatic
hypotension despite adequate treatment.
• Patients with any condition that in the investigator’s opinion
would make patients unable to comply with study procedures or make them unsuitable for their participation in the study.
• Patients who have any clinically significant abnormality or
finding from examination, tests, or history that may
compromise patient safety. Potential issues of concern
should be raised to the medical monitor during eligibility
review.
• For new CVT-301 naïve patients, patients who have been
treated with an investigational drug within 4 weeks or 5 halflives (whichever is longer) prior to the beginning of the
screening period (this includes investigational formulations
of marketed products). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoints related to the primary objective of the study are the pulmonary safety measures, FEV1, FVC and FEV1/ FVC ratio, assessed over a 12 month period. FEV1, FVC and FEV1/FVC ratio will be recorded from the single “best test” (based on effort with highest summed FEV1 and FVC). Variables will include the absolute FEV1, FVC, and FEV1/FVC ratio and FEV1 and FVC expressed as % of predicted value.
Percent Predicted = 100 * (Observed) / Predicted, where predicted is calculated and provided to INC by Biomedical Systems (BMS). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Changes from baseline (TV1) for each variable will be calculated at each subsequent visit. |
|
| E.5.2 | Secondary end point(s) |
•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 at 60 minutes after study drug administration (per the examiner’s subjective assessment). This endpoint will be based on the examiner’s subjective assessment. In case the assessment of turning on within 60 minutes is missing but the assessment of maintaining the ON at 60 minutes has been done, the patient will be classified based on the available assessment. In case the assessment of maintenance of ON at 60 minutes is missing, the patient will be classified as having missing data.
•Change from baseline (3 consecutive days prior to TV1, or in case of missing data, the last 3 recorded days before TV1) in patient-recorded total daily OFF time, assessed by the patient and recorded in the PD Diary for 3 consecutive days prior to in-clinic visits (or in case of missing data, the last 3 recorded days before the visit). The validity of the PD diary entries will be checked prior to including a diary day in the summary calculations. Only valid diary days will be included in the diary summarizations. Change from baseline in total daily ON time without dyskinesia, total daily ON time with non-troublesome dyskinesia, and total daily ON time with troublesome dyskinesia will be calculated similarly.
•A day will be considered as being valid if at least 80% of the entries during the day have been completed per instructions. That is, for each half hour period, only one entry among the responses (Asleep, OFF, ON without dyskinesia, ON with non-troublesome dyskinesia, or ON with troublesome dyskinesia) has been checked. The entry will not be used if no responses are checked or more than one response is checked. However, if the proportion of entries rejected due to multiple checked responses is large, sensitivity analysis will be performed by using the worst case out of the entries that had been checked. The worst case will be defined in the following order: OFF, ON with troublesome dyskinesia, ON with non-troublesome dyskinesia, ON without dyskinesia, Asleep. In case there are duplicate entries (i.e., multiple entries recorded with same date and time interval), the worst entry will be used for the date and time interval in question. The worst entry will be selected in the order defined above.
•All diary data will be normalized to 16 awake hours per day. The daily OFF time will be extrapolated to a 16 hour period by determining the percentage of OFF time among accurately recorded entries, excluding Asleep time and missing/non-valid recordings, and by multiplying this percentage by 16 hours.
Off Time / (Total time recorded – Asleep Time – missing time interval) x 16
•The mean daily OFF time prior to each visit will be calculated as mean value of the valid days documented in the patient’s diary prior to that visit. In case there are gaps within the 3 days preceding the visit, the last 3 recorded days before the visit will be used regardless of the gaps. If there are more than 3 valid days, only the last 3 days will be used. If there are only 1 or 2 valid days, the average of these days will be used.
•Change from TV1 in PDQ-39 sub-scores and summary index score. The questionnaire provides scores on eight dimensions: mobility, activities of daily living, emotional well-being, stigma, social support, cognitions, communication, bodily discomfort.
•Change from TV1 (pre-dose) to TV6 (pre-dose) in 9-Item PHQ-9 sum score. The sum score will be calculated as the sum of the 9 individual questions. In case of 1 or more missing questions, the sum score will be set as missing.
•Change from baseline to TV6 in Impact of Parkinson’s OFF Episodes Patient Survey. The Impact of Parkinson’s OFF episodes patient survey score will be calculated as the sum of the individual items of the Impact of Parkinson’s OFF Episodes Patient Survey questionnaire. Missing individual items will not be imputed and the sum score will be missing in case of 1 or more missing items.
•The PGI-C score. The non-missing values will be categorized as improvements (much improved, improved, a little improved) or non-improvements (no change, a little worse, worse, much worse).
•Change from TV1 (baseline) Schwab and England (S&E) Activities of Daily Living (ADL). No further derivation will be done for the S&E scores.
•Change from TV1 (pre-dose) to TV6 (pre-dose) in the UPDRS Part 2 score. The UPDRS Part 2 score will be calculated as the sum of the individual items of the UPDRS Part 2 questionnaire (UPDRS items 5-17). Missing individual items will not be imputed and the sum score will be missing in case of 1 or more missing items. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Changes from baseline (TV1) for each variable will be calculated at each subsequent visit. |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Canada |
| Czech Republic |
| Poland |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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