Parkinson's Disease
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy and safety of TVP-1012 (1 mg/day) administered to Japanese patients with early Parkinson's disease.
Detailed description
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 study to evaluate the efficacy and safety of TVP-1012 in Japanese participants with early Parkinson's disease. The study period consisted of a 28-week trial period. The participants who fulfill the inclusion criteria and not meeting any of the exclusion criteria were enrolled, and randomized in a 1:1 ratio to either the 1 mg of TVP-1012 or the placebo group. In each treatment group, participants received either 1 mg of TVP-1012 or placebo once daily in a double-blinded manner.
Interventions
DRUGTVP-1012
TVP-1012 1mg Tablets
DRUGPlacebo
Placebo tablets
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Run-in period * In the opinion of the investigator or sub-investigator, the participant is capable of understanding and complying with protocol requirements. * The participant signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures. * The participant has a diagnosis of Parkinson's disease with at least two of the following signs: resting tremor, akinesia/bradykinesia, and muscle rigidity. * The participant has a Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II + Part III total score of \>=14 at the start of the run-in period. * The participant has Modified Hoehn & Yahr stage 1 to 3 at the start of the run-in period. * The participant has the Parkinson's disease diagnosed within 5 years prior to the start of the run-in period. * The participant is an outpatient of either sex aged \>= 30 and \< 80 years. * A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent to 1 month after the last dose of the investigational drug. Treatment period \- The participant has a MDS-UPDRS Part II + Part III total score of \>= 14 at baseline.
Exclusion criteria
Run-in period * The participant has received any investigational medication within 90 days prior to the start of the run-in period. * The participant has received TVP-1012 in the past. * The participant is study site employee, an immediate family member, or in a dependent relationship with a study site employee who is involved in the conduct of this study (e.g., spouse, parent, child, sibling) or may consent under duress. * Participant has donated 400 mL or more of his or her blood volume within 90 days prior to the start of the run-in period. * The participant has unstable systemic disease. * The participant has Mini-Mental State Examination (MMSE) score of \<= 24 at the start of the run-in period. * The participant has known or a history of schizophrenia, major or severe depression, or any other clinically significant psychiatric disease. * The participant has a history of hypersensitivity or allergies to TVP-1012 (including any associated excipients) or selegiline. * The participant has a history of clinically significant hypertension or other reactions associated with ingestion of tyramine-rich food (e.g., cheese, lever, herring, yeast, horsebean, banana, beer or wine). * The participant has a history or concurrent of drug abuse or alcohol dependence. * The participant has received neurosurgical intervention for Parkinson's disease (e.g., pallidotomy, thalamotomy, deep brain stimulation). * The participant has received transcranial magnetic stimulation within 6 months prior to the start of the run-in period * The participant has received amantadine or anticholinergic medication for \>= 180 days. * The participant has received selegiline, a levodopa-containing product or dopamine agonist for \>= 90 days. * The participant has received selegiline, pethidine, tramadol, reserpine or methyldopa within 90 days prior to the start of the run-in period. * The participant has received a levodopa-containing product, dopamine agonist, amantadine or anticholinergic drug within 30 days prior to the start of the run-in period. * The participant has received any psychoneurotic agent or antiemetic medication of dopamine antagonist within 14 days prior to the start of the run-in period. However, the participant has been receiving quetiapine or domperidone with a stable dose regimen for \>= 14 days prior to the start of the run-in period may be included in the study. * The participant has previously received a catechol-O-methyltransferase (COMT) inhibitor, droxidopa, zonisamide or istradefylline. * The participant is required to take any of the prohibited concomitant medications or treatments. * If female, the participant is pregnant or lactating or intending to become pregnant during this study, or within 1 month after the last dose of the investigational drug; or intending to donate ova during such time period. * The participant has clinically significant neurologic, cardiovascular, pulmonary, hepatic (including mild cirrhosis), renal, metabolic, gastrointestinal, urological, endocrine, or hematological disease. * The participant has clinically significant or unstable brain or cardiovascular disease, such as: * clinically significant arrhythmia or cardiac valvulopathy, * cardiac arrest of NYHA Class II or higher, * concurrent or a history of ischemic cardiac disease within 6 months prior to the start of the run-in period, * concurrent or a history of clinically significant cerebrovascular disease within 6 months prior to the start of the run-in period, * sever hypertension (systolic blood pressure of 180 mmHg or higher, or diastolic blood pressure of 110 mmHg or higher), * clinically significant orthostatic hypotension (including those with systolic pressure decrease of 30 mmHg or more following postural change from supine/sitting position to standing position), * a history of syncope due to hypotension within 2 years prior to the start of the run-in period. * The participant is required surgery or hospitalization for surgery during the study period * Participant has a history of cancer within 5 years prior to the start of the run-in period, except cervix carcinoma in situ which has completely cured. * The participant has acquired immunodeficiency syndrome (AIDS) \[including human immunodeficiency virus (HIV) carrier\], or hepatitis \[including viral hepatitis carrier such as hepatitis B surface (HBs) antigen or hepatitis C antibody (HCV) positive\]. However, the participant who has a negative result for HCV antigen or HCV-RNA can be included in the study. * The participant who, in the opinion of the investigator or sub-investigator, is unsuitable for any other reason. Treatment period * The participant whose diagonosis of Parkinson's disease is ruled out by dopamine transporter scintigraphy performed during the run-in period if conducted. * The participant has laboratory data meeting any of the following at the start of the run-in period: * Creatinine \>= 2 x upper limit of normal (ULN) * Total bilirubin \>= 2 x ULN * ALT or AST \>= 1.5 x ULN * ALP \>= 3 x ULN * The participant has received any of the prohibited concomitant medications or treatments during the run-in period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II + Part III Total Score | From Baseline to Week 26 (LOCF) | Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) retains the four-scale structure with a reorganization of the various subscale; (Part I; 13 items) non-motor experiences of daily living, (Part II; 13) motor experiences of daily living, (Part III; 34) motor examination, and (Part IV; 6) motor complications. Each items had 0-4 ratings, where 0 (normal) to 4 (severe) and score for each was summed to calculate the total scores. The scale range for Part II+III Total Score was 0-188, with higher scores reflecting greater severity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in MDS-UPDRS Part II Total Score | Baseline and Week 26 (LOCF) | For MDS-UPDRS Part II (motor experiences of daily living) scores, the scale range for Part II Total Score was 0-52, with higher scores reflecting greater severity. |
| Change From Baseline in MDS-UPDRS Part III Total Score | Baseline and Week 26 (LOCF) | For MDS-UPDRS Part III (motor examination) scores, the scale range for Part III Total Score was 0-132, with higher scores reflecting greater severity. |
| Number of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Up to Week 26 | — |
| Change From Baseline in MDS-UPDRS Part I Total Score | Baseline and Week 26 (LOCF) | For MDS-UPDRS Part I (non-motor experiences of daily living) scores, the scale range for Part I Total Score was 0-52, with higher scores reflecting greater severity. |
| Number of Participants With TEAE Related to Body Weight | Up to Week 26 | — |
| Number of Participants With TEAE Related to Electrocardiograms (ECG) | Up to Week 26 | — |
| Number of Participants With TEAE Related to Clinical Laboratory Tests | Up to Week 26 | — |
| Number of Participants With Markedly Abnormal Vital Signs Values | Up to Week 26 | — |
Countries
Japan
Participant flow
Recruitment details
Participants took part in the study at 68 investigative sites in Japan, from 07-Feb-2015 to 15-Sep-2016.
Pre-assignment details
Participants with diagnosis of Parkinson's disease were enrolled and received one tablet of placebo orally, once daily in a run-in period (Week -2 to 0). After that, the participants who fulfilled the inclusion criteria and did not meet any of the exclusion criteria at Week -2 and Week 0 were randomized in 1:1 to TVP-1012 1 mg or Placebo at Week 0.
Participants by arm
| Arm | Count |
|---|---|
| Placebo For 2 weeks during the run-in period, one tablet of placebo orally, once daily before or after breakfast, followed by 26 weeks during the treatment period, one tablet of placebo orally, once daily before or after breakfast. | 126 |
| TVP-1012 1mg For 2 weeks during the run-in period, one tablet of placebo orally, once daily before or after breakfast, followed by 26 weeks during the treatment period, one tablet of TVP-1012 1 mg orally, once daily before or after breakfast. | 118 |
| Total | 244 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 4 | 0 |
| Overall Study | Major Protocol Deviation | 0 | 1 |
| Overall Study | Pretreatment Event/AE before Treatment | 0 | 1 |
| Overall Study | Pretreatment Event/AE in Treatment | 8 | 3 |
| Overall Study | Voluntary Withdrawal | 14 | 3 |
Baseline characteristics
| Characteristic | Placebo | TVP-1012 1mg | Total |
|---|---|---|---|
| Age, Continuous | 65.4 years STANDARD_DEVIATION 8.81 | 67.4 years STANDARD_DEVIATION 8.96 | 66.4 years STANDARD_DEVIATION 8.92 |
| BMI | 22.35 kg/m^2 STANDARD_DEVIATION 2.752 | 22.78 kg/m^2 STANDARD_DEVIATION 3.303 | 22.56 kg/m^2 STANDARD_DEVIATION 3.031 |
| Duration of Parkinson's Disease | 1.56 years STANDARD_DEVIATION 1.237 | 1.97 years STANDARD_DEVIATION 1.972 | 1.76 years STANDARD_DEVIATION 1.644 |
| Height | 159.3 cm STANDARD_DEVIATION 9.24 | 158.8 cm STANDARD_DEVIATION 8.86 | 159.0 cm STANDARD_DEVIATION 9.04 |
| MDS-UPDRS Part II+III Total Score | 33.8 Scores on a scale STANDARD_DEVIATION 14.43 | 34.4 Scores on a scale STANDARD_DEVIATION 16.95 | 34.1 Scores on a scale STANDARD_DEVIATION 15.66 |
| MDS-UPDRS Part III Total Score | 26.8 Scores on a scale STANDARD_DEVIATION 11.59 | 27.2 Scores on a scale STANDARD_DEVIATION 13.8 | 27.0 Scores on a scale STANDARD_DEVIATION 12.68 |
| MDS-UPDRS Part II Total Score | 7.0 Scores on a scale STANDARD_DEVIATION 4.64 | 7.2 Scores on a scale STANDARD_DEVIATION 5.47 | 7.1 Scores on a scale STANDARD_DEVIATION 5.05 |
| MDS-UPDRS Part I Total Score | 5.7 Scores on a scale STANDARD_DEVIATION 3.58 | 5.5 Scores on a scale STANDARD_DEVIATION 3.83 | 5.6 Scores on a scale STANDARD_DEVIATION 3.7 |
| Modified Hoehn & Yahr Stage | 2.15 Units on a scale STANDARD_DEVIATION 0.615 | 2.18 Units on a scale STANDARD_DEVIATION 0.626 | 2.17 Units on a scale STANDARD_DEVIATION 0.619 |
| Region of Enrollment Japan | 126 Participants | 118 Participants | 244 Participants |
| Sex: Female, Male Female | 72 Participants | 65 Participants | 137 Participants |
| Sex: Female, Male Male | 54 Participants | 53 Participants | 107 Participants |
| Smoking Classification Current Smoker | 8 Participants | 5 Participants | 13 Participants |
| Smoking Classification Ex-Smoker | 43 Participants | 49 Participants | 92 Participants |
| Smoking Classification Never Smoked | 75 Participants | 64 Participants | 139 Participants |
| Timing of Study Drug Dose After Breakfast | 66 Participants | 59 Participants | 125 Participants |
| Timing of Study Drug Dose Before Breakfast | 60 Participants | 59 Participants | 119 Participants |
| Weight | 56.97 kg STANDARD_DEVIATION 10.218 | 57.91 kg STANDARD_DEVIATION 11.803 | 57.42 kg STANDARD_DEVIATION 10.997 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 24 / 126 | 23 / 117 |
| serious Total, serious adverse events | 8 / 126 | 4 / 117 |
Outcome results
Primary
Change From Baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II + Part III Total Score
Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) retains the four-scale structure with a reorganization of the various subscale; (Part I; 13 items) non-motor experiences of daily living, (Part II; 13) motor experiences of daily living, (Part III; 34) motor examination, and (Part IV; 6) motor complications. Each items had 0-4 ratings, where 0 (normal) to 4 (severe) and score for each was summed to calculate the total scores. The scale range for Part II+III Total Score was 0-188, with higher scores reflecting greater severity.
Time frame: From Baseline to Week 26 (LOCF)
Population: Full Analysis Set included all randomized participants who received at least 1 dose of the study drug for the treatment period. Here number of participants analyzed are participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II + Part III Total Score | 1.87 Units on a scale | Standard Error 0.752 |
| TVP-1012 1mg | Change From Baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II + Part III Total Score | -4.52 Units on a scale | Standard Error 0.784 |
p-value: <0.000195% CI: [-8.53, -4.25]ANCOVA
Secondary
Change From Baseline in MDS-UPDRS Part III Total Score
For MDS-UPDRS Part III (motor examination) scores, the scale range for Part III Total Score was 0-132, with higher scores reflecting greater severity.
Time frame: Baseline and Week 26 (LOCF)
Population: Full Analysis Set included all randomized participants who received at least 1 dose of the study drug for the treatment period. Here number of participants analyzed are participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in MDS-UPDRS Part III Total Score | -0.48 Units on a scale | Standard Error 0.639 |
| TVP-1012 1mg | Change From Baseline in MDS-UPDRS Part III Total Score | -4.47 Units on a scale | Standard Error 0.666 |
Secondary
Change From Baseline in MDS-UPDRS Part II Total Score
For MDS-UPDRS Part II (motor experiences of daily living) scores, the scale range for Part II Total Score was 0-52, with higher scores reflecting greater severity.
Time frame: Baseline and Week 26 (LOCF)
Population: Full Analysis Set included all randomized participants who received at least 1 dose of the study drug for the treatment period. Here number of participants analyzed are participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in MDS-UPDRS Part II Total Score | 2.32 Units on a scale | Standard Error 0.335 |
| TVP-1012 1mg | Change From Baseline in MDS-UPDRS Part II Total Score | 0.13 Units on a scale | Standard Error 0.35 |
Secondary
Change From Baseline in MDS-UPDRS Part I Total Score
For MDS-UPDRS Part I (non-motor experiences of daily living) scores, the scale range for Part I Total Score was 0-52, with higher scores reflecting greater severity.
Time frame: Baseline and Week 26 (LOCF)
Population: Full Analysis Set included all randomized participants who received at least 1 dose of the study drug for the treatment period. Here number of participants analyzed are participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in MDS-UPDRS Part I Total Score | 0.98 Units on a scale | Standard Error 0.247 |
| TVP-1012 1mg | Change From Baseline in MDS-UPDRS Part I Total Score | 0.18 Units on a scale | Standard Error 0.257 |
Secondary
Number of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time frame: Up to Week 26
Population: Safety Analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 66 Participants |
| Placebo | Number of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 8 Participants |
| TVP-1012 1mg | Number of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 73 Participants |
| TVP-1012 1mg | Number of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 4 Participants |
Secondary
Number of Participants With Markedly Abnormal Vital Signs Values
Time frame: Up to Week 26
Population: Safety Analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Markedly Abnormal Vital Signs Values | Temperature (<35.6 °C) | 20 Participants |
| Placebo | Number of Participants With Markedly Abnormal Vital Signs Values | Temperature (>37.7 °C) | 1 Participants |
| Placebo | Number of Participants With Markedly Abnormal Vital Signs Values | Systolic Blood Pressure (<90 mmHg) | 2 Participants |
| Placebo | Number of Participants With Markedly Abnormal Vital Signs Values | Diastolic Blood Pressure (<50 mmHg) | 3 Participants |
| Placebo | Number of Participants With Markedly Abnormal Vital Signs Values | Diastolic Blood Pressure (>100 mmHg) | 6 Participants |
| Placebo | Number of Participants With Markedly Abnormal Vital Signs Values | Pulse (<45 bpm) | 0 Participants |
| TVP-1012 1mg | Number of Participants With Markedly Abnormal Vital Signs Values | Diastolic Blood Pressure (>100 mmHg) | 9 Participants |
| TVP-1012 1mg | Number of Participants With Markedly Abnormal Vital Signs Values | Temperature (<35.6 °C) | 17 Participants |
| TVP-1012 1mg | Number of Participants With Markedly Abnormal Vital Signs Values | Diastolic Blood Pressure (<50 mmHg) | 0 Participants |
| TVP-1012 1mg | Number of Participants With Markedly Abnormal Vital Signs Values | Temperature (>37.7 °C) | 0 Participants |
| TVP-1012 1mg | Number of Participants With Markedly Abnormal Vital Signs Values | Pulse (<45 bpm) | 1 Participants |
| TVP-1012 1mg | Number of Participants With Markedly Abnormal Vital Signs Values | Systolic Blood Pressure (<90 mmHg) | 3 Participants |
Secondary
Number of Participants With TEAE Related to Body Weight
Time frame: Up to Week 26
Population: Safety Analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With TEAE Related to Body Weight | 0 Participants |
| TVP-1012 1mg | Number of Participants With TEAE Related to Body Weight | 0 Participants |
Secondary
Number of Participants With TEAE Related to Clinical Laboratory Tests
Time frame: Up to Week 26
Population: Safety Analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With TEAE Related to Clinical Laboratory Tests | Liver function test abnormal | 0 Participants |
| Placebo | Number of Participants With TEAE Related to Clinical Laboratory Tests | Blood creatine phosphokinase increased | 3 Participants |
| Placebo | Number of Participants With TEAE Related to Clinical Laboratory Tests | Gamma-glutamyltransferase increased | 2 Participants |
| Placebo | Number of Participants With TEAE Related to Clinical Laboratory Tests | Blood alkaline phosphatase increased | 1 Participants |
| Placebo | Number of Participants With TEAE Related to Clinical Laboratory Tests | Glycosylated haemoglobin increased | 0 Participants |
| Placebo | Number of Participants With TEAE Related to Clinical Laboratory Tests | Hepatic enzyme increased | 1 Participants |
| TVP-1012 1mg | Number of Participants With TEAE Related to Clinical Laboratory Tests | Glycosylated haemoglobin increased | 1 Participants |
| TVP-1012 1mg | Number of Participants With TEAE Related to Clinical Laboratory Tests | Liver function test abnormal | 1 Participants |
| TVP-1012 1mg | Number of Participants With TEAE Related to Clinical Laboratory Tests | Blood alkaline phosphatase increased | 0 Participants |
| TVP-1012 1mg | Number of Participants With TEAE Related to Clinical Laboratory Tests | Blood creatine phosphokinase increased | 0 Participants |
| TVP-1012 1mg | Number of Participants With TEAE Related to Clinical Laboratory Tests | Hepatic enzyme increased | 0 Participants |
| TVP-1012 1mg | Number of Participants With TEAE Related to Clinical Laboratory Tests | Gamma-glutamyltransferase increased | 0 Participants |
Secondary
Number of Participants With TEAE Related to Electrocardiograms (ECG)
Time frame: Up to Week 26
Population: Safety Analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With TEAE Related to Electrocardiograms (ECG) | Extrasystoles | 0 Participants |
| Placebo | Number of Participants With TEAE Related to Electrocardiograms (ECG) | Myocardial infarction | 1 Participants |
| Placebo | Number of Participants With TEAE Related to Electrocardiograms (ECG) | Electrocardiogram QT prolonged | 0 Participants |
| TVP-1012 1mg | Number of Participants With TEAE Related to Electrocardiograms (ECG) | Extrasystoles | 1 Participants |
| TVP-1012 1mg | Number of Participants With TEAE Related to Electrocardiograms (ECG) | Myocardial infarction | 0 Participants |
| TVP-1012 1mg | Number of Participants With TEAE Related to Electrocardiograms (ECG) | Electrocardiogram QT prolonged | 1 Participants |