A Phase 3 Study of TVP-1012 (1 mg) in Early Parkinson's Disease Patients

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02337725
• Collaborator: (none)
• Enrollment: 244
• Locations: 55
• Arms: 2
• Actual Duration (Months): 19.3
• Patients Per Site: 4.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Parkinson's Disease	Drug: TVP-1012; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 244 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Phase 3 Study to Evaluate the Efficacy and Safety of TVP-1012 at 1 mg in Early Parkinson's Disease Patients Not Treated With Levodopa
• Actual Study Start Date: Feb 7, 2015
• Actual Primary Completion Date: Sep 15, 2016
• Actual Study Completion Date: Sep 15, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TVP-1012 1 mg 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.	Drug: TVP-1012; TVP-1012 1mg Tablets
Placebo Comparator: 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.	Drug: Placebo; Placebo tablets

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. Number of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [Up to Week 26]

5. Number of Participants With Markedly Abnormal Vital Signs Values [Up to Week 26]

6. Number of Participants With TEAE Related to Body Weight [Up to Week 26]

7. Number of Participants With TEAE Related to Electrocardiograms (ECG) [Up to Week 26]

8. Number of Participants With TEAE Related to Clinical Laboratory Tests [Up to Week 26]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Nagoya	Aichi	Japan
2		Matsuyama	Ehime	Japan
3		Touon	Ehime	Japan
4		Kitakyushu	Fukuoka	Japan
5		Onoshiro	Fukuoka	Japan
6		Asahikawa	Hokkaido	Japan
7		Iwamizawa	Hokkaido	Japan
8		Akashi	Hyogo	Japan
9		Kobe	Hyogo	Japan
10		Tsuchiura	Ibaragi	Japan
11		Tsukuba	Ibaragi	Japan
12		Morioka	Iwate	Japan
13		Takamatsu	Kagawa	Japan
14		Fujisawa	Kanagawa	Japan
15		Sagamihara	Kanagawa	Japan
16		Yokohama	Kanagawa	Japan
17		Goushi	Kumamoto	Japan
18		Sendai	Miyagi	Japan
19		Matsumoto	Nagano	Japan
20		Higashisonogi-gun	Nagasaki	Japan
21		Nishisonogi-gun	Nagasaki	Japan
22		Tenri	Nara	Japan
23		Jouetsu	Niigata	Japan
24		Higashiosaka	Osaka	Japan
25		Suita	Osaka	Japan
26		Takatsuki	Osaka	Japan
27		Toyonaka	Osaka	Japan
28		Irima-gun	Saitama	Japan
29		Fuji	Shizuoka	Japan
30		Hamamatsu	Shizuoka	Japan
31		Izunokuni	Shizuoka	Japan
32		Shimono	Tochigi	Japan
33		Yoshinogawa	Tokushima	Japan
34		Bunkyo-ku	Tokyo	Japan
35		Fuchu	Tokyo	Japan
36		Kodaira	Tokyo	Japan
37		Meguro-ku	Tokyo	Japan
38		Nerima-ku	Tokyo	Japan
39		Ota-ku	Tokyo	Japan
40		Setagaya-ku	Tokyo	Japan
41		Shibuya-ku	Tokyo	Japan
42		Akita		Japan
43		Aomori		Japan
44		Fukuoka		Japan
45		Fukushima		Japan
46		Hiroshima		Japan
47		Kochi		Japan
48		Kyoto		Japan
49		Niigata		Japan
50		Okayama		Japan
51		Osaka		Japan
52		Tokushima		Japan
53		Toyama		Japan
54		Wakayama		Japan
55		Yamagata		Japan

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02337725
• Other Study ID Numbers: TVP-1012/CCT-001; U1111-1165-1302; JapicCTI-152760
• First Posted: Jan 14, 2015
• Last Update Posted: Mar 2, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Parkinson Disease

Study Results

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 Detail	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.

Arm/Group Title	Placebo	TVP-1012 1mg
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	126	118
COMPLETED	100	110
NOT COMPLETED	26	8

Baseline Characteristics

Arm/Group Title	Placebo	TVP-1012 1mg	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	126	118	244
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.4 (8.81)	67.4 (8.96)	66.4 (8.92)
Sex: Female, Male (Count of Participants)
Female	72 57.1%	65 55.1%	137 56.1%
Male	54 42.9%	53 44.9%	107 43.9%
Region of Enrollment (Number) [Number]
Japan	126 100%	118 100%	244 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	159.3 (9.24)	158.8 (8.86)	159.0 (9.04)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	56.97 (10.218)	57.91 (11.803)	57.42 (10.997)
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	22.35 (2.752)	22.78 (3.303)	22.56 (3.031)
Smoking Classification (Count of Participants)
Never Smoked	75 59.5%	64 54.2%	139 57%
Current Smoker	8 6.3%	5 4.2%	13 5.3%
Ex-Smoker	43 34.1%	49 41.5%	92 37.7%
Timing of Study Drug Dose (Count of Participants)
Before Breakfast	60 47.6%	59 50%	119 48.8%
After Breakfast	66 52.4%	59 50%	125 51.2%
Duration of Parkinson's Disease (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	1.56 (1.237)	1.97 (1.972)	1.76 (1.644)
Modified Hoehn & Yahr Stage (Units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units on a scale]	2.15 (0.615)	2.18 (0.626)	2.17 (0.619)
MDS-UPDRS Part II+III Total Score (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	33.8 (14.43)	34.4 (16.95)	34.1 (15.66)
MDS-UPDRS Part I Total Score (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	5.7 (3.58)	5.5 (3.83)	5.6 (3.70)
MDS-UPDRS Part II Total Score (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	7.0 (4.64)	7.2 (5.47)	7.1 (5.05)
MDS-UPDRS Part III Total Score (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	26.8 (11.59)	27.2 (13.80)	27.0 (12.68)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II + Part III Total Score
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	TVP-1012 1mg
Arm/Group Description	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.	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.
Measure Participants	125	115
Least Squares Mean (Standard Error) [Units on a scale]	1.87 (0.752)	-4.52 (0.784)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TVP-1012 1mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-6.39
	Confidence Interval	(2-Sided) 95%; -8.530 to -4.250
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated Value was reported for the least squares mean difference between TVP-1012 1mg and Placebo (TVP-1012 1mg - Placebo).

2. Secondary Outcome

Title	Change From Baseline in MDS-UPDRS Part I Total Score
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	TVP-1012 1mg
Arm/Group Description	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.	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.
Measure Participants	125	116
Least Squares Mean (Standard Error) [Units on a scale]	0.98 (0.247)	0.18 (0.257)

3. Secondary Outcome

Title	Change From Baseline in MDS-UPDRS Part II Total Score
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	TVP-1012 1mg
Arm/Group Description	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.	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.
Measure Participants	126	116
Least Squares Mean (Standard Error) [Units on a scale]	2.32 (0.335)	0.13 (0.350)

4. Secondary Outcome

Title	Change From Baseline in MDS-UPDRS Part III Total Score
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	TVP-1012 1mg
Arm/Group Description	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.	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.
Measure Participants	125	115
Least Squares Mean (Standard Error) [Units on a scale]	-0.48 (0.639)	-4.47 (0.666)

5. Secondary Outcome

Title	Number of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time Frame	Up to Week 26

Outcome Measure Data

Analysis Population Description

Safety Analysis set included all participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	TVP-1012 1mg
Arm/Group Description	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.	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.
Measure Participants	126	117
TEAEs	66 52.4%	73 61.9%
SAEs	8 6.3%	4 3.4%

6. Secondary Outcome

Title	Number of Participants With Markedly Abnormal Vital Signs Values
Time Frame	Up to Week 26

Outcome Measure Data

Analysis Population Description

Safety Analysis set included all participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	TVP-1012 1mg
Arm/Group Description	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.	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.
Measure Participants	126	117
Temperature (<35.6 °C)	20 15.9%	17 14.4%
Temperature (>37.7 °C)	1 0.8%	0 0%
Systolic Blood Pressure (<90 mmHg)	2 1.6%	3 2.5%
Diastolic Blood Pressure (<50 mmHg)	3 2.4%	0 0%
Diastolic Blood Pressure (>100 mmHg)	6 4.8%	9 7.6%
Pulse (<45 bpm)	0 0%	1 0.8%

7. Secondary Outcome

Title	Number of Participants With TEAE Related to Body Weight
Time Frame	Up to Week 26

Outcome Measure Data

Analysis Population Description

Safety Analysis set included all participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	TVP-1012 1mg
Arm/Group Description	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.	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.
Measure Participants	126	117
Count of Participants [Participants]	0 0%	0 0%

8. Secondary Outcome

Title	Number of Participants With TEAE Related to Electrocardiograms (ECG)
Time Frame	Up to Week 26

Outcome Measure Data

Analysis Population Description

Safety Analysis set included all participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	TVP-1012 1mg
Arm/Group Description	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.	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.
Measure Participants	126	117
Extrasystoles	0 0%	1 0.8%
Myocardial infarction	1 0.8%	0 0%
Electrocardiogram QT prolonged	0 0%	1 0.8%

9. Secondary Outcome

Title	Number of Participants With TEAE Related to Clinical Laboratory Tests
Time Frame	Up to Week 26

Outcome Measure Data

Analysis Population Description

Safety Analysis set included all participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	TVP-1012 1mg
Arm/Group Description	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.	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.
Measure Participants	126	117
Blood creatine phosphokinase increased	3 2.4%	0 0%
Gamma-glutamyltransferase increased	2 1.6%	0 0%
Blood alkaline phosphatase increased	1 0.8%	0 0%
Glycosylated haemoglobin increased	0 0%	1 0.8%
Hepatic enzyme increased	1 0.8%	0 0%
Liver function test abnormal	0 0%	1 0.8%

Adverse Events

Time Frame	Baseline up to Week 26
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Placebo		TVP-1012 1mg
Arm/Group Description	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.		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.
All Cause Mortality
	Placebo		TVP-1012 1mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		TVP-1012 1mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/126 (6.3%)		4/117 (3.4%)
Cardiac disorders
Myocardial infarction	1/126 (0.8%)		0/117 (0%)
Gastrointestinal disorders
Gastric ulcer	1/126 (0.8%)		0/117 (0%)
Leukoplakia oral	0/126 (0%)		1/117 (0.9%)
Infections and infestations
Herpes zoster	1/126 (0.8%)		0/117 (0%)
Injury, poisoning and procedural complications
Femoral neck fracture	1/126 (0.8%)		1/117 (0.9%)
Spinal compression fracture	0/126 (0%)		1/117 (0.9%)
Nervous system disorders
Cerebral infarction	1/126 (0.8%)		0/117 (0%)
Cubital tunnel syndrome	1/126 (0.8%)		0/117 (0%)
Intracranial aneurysm	0/126 (0%)		1/117 (0.9%)
Thrombotic cerebral infarction	1/126 (0.8%)		0/117 (0%)
Psychiatric disorders
Completed suicide	1/126 (0.8%)		0/117 (0%)
Vascular disorders
Aortic dissection	1/126 (0.8%)		0/117 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		TVP-1012 1mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/126 (19%)		23/117 (19.7%)
Infections and infestations
Nasopharyngitis	19/126 (15.1%)		18/117 (15.4%)
Injury, poisoning and procedural complications
Fall	7/126 (5.6%)		6/117 (5.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.