Rosiglitazone (Extended Release Tablets) As Monotherapy In Subjects With Mild To Moderate Alzheimer's Disease

Alzheimer's Disease Clinical Trial

Official title:

A 24-week, Double-blind, Double-dummy, Randomized, Parallel-group Study to Investigate the Effects of Rosiglitazone (Extended Release Tablets), Donepezil, and Placebo as Monotherapy on Cognition and Overall Clinical Response in APOE ε4-stratified Subjects With Mild to Moderate Alzheimer's Disease. (REFLECT-1)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00428090
• Other study ID #: 105640
• Status: Completed
• Phase: Phase 3
• First received: January 25, 2007
• Last updated: November 15, 2016
• Start date: February 2007
• Est. completion date: September 2008

Study information

• Verified date: November 2016
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

Rosiglitazone (RSG) has been tested and is approved as a treatment for type II diabetes mellitus, a disease that occurs when the body ineffectively uses glucose. RSG XR, the investigational drug, is an extended-release form of RSG. This study tests whether RSG XR safely provides benefit to people with mild to moderate Alzheimer's disease (AD). RSG XR is a new approach to AD therapy and this study tests whether one's genes alter the effectiveness of RSG XR. Glucose is used by cells to make energy that they need to live. Changes in the ability of cells to use of glucose can lead to diseases like diabetes. Glucose levels may be lower in the brains of AD patients, and their brain cells may also use glucose less well than in unaffected people. The proper function of brain cells may be critical to memory and thought. If brain cells use glucose poorly, this might impact AD. Drugs that help brain cells properly use glucose may help a person maintain normal memory and thinking. Data suggesting that RSG may help AD patients was first seen in a small study at the Univ. of Washington and then from a larger international GSK study. In the first study, those receiving RSG once daily for 6 months scored better on 3 tests of memory and thought than those who did not receive RSG. In the GSK study, those that benefited most from therapy with RSG XR had a specific genetic pattern. They lacked the gene that caused them to produce apolipoprotein E e4 (APOE e4). Subjects who have the APOE e4 gene may have two copies, one from each parent, or they may have only one APOE e4 gene meaning that they inherited either the APOE e2 or APOE e3 version of the gene from one parent. Subjects with one copy of the APOE e4 gene remained fairly stable while those with two copies of APOE e4 continued to worsen during the 6-month treatment. This study will directly test the effect of RSG XR on people who either have or lack the APOE e4 gene.

Description:

A 24-week, double-blind, double-dummy, randomized, parallel-group study to investigate the effects of rosiglitazone (extended release tablets), donepezil, and placebo as monotherapy on cognition and overall clinical response in APOE e4-stratified subjects with mild to moderate Alzheimer's disease. (REFLECT-1)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 862
• Est. completion date: September 2008
• Est. primary completion date: September 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 50 Years to 90 Years

Eligibility

Inclusion criteria:

• Clinical diagnosis of probable Alzheimer's Disease (AD).

• MMSE score 10 to 23

• Has not taken an approved AD therapy in last 30 days.

• No previous hypersensitivity/intolerance to AChEIs

• Have a regular caregiver.

Exclusion criteria:

• Diagnosis of vascular dementia.

• Type I or secondary diabetes mellitus.

• Type II diabetes mellitus treated with insulin, sulfonylurea or glipizide.

• History or evidence of congestive heart failure, clinically significant peripheral edema or anemia.

• History of significant psychiatric illness, major depressive disorder or current depression needing initiation of treatment.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Disease

Intervention

Drug:
• Rosiglitazone
XR (extended release) oral tablets

Locations

Country	Name	City	State
Austria	GSK Investigational Site	Graz-Eggenberg
Austria	GSK Investigational Site	Hall in Tirol
Austria	GSK Investigational Site	Linz
Austria	GSK Investigational Site	Linz
Austria	GSK Investigational Site	Vienna
Austria	GSK Investigational Site	Vienna
Austria	GSK Investigational Site	Vienna
Bulgaria	GSK Investigational Site	Plovdiv
Bulgaria	GSK Investigational Site	Sofia
Bulgaria	GSK Investigational Site	Sofia
Bulgaria	GSK Investigational Site	Sofia
Chile	GSK Investigational Site	Providencia / Santiago	Región Metro De Santiago
Chile	GSK Investigational Site	Puente Alto - Santiago	Región Metro De Santiago
Chile	GSK Investigational Site	Santiago	Región Metro De Santiago
Chile	GSK Investigational Site	Viña del Mar	Valparaíso
China	GSK Investigational Site	Beijing
China	GSK Investigational Site	Beijing
China	GSK Investigational Site	Guangzhou	Guangdong
China	GSK Investigational Site	Shanghai
China	GSK Investigational Site	Shanghai
China	GSK Investigational Site	Shanghai
China	GSK Investigational Site	Tianjin
Croatia	GSK Investigational Site	Dubrovnik
Croatia	GSK Investigational Site	Zagreb
Estonia	GSK Investigational Site	Tallinn
Estonia	GSK Investigational Site	Tallinn
Estonia	GSK Investigational Site	Tallinn
Estonia	GSK Investigational Site	Tartu
Germany	GSK Investigational Site	Achim	Niedersachsen
Germany	GSK Investigational Site	Bad Homburg	Hessen
Germany	GSK Investigational Site	Baesweiler	Nordrhein-Westfalen
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Bielefeld	Nordrhein-Westfalen
Germany	GSK Investigational Site	Bochum	Nordrhein-Westfalen
Germany	GSK Investigational Site	Chemnitz	Sachsen
Germany	GSK Investigational Site	Dresden	Sachsen
Germany	GSK Investigational Site	Dresden	Sachsen
Germany	GSK Investigational Site	Duisburg	Nordrhein-Westfalen
Germany	GSK Investigational Site	Ellwangen	Baden-Wuerttemberg
Germany	GSK Investigational Site	Gera	Thueringen
Germany	GSK Investigational Site	Guenzburg	Bayern
Germany	GSK Investigational Site	Halle	Sachsen-Anhalt
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Hannover	Niedersachsen
Germany	GSK Investigational Site	Itzehoe	Schleswig-Holstein
Germany	GSK Investigational Site	Juelich	Nordrhein-Westfalen
Germany	GSK Investigational Site	Koeln	Nordrhein-Westfalen
Germany	GSK Investigational Site	Leipzig	Sachsen
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Nuernberg	Bayern
Germany	GSK Investigational Site	Schwerin	Mecklenburg-Vorpommern
Germany	GSK Investigational Site	Schwerin	Mecklenburg-Vorpommern
Germany	GSK Investigational Site	Tuebingen	Baden-Wuerttemberg
Germany	GSK Investigational Site	Ulm	Baden-Wuerttemberg
Germany	GSK Investigational Site	Ulm	Baden-Wuerttemberg
Germany	GSK Investigational Site	Unterhaching	Bayern
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Melissia
Greece	GSK Investigational Site	Thessaloniki
Hungary	GSK Investigational Site	Budapest
Hungary	GSK Investigational Site	Gyula
Hungary	GSK Investigational Site	Kaposvár
Hungary	GSK Investigational Site	Pécs
Hungary	GSK Investigational Site	Szeged
India	GSK Investigational Site	Bangalore
India	GSK Investigational Site	Nagpur
India	GSK Investigational Site	Tirupati
Korea, Republic of	GSK Investigational Site	Seongnam-si,
Korea, Republic of	GSK Investigational Site	Seoul
Mexico	GSK Investigational Site	Mexico
Mexico	GSK Investigational Site	Monterrey	Nuevo León
Mexico	GSK Investigational Site	Saltillo	Coahuila
New Zealand	GSK Investigational Site	Auckland
Pakistan	GSK Investigational Site	Karachi
Pakistan	GSK Investigational Site	Lahore
Pakistan	GSK Investigational Site	Lahore
Peru	GSK Investigational Site	Lima
Philippines	GSK Investigational Site	Pasig City
Philippines	GSK Investigational Site	Quezon City
Puerto Rico	GSK Investigational Site	Cabo Rojo
Puerto Rico	GSK Investigational Site	San Juan
Puerto Rico	GSK Investigational Site	San Juan
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	St. Petersburg
Russian Federation	GSK Investigational Site	St.-Petersburg
United Kingdom	GSK Investigational Site	Bradford
United Kingdom	GSK Investigational Site	Derriford, Plymouth
United Kingdom	GSK Investigational Site	West of Scotland Science Park, Glasgow
United States	GSK Investigational Site	Albany	New York
United States	GSK Investigational Site	Atlanta	Georgia
United States	GSK Investigational Site	Centerville	Ohio
United States	GSK Investigational Site	Cleveland	Ohio
United States	GSK Investigational Site	Cleveland	Ohio
United States	GSK Investigational Site	Deerfield Beach	Florida
United States	GSK Investigational Site	Delray Beach	Florida
United States	GSK Investigational Site	Denver	Colorado
United States	GSK Investigational Site	DeSoto	Texas
United States	GSK Investigational Site	Destin	Florida
United States	GSK Investigational Site	Fairfield	Connecticut
United States	GSK Investigational Site	Hialeah	Florida
United States	GSK Investigational Site	Jenkintown	Pennsylvania
United States	GSK Investigational Site	Kenilworth	New Jersey
United States	GSK Investigational Site	Las Vegas	Nevada
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Melbourne	Florida
United States	GSK Investigational Site	Memphis	Tennessee
United States	GSK Investigational Site	Middleton	Wisconsin
United States	GSK Investigational Site	Nashville	Tennessee
United States	GSK Investigational Site	Newport Beach	California
United States	GSK Investigational Site	Norwalk	Connecticut
United States	GSK Investigational Site	Oklahoma City	Oklahoma
United States	GSK Investigational Site	Oklahoma City	Oklahoma
United States	GSK Investigational Site	Palo Alto	California
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Phoenix	Arizona
United States	GSK Investigational Site	Plantation	Florida
United States	GSK Investigational Site	Reseda	California
United States	GSK Investigational Site	San Antonio	Texas
United States	GSK Investigational Site	San Antonio	Texas
United States	GSK Investigational Site	San Diego	California
United States	GSK Investigational Site	San Francisco	California
United States	GSK Investigational Site	St. Paul	Minnesota
United States	GSK Investigational Site	Sunrise	Florida
United States	GSK Investigational Site	Syracuse	New York
United States	GSK Investigational Site	Tampa	Florida
United States	GSK Investigational Site	Toledo	Ohio
United States	GSK Investigational Site	Toms River	New Jersey
United States	GSK Investigational Site	Tulsa	Oklahoma

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Austria,  Bulgaria,  Chile,  China,  Croatia,  Estonia,  Germany,  Greece,  Hungary,  India,  Korea, Republic of,  Mexico,  New Zealand,  Pakistan,  Peru,  Philippines,  Puerto Rico,  Russian Federation,  United Kingdom, 

References & Publications (1)

Gold M, Alderton C, Zvartau-Hind M, Egginton S, Saunders AM, Irizarry M, Craft S, Landreth G, Linnamägi U, Sawchak S. Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord. 2010;30(2):131-46. doi: 10.1159/000318845. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from baseline in mean ADAS-Cog total score at W24 as a function of APOE e4 status in APOE4 negative cohort	The 11-item ADAS-Cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Items were evaluated by tests and clinician ratings on a 5-point scale. Scores ranged from 0-70 with higher scores indicates more dysfunction. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline is defined as value at W0. Estimated value was calculated by Active treatment minus Placebo. The adjusted means were presented.	Baseline and W24	No
Primary	Change from baseline in mean ADAS-Cog total score at W24 as a function of APOE e4 status in all except e4/e4's cohort	The 11-item ADAS-Cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Items were evaluated by tests and clinician ratings on a 5-point scale. Scores ranged from 0-70 with higher scores indicates more dysfunction. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline is defined as value at W0. Estimated value was calculated by Active treatment minus Placebo.	Baseline and W24	No
Primary	Change from baseline in mean ADAS-Cog total score at W24 as a function of APOE e4 status in full population cohort	The 11-item ADAS-Cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Items were evaluated by tests and clinician ratings on a 5-point scale. Scores ranged from 0-70 with higher scores indicates more dysfunction. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline is defined as value at W0. Estimated value was calculated by Active treatment minus Placebo.	Baseline and W24	No
Primary	Change from baseline in mean CIBIC+ global functioning total score at W24 as a function of APOE e4 status in APOE4 negative cohort	The CIBIC+ assessment comprised of a 7-point rating of severity (at baseline) and change (at indicated time points). It was based on interviews with the par. and caregiver by an independent rater. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived. Estimated value was calculated by Active treatment minus Placebo.	Baseline and W24	No
Primary	Change from baseline in mean CIBIC+ global functioning total score at W24 as a function of APOE e4 status in all except e4/e4's cohort	The CIBIC+ assessment comprised of a 7-point rating of severity (at baseline) and change (at indicated time points). It was based on interviews with the par. and caregiver by an independent rater. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived. Estimated value was calculated by Active treatment minus Placebo.	Baseline and W24	No
Primary	Change from baseline in mean CIBIC+ global functioning total score at W24 as a function of APOE e4 status in full population cohort	The CIBIC+ assessment comprised of a 7-point rating of severity (at baseline) and change (at indicated time points). It was based on interviews with the par. and caregiver by an independent rater. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived. Estimated value was calculated by Active treatment minus Placebo.	Baseline and W24	No
Secondary	Change from baseline in mean ADAS-Cog total score at W8, W16, W24	The 11-item ADAS-Cog assessed a range of cognitive abilities including memory, comprehension, orientation in time and place and spontaneous speech. Most items were evaluated by tests, but some were dependent on clinician ratings on a 5-point scale. Scores ranged from 0-70 with higher scores indicating greater dysfunction. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline is defined as value at W0. Endpoint treatment differences were adjusted to take account of missing data. It was evaluated at Baseline, W8, W16 and W24.	Baseline and up to W24	No
Secondary	Change from baseline in mean CIBIC+ global functioning total score at W8, W16, W24	The CIBIC+ assessment comprised of a 7-point rating of severity (at baseline) and change (at indicated time points). The scale was based on interviews with the par. and caregiver and was completed by an independent rater. It required separate structured 15-20 minute interviews with the par. and caregiver. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived. It was evaluated at Baseline, W8, W16 and W24.	Baseline and up to W24	No
Secondary	Change from baseline in mean Neuropsychiatric Inventory total score at W8, W16, W24	The Neuropsychiatric Inventory (NPI) was an assessment of behavioural disturbances in dementia. It comprises 10 dimensions: delusions, hallucinations, dysphoria, apathy, euphoria, disinhibition, aggressiveness and agitation, irritability, anxiety, aberrant motor activity. Each dimension had screening and follow-up questions relating to symptoms. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived.	Baseline and up to W24	No
Secondary	Change from baseline in mean Disability Assessment for Dementia scale total score at W8, W16, W24	The Disability Assessment for Dementia (DAD), assessed the ability of a par. to execute basic and instrumental activities of daily living (ADL) and leisure activities. The scale consists of 40 questions assessing basic and instrumental ADLs. The percentage score was calculated as (DAD Total score/Total number of applicable items) multiplied by 100. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived	Baseline and up to W24	No
Secondary	Change from baseline in mean Short Term Memory Assessment total score (ADAS-Cog Q1 plus Q7) at W8, W16, W24	Change from baseline in Short Term Memory Assessment score was assessed from a combined analysis of items 1 and 7 of ADAS-Cog scale. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived.	Baseline and up to W24	No
Secondary	Change from baseline in mean European Quality of Life -5 Dimensions Proxy version (EQ-5D Proxy) total score at W12, W24 assessed by utility	The EQ-5D Proxy was a 2 part scale used to assess the quality of life and utility benefit. The data for Part 1 is presented. It is a 5 dimensional Health State Classification. Carers were asked to respond as they feel the par. would on dimensions of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Answers to each question were responded to on a three-point scale which indicates the level of impairment (level 1= no problem; level 2=some or moderate problem(s) and level 3=unable, or extreme problem. EQ-5D Proxy assessments was performed at Baseline, W12 and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived.	Baseline and up to W24	No
Secondary	Change from baseline in mean European Quality of Life -5 Dimensions Proxy version (EQ-5D Proxy) total score at W12, W24 assessed by Thermometer (Visual Analog Scale [VAS])	The EQ-5D Proxy is a 2 part scale used to assess the quality of life and utility benefit. The data for Part 2 is presented. It is a the visual analogue scale Thermometer which assessed caregiver's impression of par. overall health. The Thermometer has endpoints of 100 (best imaginable health state) and 0 (worst imaginable health state). EQ-5D Proxy assessments was performed at Baseline, W12 and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived.	Baseline and up to W24	No
Secondary	Time spent caring for basic and instrumental activities Resource Utilization in Dementia (RUD) scale at W12 and W24	The RUD instrument was developed as a comprehensive tool to assess the amount of resource use among demented par. RUD assess both formal and informal resource use of the par. and the primary caregiver, making it possible to calculate costs from a societal perspective. Q1 relates to assisting par. with basic activities of daily living and Q2 relates to instrumental activities of daily living. The assessments was performed at Baseline, W12 and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived.	Baseline and up to W24	No
Secondary	Change from baseline in Alzheimer's Carer's Quality of Life Instrument (ACQLI) score at W12 and W24.	The ACQLI was an assessment of caregiver quality of life. This instrument consists of 30 questions exploring various aspects of carer's quality of life. Each of the questions had a two point response, and the 30 questions were summed to provide a total score. The assessments was performed at Baseline, W12 and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived.	Baseline and up to W24	No
Secondary	Change from baseline in Mini Mental State Examination (MMSE) total score at W24.	The MMSE consists of 11 tests of orientation, memory (recent and immediate), concentration, language and praxis. Scores range from 0 to 30, with lower scores indicating greater cognitive impairment. The scale is completed by the investigator, based on the performance of the par. and takes approximately 5 to 10 minutes to administer. The assessments was performed at Baseline and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived	Baseline and W24	No
Secondary	Change from baseline in Glycosylated hemoglobin (HbA1c) at W24.	The blood sample was collected for assessments of HbA1c levels at Baseline and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0. Endpoint treatment differences which were adjusted to take account of missing data are derived.	Baseline and W24	No
Secondary	Number of participants with adverse events defined by severity	An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE included significant or unexpected worsening or exacerbation of the condition/indication under study, exacerbation of a chronic or intermittent pre-existing condition, new conditions detected or diagnosed, signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational product or a concurrent medication. Number of participants with any AE and as per severity were reported. Refer to the general AE/SAE module for a list of AEs and SAEs.	Up to W24	No
Secondary	Number of participants with systolic and diastolic blood pressure (SBP and DBP), heart rate (HR) and weight values of potential clinical concern (PCC) any time on treatment (ATOT).	SBP, DBP and HR of par. were recorded in sitting posture as vital signs, while body weight was measured without shoes and wearing light clothing at each visit. The blood pressure (BP) and HR values were identified as of PCC if the vales were out of the reference range (for SBP, 90 to 140 millimeters of mercury (mmHg), DBP, 50 to 90 mmHg, and HR >100 or <50 beats per minute [bpm]) or meet a change from Baseline criterion. For SBP it was increase from Baseline (high) if increased by more than or equal to (>=) 40 mmHg; decrease from Baseline (low) if decreased by >=30 mmHg. For DBP, increase from Baseline (high) if increased by >=30 mmHg; decrease from Baseline (low) if decreased by >=20 mmHg. For HR, increase from Baseline (high) if increased by >=30 bpm; decrease from Baseline (low) if decreased by >=30 bpm. For weight, increase from Baseline (high) if increased by >=7%; decrease from Baseline (low) if decreased by >=7%. Baseline was defined as value at W0.	Up to W24	No
Secondary	Change from baseline in 12-lead Electrocardiogram (ECG)	Triplicate 12-lead ECG measures was obtained digitally, approximately one minute apart after the par. had rested in the supine position in a quiet room (no TV, minimal talking) for at least 10 minutes. Conduction intervals from the 12-lead ECGs were manually read and confirmed by an external cardiologist/vendor. The ECG parameters includes PR interval, QRS duration, QT - uncorrected interval, QTc Bazett (QTcB), QTc Fridericia (QTcF) and RR interval of Central Cardiologist are reported. The assessments was performed at Baseline and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at Screening/Visit 1/W-6.	Baseline and up to W24	No
Secondary	Change from baseline in heart rate (HR) measured from 12-lead Electrocardiogram (ECG)	Triplicate 12-lead ECG measures was obtained digitally, approximately one minute apart after the par. had rested in the supine position in a quiet room (no TV, minimal talking) for at least 10 minutes. Conduction intervals from the 12-lead ECGs were manually read and confirmed by an external cardiologist/vendor. The ECG HR of Central Cardiologist reported. The assessments was performed at Baseline and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at Screening/Visit 1/W-6.	Baseline and up to W24	No
Secondary	Change from baseline in body weight	Body weight will be measured at all visits, without shoes and wearing light clothing. The assessments was performed at Baseline, W4, W8, W12, W16, and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0.	Baseline and up to W24	No
Secondary	Change from baseline in hemoglobin	Hematology parameters were assessed at Baseline, W4, W12 and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0.	Baseline and Up to W24	No
Secondary	Change from baseline in hematocrit	Hematology parameters were assessed at Baseline, W4, W12 and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0.	Baseline and Up to W24	No
Secondary	Change from Baseline in Periodic HbA1c assessment	HbA1c assessment was performed par. with type 2 diabetes mellitus or HbA1c >=6.5% at Screening only. HbA1c levels were assessed at Baseline, W12 and W24. Change from Baseline was calculated as value at scheduled time point minus Baseline value. Baseline was defined as value at W0.	Baseline and up to W24	No
Secondary	Number of par. with hematology data of potential clinical concern any time on treatment	Haematology parameters were identified as of PCC (high [H], low [L]), if the values were out of the reference range (RR). The range for parameters was: platelet (100AV-500AV), red blood cell (RBC, 0.8-1.2), hemoglobin (L: female [F]:10, male [M]:11; H: F:16.5-AV, M:18), hematocrit (0.8-1.2), white blood cell (WBC, 3-15), neutrophils (0.75-1.5), lymphocytes (0.75-1.5), monocytes (0.75-2), eosinophils (none-2), basophils (none-2), mean corpuscle volume (MCV, 0.8-1.2), mean corpuscular hemoglobin (MCH, 0.8-1.2), mean corpuscular hemoglobin concentration (MCHC, 0.8-1.2), red cell distribution width (RDW, 0.8-1.2). Data for mean platelet volume (reference range not established) not reported	Up to W24	No
Secondary	Number of par. with clinical chemistry values of potential clinical concern any time on treatment	Clinical chemistry parameters were identified as of PCC (H, L), if values were out of RR: Alanine aminotransferase (ALT, none-120 [250% upper limit of RR, ULRR]), Albumin (0.75-2), Aspartate aminotransferase (AST,none-105 (3-64y), 137.5 (65+y), >250%ULRR), Alkaline phosphatase (ALP,none-312.5 (20+y), >250%ULRR), blood urea nitrogen (BUN)/Creatinine ratio (none-1.25), BUN (none-11), Chloride (80-115), Calcium (0.75-1.25), Carbon dioxide (CO2, 15-40) content, Creatinine (22, <50% lower limit of RR [LLRR]-155, >125%ULRR), Creatine phosphokinase (CPK, none-1.25), Gamma glutamyl transferase (GGT,none-2.5), Glucose (3.6-7.8), High density lipoprotein (HDL,0.65-none), Lactate dehydrogenase (LDH,none-1.25), Low density lipoprotein (LDL,none-2), Magnesium (0.5-2), Potassium (3-5.5), Phosphorus inorganic (0.5-1.5), Sodium (130-150), Total protein (0.8-1.5), Total cholesterol (none-1.25), Total bilirubin (none-1.95), Triglycerides (none-9). Data for Creatinine clearance not reported.	Up to W24	No

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