A Study Comparing the Effect of Albiglutide With Exenatide on Regional Brain Activity Related to Nausea in Healthy Subjects

BOLD signal fMRI Visual Nauseogenic Task data were to be collected at indicated time-points. The seed-to-voxel driven approach included a priori seed Regions of interest (ROIs) placed in brain areas subserving nausea-related processing included regions like interoceptive/sensory (insula, Dorsal anterior cingulate cortex \[dACC\]), emotional/affective (amygdala, Pregenual anterior cingulate cortex \[pgACC\]), and cognitive/evaluative (dorsolateral prefrontal cortex \[dlPFC\]/ Occipitofrontal Circumference \[OFC\]) brain areas, primary visual (V1) and extrastriate cortices. The primary endpoints of this exploratory study involved combining data from Part A and Part B. The purpose of Part A was decision making for Part B. Placebo was used to enable albiglutide and exenatide to be dosed at different times relative to MRI due to differences in Tmax, while preserving single-blind (similar to double dummy), hence data was to be reported in albiglutide, exenatide and off-therapy arms only.

Time frame: Up to Week 11

Population: All randomized Population (included participants who were randomized to receive study treatment, regardless of whether they took randomized study treatment). Imaging data were analyzed in Part A for only one participant who experienced nausea out of four study participants, and that, as a consequence, data cannot be summarized for Part A.

GABA concentrations was planned to be analyzed using proton-density weighted 1H-MRS. 1H-MRS analysis assessed regional differences GABA concentrations, normalized as a ratio with creatine. MRS quantification of metabolites of interest were based on frequency domain analysis using a LC Model. CRLBs, as reported from the LC Model analysis, were planned to be used to assess the reliability of the major metabolites and adequate SNR. CRLBs values less than 40% were further planned to be analyzed. Metabolite maps for each participant, and each session were planned to be calculated. Placebo was used to enable albiglutide and exenatide to be dosed at different times relative to MRI due to differences in Tmax, while preserving single-blind (similar to double dummy), hence data was reported in albiglutide, exenatide and off-therapy arms only.

Time frame: Up to Week 11

Population: All randomized Population. Imaging data were analyzed in Part A for only one participant who experienced nausea out of four study participants, and that, as a consequence, data cannot be summarized for Part A.

Glutamine/Glutamate (Glx) was planned to be analyzed using proton-density weighted magnetic resonance spectroscopy (1H-MRS). 1H-MRS analysis assessed regional differences in Glx concentrations, normalized as a ratio with creatine. MRS quantification of metabolites of interest were based on frequency domain analysis using a Linear Combination of Model spectra (LCModel). Cramer-Rao lower bounds (CRLBs), as reported from the LCModel analysis, were planned to be used to assess the reliability of the major metabolites and adequate Signal to noise ratio (SNR). CRLBs values less than 40% were further planned to be analyzed. Metabolite maps for each participant, and each session were planned to be calculated. Placebo was used to enable albiglutide and exenatide to be dosed at different times relative to MRI due to differences in Tmax, while preserving single-blind (similar to double dummy), hence data was reported in albiglutide, exenatide and off-therapy arms only.

Time frame: Up to Week 11

Population: All randomized Population. Imaging data were analyzed in Part A for only one participant who experienced nausea out of four study participants, and that, as a consequence, data cannot be summarized for Part A.

Pseudo-Continuous Arterial spin labeling (pCASL) data were planned to be analyzed to assess rCBF within the brain during using functional MRI scans. Quality control of imaging data were planned to be performed by visual inspection with adequate data denoted by mean rCBF values over the gray matter within a previously defined normal range (i.e., 40-60 millimeter \[mm\]/100 gram \[g\] tissue/ minute \[min\]). In addition, all data were planned to undergo motion and physiological noise correction. Placebo was used to enable albiglutide and exenatide to be dosed at different times relative to MRI due to differences in Tmax, while preserving single-blind (similar to double dummy), hence data was reported in albiglutide, exenatide and off-therapy arms only.

Time frame: Up to Week 11

Population: All randomized Population. Imaging data were analyzed in Part A for only one participant who experienced nausea out of four study participants, and that, as a consequence, data cannot be summarized for Part A.

Participant completed VAS to record their perception of stomach fullness, hunger, nausea, bloating and abdominal pain. The VAS was represented by lines, 100 millimeter in length, anchored with words describing the most negative rating on the left and the most positive rating on the right. Scores ranged from 0 mm to 100 mm. Scores of 0 mm are worst (most negative rating on the left) and scores of 100 mm are best (most positive rating on the right). NA indicates that data were not available as standard deviation could not be calculated due to low number of participants.

Time frame: Day 1 (Pre-MRI and 0.5 hour post-MRI); Day 4 (Pre-MRI and 0.5 hour post-MRI); and Day 8 (Pre-MRI and 0.5 hour post-MRI)

Population: Safety Population. Only participants present at specific time points were analyzed. Placebo was planned to be used to enable albiglutide and exenatide to be dosed at different times relative to MRI due to differences in Tmax, for preserving single-blind (like double dummy), hence data was reported in albiglutide, exenatide and off-therapy arms only

Participant completed VAS to record their perception of stomach fullness, hunger, nausea, bloating and abdominal pain. The VAS was represented by lines, 100 millimeter in length, anchored with words describing the most negative rating on the left and the most positive rating on the right. Scores ranged from 0 mm to 100 mm. Scores of 0 mm are worst (most negative rating on the left) and scores of 100 mm are best (most positive rating on the right). NA indicates that data were not available as standard deviation could not be calculated due to low number of participants.

Time frame: Day 1 (Pre-MRI and 0.5 hour post-MRI); Day 4 (Pre-MRI and 0.5 hour post-MRI); and Day 8 (Pre-MRI and 0.5 hour post-MRI)

Population: Safety Population. Only participants present at specific time points were analyzed. Placebo was planned to be used to enable albiglutide and exenatide to be dosed at different times relative to MRI due to differences in Tmax, for preserving single-blind (like double dummy), hence data was reported in albiglutide, exenatide and off-therapy arms only

Heart rate variability was to be evaluated using autonomic response measure. All peripheral autonomic physiological signals were planned to be collected at 400 Hz using Chart Data Acquisition Software (ADInstruments) on a laptop equipped with a 16-channel Powerlab DAQ System (ADInstruments). Heart rate variability was to be reported as recorded by chart data acquisition software. Placebo was planned to be used to enable albiglutide and exenatide to be dosed at different times relative to MRI due to differences in Tmax, while preserving single-blind (similar to double dummy), hence data was reported in albiglutide, exenatide and off-therapy arms only.

Time frame: Up to Week 11

Population: Safety Population. Imaging data were analyzed in Part A for only one participant who experienced nausea out of four study participants, and that, as a consequence, data cannot be summarized for Part A.

Participant completed MSAQ to quantify the severity of different dimensions of nausea induced by motion sickness. There were total 16 items: 4 related to gastro-intestinal (GI), 5 related to central (C), 3 related to peripheral (P) and 4 related to sopite-related (SR). All items were scored individually on a scale of 1-9 where 1 means 'not at all severe' and 9 means 'severe', with higher score indicates more severity. Individual 16 items with their scores are presented. NA indicates that data were not available as standard deviation could not be calculated due to low number of participants.

Time frame: Day 1 0.5 hour post-MRI; Day 4 0.5 hour post-MRI; and Day 8 0.5 hour post-MRI

Population: Safety Population. Only participants present at specific time points were analyzed. Placebo was planned to be used to enable albiglutide and exenatide to be dosed at different times relative to MRI due to differences in Tmax, for preserving single-blind (like double dummy), hence data was reported in albiglutide, exenatide and off-therapy arms only

Participant completed MSAQ to quantify the severity of different dimensions of nausea induced by motion sickness. There were total 16 items: 4 related to gastro-intestinal (GI), 5 related to central (C), 3 related to peripheral (P) and 4 related to sopite-related (SR). All items were scored individually on a scale of 1-9 where 1 means 'not at all severe' and 9 means 'severe', with higher score indicates more severity. Individual 16 items with their scores are presented. NA indicates that data were not available as standard deviation could not be calculated due to low number of participants.

Time frame: Day 1 0.5 hour post-MRI; Day 4 0.5 hour post-MRI; and Day 8 0.5 hour post-MRI

Population: Safety Population. Only participants present at specific time points were analyzed. Placebo was planned to be used to enable albiglutide and exenatide to be dosed at different times relative to MRI due to differences in Tmax, for preserving single-blind (like double dummy), hence data was reported in albiglutide, exenatide and off-therapy arms only

Nausea ratings were planned to be collected during motion sickness provocation using a 0-4 numerical rating scale (NRS), where 1 is rated as minimal nausea experienced and 4 as severe nausea was experienced. Participants were asked to press buttons on a MRI compatible button-box to rate nausea from 0 to 4. Placebo was planned to be used to enable albiglutide and exenatide to be dosed at different times relative to MRI due to differences in Tmax, while preserving single-blind (similar to double dummy), hence data was reported in albiglutide, exenatide and off-therapy arms only.

Time frame: Up to Week 11

Population: Safety Population. Imaging data were analyzed in Part A for only one participant who experienced nausea out of four study participants, and that, as a consequence, data cannot be summarized for Part A.

Clinical chemistry parameters included assessment of blood urea nitrogen (BUN), creatinine, epidermal growth factor receptor (eGRF), potassium, sodium, calcium, Aspartate transaminase (AST), Alanine transaminase (AST), Alkaline phosphatase, total and direct bilirubin, total protein and albumin.

Time frame: Up to Week 11

Population: Safety Population. The data was reported in cumulative format as placebo was included to maintain the single blind only; similar to double dummy.

ECGs intervals were to be evaluated for the participant during the scanning session using autonomic response measures. ECG signal were planned to be collected with an MRI-compatible participant Monitoring system (Biopac 150, Biopac Systems Inc.) through MRI-compatible electrodes (VerMed, Bellows Falls) placed on the chest. Placebo was planned to be used to enable albiglutide and exenatide to be dosed at different times relative to MRI due to differences in Tmax, while preserving single-blind (similar to double dummy), hence data was reported in albiglutide, exenatide and off-therapy arms only.

Time frame: Up to Week 11

Population: Safety Population. Imaging data were analyzed in Part A for only one participant who experienced nausea out of four study participants, and that, as a consequence, data cannot be summarized for Part A.

Glycemic parameters included assessment of capillary blood glucose and fasting plasma glucose.

Time frame: Up to Week 11

Population: Safety Population.The data was reported in cumulative format as placebo was included to maintain the single blind only; similar to double dummy.

Data of participants with abnormal heart rate (measured during site visits by sphygmomanometer) were reported. Participants with low and high heart rate has been presented. Potential clinical concern value for heart rate is \< 50 beats per minute to \> 120 beats per minute. Safety Population comprised of all participants who received at least one dose of the study treatment.

Time frame: Day 1: pre-MRI, 0.5 hour post-MRI; Day 4: -2 hours pre-MRI, 0.5 and 1 hour post MRI; Day 5; Day 8: -2 hour pre-MRI, 0.5 and 1 hour post-MRI

Population: Safety Population. Only participants present at specific time points were analyzed. Placebo was planned to be used to enable albiglutide and exenatide to be dosed at different times relative to MRI due to differences in Tmax, for preserving single-blind (like double dummy), hence data was reported in albiglutide, exenatide and off-therapy arms only

Data of participants with abnormal heart rate (measured during site visits by sphygmomanometer) were reported. Participants with low and high heart rate has been presented. Potential clinical concern value for heart rate is \< 50 beats per minute to \> 120 beats per minute.

Time frame: Day 1: pre-MRI, 0.5 hour post-MRI; Day 4: -2 hours pre-MRI, 0.5 and 1 hour post MRI; Day 5; Day 8: -2 hour pre-MRI, 0.5 and 1 hour post-MRI

Population: Safety Population. Only participants present at specific time points were analyzed. Placebo was planned to be used to enable albiglutide and exenatide to be dosed at different times relative to MRI due to differences in Tmax, for preserving single-blind (like double dummy), hence data was reported in albiglutide, exenatide and off-therapy arms only

Hematology parameters included assessment of platelet count, red blood cell (RBC) count, hemoglobin, hemotocrit, RBC indices including mean corpuscular volume and mean corpuscular hemoglobin (MCH), and White blood cells (WBC) count with differential count including, neutrophils, lymphocytes, monocytes, eosinophils and basophils.

Time frame: Up to Week 11

Population: Safety Population. The data was reported in cumulative format as placebo was included to maintain the single blind only; similar to double dummy.

Number of participants with abnormal respiratory rate are reported during imaging session was to be evaluated using autonomic response measures. All peripheral autonomic physiological signals were planned to be collected at 400 Hz using Chart Data Acquisition Software (ADInstruments) on a laptop equipped with a 16-channel Powerlab DAQ System (ADInstruments). Placebo was planned to be used to enable albiglutide and exenatide to be dosed at different times relative to MRI due to differences in Tmax, while preserving single-blind (similar to double dummy), hence data was reported in albiglutide, exenatide and off-therapy arms only.

Time frame: Up to Week 11

Population: Safety Population. Imaging data were analyzed in Part A for only one participant who experienced nausea out of four study participants, and that, as a consequence, data cannot be summarized for Part A.

SBP and DBP were measured in supine position after 5 minutes rest. Data for Session 1 and 2 and for Pre and Post MRI has been presented. Potential clinical concern value for SBP is \<100 millimeters of mercury (mmHg) and \>170 mmHg. Potential clinical concern value for DBP is \<50 mmHg and \>110 mmHg.

Time frame: Day 1: pre-MRI, 0.5 hour post-MRI; Day 4: -2 hours pre-MRI, 0.5 and 1 hour post MRI; Day 5; Day 8: 0.5 and 1 hour post-MRI

Population: Safety Population. Only participants present at specific time points were analyzed. Placebo was planned to be used to enable albiglutide and exenatide to be dosed at different times relative to MRI due to differences in Tmax, for preserving single-blind (like double dummy), hence data was reported in albiglutide, exenatide and off-therapy arms only

SBP and DBP were measured in supine position after 5 minutes rest. Data for Session 1 and 2 and for Pre and Post MRI has been presented. Potential clinical concern value for SBP is \<100 millimeters of mercury (mmHg) and \>170 mmHg. Potential clinical concern value for DBP is \<50 mmHg and \>110 mmHg.

Time frame: Day 1: pre-MRI, 0.5 hour post-MRI; Day 4: -2 hours pre-MRI, 0.5 and 1 hour post MRI; Day 5; Day 8: 0.5 and 1 hour post-MRI

Population: Safety Population. Only participants present at specific time points were analyzed. Placebo was planned to be used to enable albiglutide and exenatide to be dosed at different times relative to MRI due to differences in Tmax, for preserving single-blind (like double dummy), hence data was reported in albiglutide, exenatide and off-therapy arms only

Urinalysis parameters included assessment of specific gravity, microscopic analysis, and potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick method.

Time frame: Up to Week 11

Population: Safety Population. The data was reported in cumulative format as placebo was included to maintain the single blind only; similar to double dummy.

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment were categorized as SAE. Data of participants with non-serious AEs ( with incidence \>= 2%) and SAEs has been presented. Placebo was included to maintain the single blind only; similar to double dummy.

Time frame: Up to Week 13

Population: Safety Population.

Skin conductance level was to planned to be evaluated with MRI-compatible bipolar Silver (Ag)/Silver chloride (AgCl) finger electrodes placed on the palmar aspect of the second and fourth fingers of the non-dominant (left) hand, prior to the MRI session. All peripheral autonomic physiological signals were planned to be collected at 400 Hz using Chart Data Acquisition Software (ADInstruments) on a laptop equipped with a 16-channel Powerlab DAQ System (ADInstruments). Placebo was planned to be used to enable albiglutide and exenatide to be dosed at different times relative to MRI due to differences in Tmax, while preserving single-blind (similar to double dummy), hence data was reported in albiglutide, exenatide and off-therapy arms only.

Time frame: Up to Week 11

Population: Safety Population. Imaging data were analyzed in Part A for only one participant who experienced nausea out of four study participants, and that, as a consequence, data cannot be summarized for Part A.