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

NCT02802514 | Terminated Phase 4 Results

• 1 other identifier: 201840
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

The drug effects will be studied after a single dose of 50 milligram (mg) albiglutide and a single dose of 10 microgram exenatide, to gain insight into the central mechanisms of nausea associated with Glucagon-like peptide-1 receptor (GLP-1R) agonists. This study will explore the potential differences at the expected time of maximum concentration (Cmax) between a long-acting (albiglutide) and short-acting (exenatide) GLP-1R agonist in brain activation of healthy volunteers assessed by magnetic resonance imaging (MRI). This is a phase IV, 2-part, 2-period crossover (session), single dose, randomized, single blind (blinded to both the subject and the imaging evaluators analysing the MRI data), placebo- and active-controlled study in adult healthy volunteers who are susceptible to motion sickness. Part A and Part B are the same in design, both consisting of a screening stage, a dosing/assessment stage, and a follow-up visit. Data from Part A will inform progression, methods, and analysis plan for Part B. Each sequence includes three scanning visits: albiglutide plus scan, exenatide plus scan and an off-therapy -natural history scan with a 6-9 week washout period between the dosing scans. A total of 24 to 28 subjects will be randomized in the study (Part A and Part B). The cross over design is divided into 2 sessions and schedule is as follow, on Day 1 (either Session 1 (S1) or Session 2 (S2) per, if randomized) subject will under go an off-therapy MRI scan, on Day 5 subject will receive a single dose of 50 mg albiglutide or albiglutide placebo, and Day 8 subject will receive a single dose of 10 microgram exenatide or saline placebo followed by a post-dose MRI scan. At each session subject will receive only one active drug (albiglutide or exenatide).

Conditions

Diabetes Mellitus

Keywords

Gastrointestinal; Glucagon like peptide; Nausea; Magnetic resonance imaging

Outcome Measures

Primary Outcomes (4)

• Blood Oxygen Level Dependent (BOLD) Signal by Functional Magnetic Resonance Imaging (fMRI) Visual Nauseogenic Task

  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.

  Up to Week 11

• Regional Cerebral Blood Flow (rCBF) by Functional MRI (fMRI)-Arterial Spin Labeling (ASL)

  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.

  Up to Week 11

• Glutamate Concentration in Nausea-associated Brain Regions by Magnetic Resonance Spectroscopy (MRS)

  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.

  Up to Week 11

• Gama-aminobutyric Acid (GABA) Concentration in Nausea-associated Brain Regions by MRS

  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.

  Up to Week 11

Secondary Outcomes (18)

• Heart Rate Variability Using Autonomic Response Measures by MRI

  Up to Week 11

• Number of Participants With Abnormal Electrocardiogram (ECG) Intervals Using Autonomic Response Measures by MRI

  Up to Week 11

• Number of Participants With Abnormal Respiratory Rate Using Autonomic Response Measures by MRI

  Up to Week 11

• Number of Participants With Skin Conductance Level Using Autonomic Response Measures by MRI

  Up to Week 11

• Number of Participants With Abnormal Heart Rate for Session 1

  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

Study Arms (4)

With Off therapy MRI in S1:Albiglutide-S1 & Exenatide-S2

EXPERIMENTAL

In session 1, eligible subject will undergo off-therapy MRI scan Subject will receive single dose each of 50 mg albiglutide on Day 5 and exenatide placebo on Day 8 followed by a post-dose MRI. In session 2, subject will receive single dose each of albiglutide placebo on Day 1 (Week 9) and 10 microgram exenatide on Day 4 followed by a post-dose MRI scan. There will be 6-9 week washout period between Session 1 and Session 2

Drug: Albiglutide 50mg; Drug: Albiglutide matching placebo; Drug: Exenatide 10microgram; Drug: Exenatide placebo (saline)

Without Off therapy MRI in S1:Albiglutide-S1 & Exenatide-S2

EXPERIMENTAL

In session 1, eligible subject will receive single dose each of 50 mg albiglutide on Day 1 and exenatide placebo on Day 4 followed by a post-dose MRI scan. In session 2, Day 1 (Week 9) subject will undergo off-therapy MRI scan. Subject will receive single dose each of albiglutide placebo on Day 5 and 10 microgram of exenatide on Day 8 followed by a post-dose MRI scan. There will be 6-9 week washout period between Session 1 and Session 2

Drug: Albiglutide 50mg; Drug: Albiglutide matching placebo; Drug: Exenatide 10microgram; Drug: Exenatide placebo (saline)

With Off therapy MRI in S1:Exenatide-S1 & Albiglutide-S2

EXPERIMENTAL

In session 1, Day 1 subject will undergo off-therapy MRI scan Subject will receive single dose each of albiglutide placebo on Day 5 and 10 microgram of exenatide on Day 8 followed by a post-dose MRI scan In session 2, eligible subject will receive single dose each of 50 mg albiglutide on Day 1 (Week 9) and exenatide placebo Day 4 followed by a post-dose MRI scan. There will be 6-9 week washout period between Session 1 and Session 2

Drug: Albiglutide 50mg; Drug: Albiglutide matching placebo; Drug: Exenatide 10microgram; Drug: Exenatide placebo (saline)

Without Off therapy MRI in S1: Exenatide-S1 & Albiglutide-S2

EXPERIMENTAL

In session 1, subject will receive single dose each of albiglutide placebo on Day 1 and 10 microgram exenatide on Day 4 followed by a post-dose MRI scan. In session 2, subject will undergo off-therapy MRI scan on Day 1 (Week 9). Subject will receive single dose each of 50 mg albiglutide on Day 5 and exenatide placebo on Day 8 followed by a post-dose MRI scan.. There will be 6-9 week washout period between Session 1 and Session 2

Drug: Albiglutide 50mg; Drug: Albiglutide matching placebo; Drug: Exenatide 10microgram; Drug: Exenatide placebo (saline)

Interventions

Albiglutide 50mg DRUG

It is provided as a single use fixed dose disposable pen injector (0.5 mL) system for SC delivery. A 50 mg pen contains 67 mg lyophilized albiglutide and 0.65 mL diluents. It will be injected subcutaneously (SC) in the upper arm.

With Off therapy MRI in S1:Albiglutide-S1 & Exenatide-S2; With Off therapy MRI in S1:Exenatide-S1 & Albiglutide-S2; Without Off therapy MRI in S1: Exenatide-S1 & Albiglutide-S2; Without Off therapy MRI in S1:Albiglutide-S1 & Exenatide-S2

Albiglutide matching placebo DRUG

It is provided as a single use fixed dose disposable pen injector (0.5 mL) system for SC delivery. It will be injected subcutaneously (SC) in the upper arm

With Off therapy MRI in S1:Albiglutide-S1 & Exenatide-S2; With Off therapy MRI in S1:Exenatide-S1 & Albiglutide-S2; Without Off therapy MRI in S1: Exenatide-S1 & Albiglutide-S2; Without Off therapy MRI in S1:Albiglutide-S1 & Exenatide-S2

Exenatide 10microgram DRUG

It is provided as a sterile solution containing 250 microgram/mL exenatide. One dose of 10 microgram is equivalent to 0.04 ml. It will be injected subcutaneously (SC) in the upper arm

With Off therapy MRI in S1:Albiglutide-S1 & Exenatide-S2; With Off therapy MRI in S1:Exenatide-S1 & Albiglutide-S2; Without Off therapy MRI in S1: Exenatide-S1 & Albiglutide-S2; Without Off therapy MRI in S1:Albiglutide-S1 & Exenatide-S2

Exenatide placebo (saline) DRUG

It is provided as a sterile saline. It will be injected subcutaneously (SC) in the upper arm

With Off therapy MRI in S1:Albiglutide-S1 & Exenatide-S2; With Off therapy MRI in S1:Exenatide-S1 & Albiglutide-S2; Without Off therapy MRI in S1: Exenatide-S1 & Albiglutide-S2; Without Off therapy MRI in S1:Albiglutide-S1 & Exenatide-S2

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Between 18 and 50 years of age inclusive, at the time of signing the informed consent.
• Healthy as determined by the Investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
• Pure right-handed based on Edinburgh Handedness Inventory
• Motion Sickness Susceptibility Questionnaire (MSSQ) Screening score \>60 and mock fMRI nausea rating \>=2

You may not qualify if:

• Subject's body mass index (BMI) is \>=19 (kilogram per square meter)kg/m\^2 and =\<30 kg/m\^2
• Male OR
• Female: eligible to participate if she is not pregnant (as confirmed by a negative human chorionic gonadotrophin (hCG) test at screening and at other timepoints), not lactating, and at least one of the following conditions applies: a. Non-reproductive potential defined as pre-menopausal females who are having documented tubal ligation or Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion or hysterectomy or documented Bilateral Oophorectomy OR Postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause to confirm (refer to laboratory reference ranges for confirmatory levels)\]. b. Reproductive potential and agrees to follow one of the options listed for avoiding pregnancy in females of reproductive potential (FRP) requirements from 30 days prior to the first dose of study medication and for the duration of study including the completion of the follow-up visit. The options are, Contraceptive subdermal implant or Intrauterine device or intrauterine system or Combined estrogen and progestogen oral contraceptive or Injectable progestogen or Contraceptive vaginal ring or Percutaneous contraceptive patches or Male partner sterilization with documentation of azoospermia prior to the female subject's entry into the study, and this male is the sole partner for that subject. The documentation on male sterility can come from the site personnel's: review of subject's medical records, medical examination and/or semen analysis, or medical history interview provided by her or her partner.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions.
• Severe nausea (with or without vomiting) in the last three months or any event of unexplained nausea (with or without vomiting) as reported by the subject in the last 14 days before screening.
• History of vestibular or balance disorders as determined by the Investigator.
• History of smoking cigarettes or using tobacco products or any nicotine-containing products (including nicotine patches) within 3 months of screening.
• Use of eyeglasses during functional MRI (fMRI). Subjects requiring visual correction to participate in visual task that cannot be corrected with contact lenses.
• Alanine amino transferase (ALT) \>1.5xupper limit of normal (ULN)
• Bilirubin \>1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%)
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities
• QT interval corrected for heart rate according to Fridericia's formula (QTcF) \>450 msec
• Systolic blood pressure is \>=140 millimeter of Mercury (mm Hg) at Screening; repeat blood pressures should be taken if the subject's systolic blood pressure is \>=140 mm Hg and if the results are consistently \>=140 mm Hg, then the subject will be excluded and advised to consult a physician
• Diastolic blood pressure is \>=90 mm Hg at Screening; repeat blood pressures should be taken if the subject's diastolic blood pressure is \>=90 mm Hg and if the results are consistently \>=90 mm Hg, then the subject should be excluded and advised to consult a physician
• Mean resting heart rate is \>100 beats/minutes (mins) out of 3 consecutive measures taken 10 mins apart at Screening

Sponsors & Collaborators

• GlaxoSmithKline: lead
• The General Hospital Corporation d/b/a Massachusetts General Hospital: collaborator

Study Sites (1)

GSK Investigational Site

Boston, Massachusetts, 02114, United States

Location

MeSH Terms

Conditions

Diabetes Mellitus; Nausea

Interventions

rGLP-1 protein; Sodium Chloride

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Signs and Symptoms, Digestive; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 2, 2016
• First Posted: June 16, 2016
• Study Start: September 20, 2016
• Primary Completion: August 10, 2017
• Study Completion: September 7, 2017
• Last Updated: October 30, 2020
• Results First Posted: August 24, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)