Safety and Efficacy Study of Albiglutide Liquid Drug Product in Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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This is a phase III, randomized, double-blind, multicenter, parallel group, repeat-dose, study of 26 weeks duration to evaluate the efficacy, safety, tolerability and pharmacodynamic response of albiglutide liquid drug product relative to the commercial lyophilized drug product. The study will specifically evaluate the potential for immunogenicity (example [e.g.] incidences of anti-drug antibodies [ADA]) and injection site reactions (ISRs). Albiglutide is a novel analogue of glucagon-like peptide-1 (GLP-1) with a sufficiently long half-life to permit once a week injection. Currently, lyophilized albiglutide and the diluent are provided in a dual chamber cartridge (DCC), single-dose pen injector, requiring reconstitution prior to use. A liquid formulation of albiglutide will enable the commercialization of a liquid product in a single dose, ready-to-use prefilled syringe in an auto-injector. The primary hypothesis of this study is to test that liquid drug product will provide glycemic control (as measured by HbA1c change from baseline) non-inferior to lyophilized drug product for a period of 26 weeks of treatment in subjects with T2DM. This study will comprise of 3 study periods : screening (2 weeks), treatment (26 weeks) and for those subjects not entering the extension study a follow-up period (8 weeks). Approximately 300 subjects will be randomized in a 1:1 ratio to either Albiglutide active liquid auto-injector (LAI) plus Placebo lyophilized DCC pen injector (lyophilized DCC PI); or, Albiglutide lyophilized DCC PI plus Placebo LAI.

Official Title
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A Repeat-dose Study in Subjects With Type 2 Diabetes Mellitus to Assess the Efficacy, Safety, Tolerability and Pharmacodynamics, of Albiglutide Liquid Drug Product

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Lyophilized albiglutide DCC pen injector
* Drug: Lyophilized albiglutide DCC pen injector matching placebo
* Drug: Albiglutide liquid auto-injector
* Drug: Albiglutide liquid auto-injector matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 80 years of age inclusive Historical diagnosis of type 2 diabetes mellitus (T2DM) (at least 3 months), experiencing inadequate glycemic control on current regimen of diet and exercise or on a stable maximal tolerated dose of metformin, maintained for approximately 8 weeks prior to screening. HbA1c >=7.0 percent (%) and <=10%. Hemoglobin >=11 grams per deciliter (g/dL) (>=110 grams per liter [g/L]) for males and >=10 g/dL (>=100 g/L) for females. Body mass index <=40 kilograms per squared meter (kg/m^2) Male or female Able and willing to provide informed consent. Exclusion Criteria: Type 1 diabetes mellitus History of cancer that has not been in full remission for at least 3 years before screening. (A history of squamous cell or basal cell carcinoma of the skin or treated cervical intra-epithelial neoplasia I or II is allowed). Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2. History of acute or chronic pancreatitis. History of thyroid dysfunction or an abnormal (i.e., outside the normal reference range) thyroid function test assessed by thyroid stimulating hormone at screening. Severe gastroparesis, i.e., requiring regular therapy within 6 months before screening. History of significant gastrointestinal (GI) surgery that in the opinion of the investigator is likely to significantly affect upper GI or pancreatic function History of severe hypoglycemia unawareness Diabetic complications or any other clinically significant abnormality . Clinically significant Cardiovascular (CV) and/or cerebrovascular disease within 3 months before screening QT interval corrected for heart rate according to Fridericia's formula (QTcF) > 470 milliseconds (msec). ALT >2.5x upper limit of the normal range (ULN) or bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment). Estimated glomerular filtration rate (eGFR) <=30 milliliter (mL)/minute (min)/1.73 squared meter (m^2) (calculated using the Modification of Diet in Renal Disease [MDRD] formula) at screening. Fasting triglyceride level >750 milligrams per deciliter (mg/dL) at screening. Hemoglobinopathy that may affect proper interpretation of HbA1c. Medical or psychiatric disorders that would preclude effective participation in study. Use of oral or systemically injected glucocorticoids within the 3 months before randomization or high likelihood of a requirement for prolonged treatment (>1 week) in the 6 months following randomization. Use of dipeptidyl peptidase-IV inhibitors within the 3 months before randomization. History of alcohol or substance abuse within one year before screening. Known allergy to albiglutide or any product components (including yeast and human albumin), any other glucagon-like peptide-1 (GLP-1) analogue, or other study medication's excipients OR other contraindications (per the prescribing information) for the use of potential study medications. A positive pre-study drug/alcohol screen. A positive test for human immunodeficiency virus (HIV) antibody. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Albiglutide active LAI plus Placebo lyophilized DCC PI<br>Subjects will receive 30 milligrams (mg) of albiglutide liquid drug product via auto injector and matching placebo via lyophilized DCC pen injector for 4 weeks. The dose will then be up-titrated to 50mg albiglutide for the remaining 22 weeks of the study. The study treatment will be administered once weekly by subcutaneous injection in the abdomen, thigh, or upper arm. | Drug: Lyophilized albiglutide DCC pen injector matching placebo<br>* A fixed-dose, fully disposable pen injector system with a prefilled DCC containing matching placebo delivering an injection volume of 0.5mL<br>Drug: Albiglutide liquid auto-injector<br>* A fixed-dose, single use, disposable auto-injector containing albiglutide liquid (30mg or 50mg) in a prefilled glass syringe. The auto-injector delivers the albiglutide liquid in an injection volume of 0.6 mL for the 30mg dose and 1.0 mL for the 50mg dose.<br>|
| Experimental: Albiglutide lyophilized DCC PI plus Placebo LAI<br>Subjects will receive 30mg of albiglutide lyophilized drug product via DCC pen injector and matching placebo via auto injector for 4 weeks. The dose will then be up-titrated to 50mg albiglutide for the remaining 22 weeks of the study. The study treatment will be administered once weekly by subcutaneous injection in the abdomen, thigh, or upper arm. | Drug: Lyophilized albiglutide DCC pen injector<br>* A fixed-dose, fully disposable pen injector system with a prefilled dual chamber glass cartridge (DCC) containing lyophilized albiglutide (30mg or 50mg) delivering an injection volume of 0.5mL.<br>Drug: Albiglutide liquid auto-injector matching placebo<br>* A fixed-dose, single use, disposable auto-injector containing matching placebo in a prefilled glass syringe. The auto-injector delivers the matching placebo in an injection volume of 0.6 mL for the 30mg dose and 1.0 mL for the 50mg dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26 | Blood samples will be collected from participants at specific time points to evaluate HbA1c to monitor for potential hyperglycemia. The last measurement collected prior to the first dose of randomized study treatment was considered as Baseline value. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The analysis was performed using a mixed-effect model with repeated measures (MMRM) method. The primary analysis will include all HbA1c values collected at scheduled visits from Week 4 up to Week 26. This will include values after hyperglycemia rescue and discontinuation from investigational product. Imputation under the non-inferiority null hypothesis for missing data will be incorporated. | Baseline and Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With On-therapy Adverse Events (AEs) and Serious AEs (SAEs) | 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. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth effect, other situations and is associated with liver injury or impaired liver function. | Up to Week 26 | 
| Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern (PCC) | Chemistry parameters for which PCC values were identified were alanine aminotransferase (ALT) (if value >3 * upper limit of normal [ULN]), albumin (if value >5 gram/liter [g/L] above ULN or below lower limit of normal [LLN]), alkaline phosphatase (alk.phosph.) (if value >3*ULN), aspartate aminotransferase (AST) (if value >3*ULN), total bilirubin (if value >1.5 ULN), calcium (if value <1.8 or >3.0 millimoles per liter [mmol/L]), carbon di oxide (CO2) (if value <16 or >40 mmol/L), creatinine (if value >159 micromoles per liter [µmol/L]), direct bilirubin (if value >1.35*ULN), gamma glutamyl transferase (GGT) (if value >3*ULN), potassium (if value >0.5 mmol/L below LLN and >1.0 mmol/L above ULN), protein (if value >15 g/L above ULN or below LLN), sodium (>5 mmol/L below LLN or above ULN), urate (if value >654 µmol/L) and urea (if value >2*ULN). Number of participants with chemistry parameters of PCC at 'any visit post-Baseline' are presented. | Up to Week 26 | 
| Number of Participants With Hematology Parameters of PCC | Hematology parameters for which PCC values were identified were hematocrit (if value >0.05 below LLN or >0.04 above ULN), Hemoglobin (Hb) (if value >20 g/L below LLN or >10 g/L above ULN), lymphocytes (if value <0.5*LLN), neutrophils (if value <1 giga unit per liter [GI/L]) and platelets (if value <80 GI/L or >500 GI/L). Number of participants with hematology parameters of PCC at 'any visit post-Baseline' are presented. | Up to Week 26 | 
| Number of Participants With Vital Signs of PCC | Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate were measured in a seated position after at least 5 minutes of rest. SBP values <100 millimeters of mercury (mmHg) and >170 mmHg, DBP values <50 mmHg and >110 mmHg, pulse rate values <50 beats per minute (bpm) and >120 bpm were considered as PCC values. Number of participants with PCC values of vital signs for 'any visit post-Baseline' are presented. | Up to Week 34 | 
| Number of Participants With Electrocardiogram (ECG) Parameters of PCC | Single measurements of 12-lead ECG were obtained in semi recumbent position using an ECG machine that automatically calculates the heart rate and measures PR and QT interval corrected for heart rate according to Fridericia's formula (QTcF). Number of participants with ECG values of PCC at 'any visit post-Baseline' are presented. ECG mean heart rate values <50 or >120, PR interval >300 milliseconds (msec), QRS interval >200 msec, QTcF interval >=500 msec were considered as PCC values. Number of participants with PCC values of ECG parameters for 'any visit post-Baseline' are presented. | Up to Week 26 | 
| Number of Participants With Positive Result for Anti-albiglutide Antibody | Blood samples were obtained from participants at specific time points before administration of study treatment. The presence of anti-albiglutide antibodies was assessed using a validated enzyme linked immunosorbent assay (ELISA). The assay involves screening, confirmation, and titration steps (tiered-testing approach). Number of participants with positive anti- albiglutide antibody results at 'any visit post-Baseline' are presented. | Up to Week 34 | 
| Number of Participants With Injection Site Reactions (ISR) | Number of participants with ISR incidences were evaluated at specific time points. Each week included those participants with the onset of an ISR during that particular week as well as those participants with ISR from previous weeks that have not resolved. | Up to Week 34 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | Blood samples were collected from participants at specific time points to evaluate FPG to monitor for potential hyperglycemia. The last measurement collected prior to the first dose of randomized study treatment was considered as Baseline value. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The analysis was performed using a MMRM model. | Baseline and Week 26 | 
| Change From Baseline in HbA1c Over Time | Blood samples were collected from participants at specific time points to evaluate HbA1c to monitor for potential hyperglycemia. The last measurement collected prior to the first dose of randomized study treatment was considered as Baseline value. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The analysis was performed using a MMRM model and model-adjusted least square mean (LS mean) and standard error have been presented. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). | Baseline and up to Week 26 | 
| Change From Baseline in FPG Over Time | Blood samples were collected from participants at specific time points to evaluate FPG to monitor for potential hyperglycemia. The last measurement collected prior to the first dose of randomized study treatment was considered as Baseline value. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The analysis was performed using a MMRM model. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). | Baseline and up to Week 26 | 
| Trough Plasma Concentration of Albiglutide Over Time | Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of albiglutide. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). | Pre-dose at Week 12 and Week 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety, Pharmacodynamics, Albiglutide, Tolerability, Type 2 Diabetes Mellitus, Efficacy