Type 2 Diabetes
Conditions
Keywords
Diabetes, MEDI0382, D5674C00001, T2DM, Type 2 Diabetes
Brief summary
This is a Phase 2a study designed to assess the safety and tolerability of MEDI0382 titrated up to a dose level of 100, 200 or 300 µg from 50 µg vs Placebo across 48 days in Japanese subjects. The study D5674C00001 can be conducted with a reasonable expectation of safety and tolerability in Japanese T2DM patients. The design of this study has taken into account the known benefits and risks of GLP-1 receptor agonists and glucagon receptor agonists as well as the translatable effects observed in nonclinical studies of MEDI0382.
Detailed description
This is a randomized, parallel-group, placebo-controlled, double-blind, multicenter Phase Ⅱa study to evaluate the safety, efficacy, and pharmacokinetics of MEDI0382 in Japanese preobese and obese subjects with type 2 diabetes who have inadequate glycemic control with diet and exercise. Subject fulfilling all of the inclusion criteria and none of the exclusion criteria will be randomised in a 1:1:1:1 ratio to four treatment arms. This is a Phase IIa study designed to evaluate the dose range for MEDI0382 to explore the safety profile, as well as blood glucose control and weight loss effects of MEDI0382 in Japanese patients with T2DM. The design of this study has taken into account the known benefits and risks of GLP-1 receptor agonists and glucagon receptor agonists as well as the translatable effects observed in nonclinical studies of MEDI0382, such that benefit-risk balance for the Japanese preobese and obese patients with T2DM in this study is considered favourable. A treatment period of 48 days is required to properly evaluate the dose range and safety and tolerability in three different doses. Inclusion of placebo in the study allows appropriate basis of AEs, glycaemic control, and weight loss. Benefits related to participation in this trial include close follow-up of a subject's diabetes and treatment with anti-diabetes agents. Although one of possible treatments is placebo, appropriate rescue therapy for worsening glycaemic control will be implemented if required.
Interventions
DRUGMEDI0382 100 μg
Solution for injection in 1.0 mL pre-filled syringe, 100 μg per dose, 1 dose
DRUGMEDI0382 200 μg
Solution for injection in 1.0 mL pre filled syringe 200 μg per dose, 1 dose
DRUGMEDI0382 300 μg
Solution for injection in 1.0 mL pre filled syringe, 300 μg per dose, 1 dose
DRUGPlaceboA
1.0 mL liquid formulation per Vial
DRUGMEDI0382 50 ug
Solution for injection, 1.0 mL per vial, 50 ug
DRUGPlaceboB
Solution for injection in 1.0 mL pre-filled syringe.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
* Individuals whose HbA1c range of 7.0% to 10.5% (inclusive) at screening. * Individuals who are diagnosed with T2DM * Individuals whose current condition at enrolment (Visit 1) is drug naïve * BMI within the range of 24 - 40 kg/m2 (inclusive) at screening
Exclusion criteria
* Subjects with any of the following results at screening: * Aspartate transaminase (AST) ≥ 2.5 × upper limit of normal (ULN) * Alanine transaminase (ALT) ≥ 2.5 × ULN * Total bilirubin (TBL) ≥ 2 × ULN * Impaired renal function defined as estimated glomerular filtration rate (eGFR) ≤ 60 mL/minute/1.73 m2 at screening * Participation in another clinical study with an investigational product administered in the last 30 days or 5 half-lives of the drug (whichever is longer) at the time of screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in 24-Hour Heart Rate at Days 20 and 48 | Baseline (Day -1) and Days 20 and 48. | Twenty four-hour heart rate was determined using an ambulatory blood pressure monitoring (ABPM) device, and the mean change from baseline in the 24-hour heart rate is presented for Days 20 and 48. |
| Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 | Baseline (Day -1) and Days 20 and 48. | Twenty four-hour BP was determined using an ABPM device, and the mean change from baseline in the 24-hour systolic BP and 24-hour diastolic BP are presented for Days 20 and 48. |
| Mean Percentage Change From Baseline in Glucose Area Under the Plasma Concentration Curve (AUC[0-4h]) as Measured by a Standardised Mixed-Meal Test (MMT) at Day 48 | Baseline (Day -1) and Day 48: 15 minutes before standardised meal, and then at 15, 30, 45, 60, 90, 120, 180 and 240 minutes (+/-5 minutes) after consumption of the standardised meal. | The MMT was conducted following a minimum 8-hour fast. Blood samples for glucose monitoring were taken 15 minutes before the patient consumed a standardised meal, and samples were taken at intervals after the meal, up to 4 hours. The MMT glucose AUC(0-4h) was calculated using a trapezoidal method, and the mean percentage change from baseline at Day 48 was analysed using an analysis of covariance (ANCOVA) model with treatment group as a factor and baseline as a covariate. |
| Mean Percentage Change From Baseline in Body Weight at Day 48 | Baseline (Day -1) and Day 48. | The mean percentage change from baseline in body weight at Day 48 was analysed using an ANCOVA model with treatment group as a factor and baseline as a covariate. For patients who prematurely discontinued IP, the last on-treatment measurement, regardless of rescue medication, was used (last observation carried forward \[LOCF\]). |
| Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Baseline (Day -1) and Days 1, 6, 13, 20 and 48: predose and 6 hours (+/-15 minutes) postdose. | Digital ECGs were taken at baseline and predose and postdose on Days 1, 6, 13, 20 and 48. The mean change from baseline is presented. |
| Number of Patients Who Experienced Adverse Events (AEs) | Day 1 up to 14 days after the last dose of IP (approximately 9 weeks). | AEs were collected from Day 1 of treatment up to 14 days after the last dose of IP. Serious AEs (SAEs) were collected from signing of informed consent. The numbers of patients who experienced any AE, any SAE (including events with an outcome of death), and any AE leading to discontinuation of IP are presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Baseline (Day -8 to -2) and Days 1 to 5, 6 to 12, 13 to 19 and 41 to 47. | Hyp0glycaemia was defined as blood glucose \<3 mmol/L or \<54 mg/dL. Continuous glucose monitoring used a device fitted to the upper arm by trained study site staff to measure and record interstitial glucose levels every 15 minutes. Analysis was based on 24-hour readings defined as the first available time point with a valid continuous glucose monitoring glucose reading. The change in the percentage time in hypoglycaemia from the last day of baseline continuous glucose monitoring over 5 days for 50 mcg MEDI0382 and 7 days for each of the randomised dose levels (during titration) is presented, up to Day 47, per randomised group. |
| Mean Change From Baseline in HbA1c at Day 48 | Baseline (Day -1) and Day 48 (predose). | The mean change from baseline in HbA1c at Day 48 was analysed using an ANCOVA model with treatment group as a factor and baseline as a covariate. For patients who prematurely discontinued IP, or for patients who did not have a measurement taken on Day 48, the last post-baseline measurement, regardless of rescue medication, was used (LOCF). |
| Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | Samples were collected predose on days 1, 13, 20 and 48, and 7 to 14 days after administration of last dose of IP. | The number of patients who were ADA positive at baseline and/or post-baseline are presented. Persistent positive was defined as positive at ≥2 post-baseline assessments (with ≥16 weeks between first and last positive) or positive at the last post-baseline assessment. Transiently positive was defined as having at least 1 post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive. +ve = positive |
| Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48 | Blood samples collected predose on Days 1 to 6, 13, 20, 34 and 48. | To evaluate pharmacokinetics (PK), blood samples were collected predose and Ctrough of MEDI0382 was determined. Results are presented for Days 2, 5, 34 and 48. |
| Mean Change From Baseline in Fasting Plasma Glucose at Day 48 | Baseline (Day -1) and Day 48 (predose). | The mean change from baseline in fasting plasma glucose at Day 48 was analysed using an ANCOVA model with treatment group as a factor and baseline as a covariate. For patients who prematurely discontinued IP, or for patients who did not have a measurement taken on Day 48, the last post-baseline measurement, regardless of rescue medication, was used (LOCF). |
| Mean Change From Baseline in Fructosamine at Day 48 | Baseline (Day -1) and Day 48 (predose). | The mean change from baseline in fructosamine at Day 48 was analysed using an ANCOVA model with treatment group as a factor and baseline as a covariate. For patients who prematurely discontinued IP, the last on-treatment measurement, regardless of rescue medication, was used (LOCF). |
| Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Baseline (Day -8 to -2) and Days 5, 12, 19 and 47. | Hyperglycaemia was defined as blood glucose \>7.8 mmol/L or \>140 mg/dL. Continuous glucose monitoring used a device fitted to the upper arm by trained study site staff to measure and record interstitial glucose levels every 15 minutes. Analysis was based on 24-hour readings defined as the first available time point with a valid continuous glucose monitoring glucose reading. The change in the percentage time in hyperglycaemia from the last day of baseline continuous glucose monitoring over 24 hours to the end of dosing at each dose level for the indicated timepoints is presented. |
| Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Baseline (Day -8 to -2) and Days 5, 12, 19 and 47. | Hypoglycaemia was defined as blood glucose \<3 mmol/L or \<54 mg/dL. Continuous glucose monitoring used a device fitted to the upper arm by trained study site staff to measure and record interstitial glucose levels every 15 minutes. Analysis was based on 24-hour readings defined as the first available time point with a valid continuous glucose monitoring glucose reading. The change in the percentage time in hypoglycaemia from the last day of baseline continuous glucose monitoring over 24 hours to the end of dosing at each dose level for the timepoints is presented. |
| Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Baseline (Day -8 to -2) and Days 1 to 5, 6 to 12, 13 to 19 and 41 to 47. | Hyperglycaemia was defined as blood glucose \>7.8 mmol/L or \>140 mg/dL. Continuous glucose monitoring used a device fitted to the upper arm by trained study site staff to measure and record interstitial glucose levels every 15 minutes. Analysis was based on 24-hour readings defined as the first available time point with a valid continuous glucose monitoring glucose reading. The change in the percentage time in hyperglycaemia from the last day of baseline continuous glucose monitoring over 5 days for 50 mcg MEDI0382 and 7 days for each of the dose levels (during titration) is presented, up to Day 47, per randomised group. |
Countries
Japan
Participant flow
Recruitment details
Preobese/obese Japanese adults with Type 2 diabetes mellitus (T2DM) were recruited to this Phase IIa randomised, parallel-group, placebo-controlled, double-blind, study at 5 centres in Japan. The first patient started in August 2018 and the last patient completed in January 2019.
Pre-assignment details
Patients with an early stage of T2DM who had inadequate blood glucose control, defined as glycated haemoglobin (HbA1c) between 7.0% and 10.5%, and who were treated with diet and exercise were enrolled. A body mass index of 24 to 40 kg/m2 was also a requirement. Patients with acutely decompensated blood glucose control were excluded.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients were randomised to receive MEDI0382 matched placebo for 48 days. | 16 |
| MEDI0382 100 mcg Patients were randomised to receive 100 mcg MEDI0382 per day by SC injection, titrated as follows: 50 mcg/day for 5 days and then 100 mcg/day for 43 days. | 15 |
| MEDI0382 200 mcg Patients were randomised to receive 200 mcg MEDI0382 per day by SC injection, titrated as follows: 50 mcg/day for 5 days, 100 mcg/day for 7 days and then 200 mcg/day for 36 days. | 15 |
| MEDI0382 300 mcg Patients were randomised to receive 300 mcg MEDI0382 per day by SC injection, titrated as follows: 50 mcg/day for 5 days, 100 mcg/day for 7 days, 200 mcg/day for 7 days and then 300 mcg/day for 29 days. | 15 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 4 | 1 |
| Overall Study | Study specific withdrawal criteria | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by patient | 0 | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | MEDI0382 300 mcg | Total | Placebo | MEDI0382 100 mcg | MEDI0382 200 mcg |
|---|---|---|---|---|---|
| Age, Continuous | 57.5 years STANDARD_DEVIATION 9.2 | 58.2 years STANDARD_DEVIATION 9.8 | 60.0 years STANDARD_DEVIATION 8.6 | 56.7 years STANDARD_DEVIATION 10.7 | 58.7 years STANDARD_DEVIATION 11.3 |
| Race/Ethnicity, Customized Asian | 15 Participants | 61 Participants | 16 Participants | 15 Participants | 15 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 15 Participants | 61 Participants | 16 Participants | 15 Participants | 15 Participants |
| Sex: Female, Male Female | 2 Participants | 14 Participants | 3 Participants | 7 Participants | 2 Participants |
| Sex: Female, Male Male | 13 Participants | 47 Participants | 13 Participants | 8 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 15 | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 6 / 16 | 6 / 15 | 11 / 15 | 9 / 15 |
| serious Total, serious adverse events | 0 / 16 | 0 / 15 | 0 / 15 | 0 / 15 |
Outcome results
Primary
Mean Change From Baseline in 24-Hour Heart Rate at Days 20 and 48
Twenty four-hour heart rate was determined using an ambulatory blood pressure monitoring (ABPM) device, and the mean change from baseline in the 24-hour heart rate is presented for Days 20 and 48.
Time frame: Baseline (Day -1) and Days 20 and 48.
Population: The Safety Analysis Set included all randomised patients who received at least 1 dose of IP, analysed according to the treatment received. Patients with data available at each timepoint are presented.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change From Baseline in 24-Hour Heart Rate at Days 20 and 48 | Day 20 | -1.86 beats/minute | Standard Deviation 7.43 |
| Placebo | Mean Change From Baseline in 24-Hour Heart Rate at Days 20 and 48 | Day 48 | -0.25 beats/minute | Standard Deviation 7.24 |
| MEDI0382 100 mcg | Mean Change From Baseline in 24-Hour Heart Rate at Days 20 and 48 | Day 48 | 7.87 beats/minute | Standard Deviation 8.6 |
| MEDI0382 100 mcg | Mean Change From Baseline in 24-Hour Heart Rate at Days 20 and 48 | Day 20 | 6.65 beats/minute | Standard Deviation 7.46 |
| MEDI0382 200 mcg | Mean Change From Baseline in 24-Hour Heart Rate at Days 20 and 48 | Day 20 | 13.50 beats/minute | Standard Deviation 5.86 |
| MEDI0382 200 mcg | Mean Change From Baseline in 24-Hour Heart Rate at Days 20 and 48 | Day 48 | 12.81 beats/minute | Standard Deviation 4.93 |
| MEDI0382 300 mcg | Mean Change From Baseline in 24-Hour Heart Rate at Days 20 and 48 | Day 20 | 15.80 beats/minute | Standard Deviation 7.86 |
| MEDI0382 300 mcg | Mean Change From Baseline in 24-Hour Heart Rate at Days 20 and 48 | Day 48 | 15.22 beats/minute | Standard Deviation 5.5 |
Primary
Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48
Twenty four-hour BP was determined using an ABPM device, and the mean change from baseline in the 24-hour systolic BP and 24-hour diastolic BP are presented for Days 20 and 48.
Time frame: Baseline (Day -1) and Days 20 and 48.
Population: The Safety Analysis Set included all randomised patients who received at least 1 dose of IP, analysed according to the treatment received. Patients with data available at each timepoint are presented.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 | 24-hour Systolic BP: Day 20 | 2.98 millimetres of mercury | Standard Deviation 9 |
| Placebo | Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 | 24-hour Systolic BP: Day 48 | 0.08 millimetres of mercury | Standard Deviation 14.32 |
| Placebo | Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 | 24-hour Diastolic BP: Day 20 | 0.98 millimetres of mercury | Standard Deviation 4.34 |
| Placebo | Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 | 24-hour Diastolic BP: Day 48 | -0.06 millimetres of mercury | Standard Deviation 6.82 |
| MEDI0382 100 mcg | Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 | 24-hour Systolic BP: Day 48 | -2.27 millimetres of mercury | Standard Deviation 12.42 |
| MEDI0382 100 mcg | Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 | 24-hour Diastolic BP: Day 20 | -0.62 millimetres of mercury | Standard Deviation 3.42 |
| MEDI0382 100 mcg | Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 | 24-hour Diastolic BP: Day 48 | -0.66 millimetres of mercury | Standard Deviation 4.56 |
| MEDI0382 100 mcg | Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 | 24-hour Systolic BP: Day 20 | -4.09 millimetres of mercury | Standard Deviation 8.93 |
| MEDI0382 200 mcg | Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 | 24-hour Diastolic BP: Day 20 | -1.41 millimetres of mercury | Standard Deviation 4.56 |
| MEDI0382 200 mcg | Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 | 24-hour Systolic BP: Day 48 | -5.17 millimetres of mercury | Standard Deviation 19.35 |
| MEDI0382 200 mcg | Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 | 24-hour Diastolic BP: Day 48 | -0.27 millimetres of mercury | Standard Deviation 9.17 |
| MEDI0382 200 mcg | Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 | 24-hour Systolic BP: Day 20 | -7.24 millimetres of mercury | Standard Deviation 10.54 |
| MEDI0382 300 mcg | Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 | 24-hour Diastolic BP: Day 48 | -0.68 millimetres of mercury | Standard Deviation 3.88 |
| MEDI0382 300 mcg | Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 | 24-hour Systolic BP: Day 48 | -6.97 millimetres of mercury | Standard Deviation 7.48 |
| MEDI0382 300 mcg | Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 | 24-hour Systolic BP: Day 20 | -2.48 millimetres of mercury | Standard Deviation 9.28 |
| MEDI0382 300 mcg | Mean Change From Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 | 24-hour Diastolic BP: Day 20 | 0.81 millimetres of mercury | Standard Deviation 5.58 |
Primary
Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48.
Digital ECGs were taken at baseline and predose and postdose on Days 1, 6, 13, 20 and 48. The mean change from baseline is presented.
Time frame: Baseline (Day -1) and Days 1, 6, 13, 20 and 48: predose and 6 hours (+/-15 minutes) postdose.
Population: The Safety Analysis Set included all randomised patients who received at least 1 dose of IP, analysed according to the treatment received. Patients with data available at each timepoint are presented.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 20: 6 hours postdose | 0.29 beats/minute | Standard Deviation 9.15 |
| Placebo | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 20: predose | -1.85 beats/minute | Standard Deviation 7.52 |
| Placebo | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 48: 6 hours postdose | -6.25 beats/minute | Standard Deviation 10.34 |
| Placebo | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 13: predose | -2.63 beats/minute | Standard Deviation 5.58 |
| Placebo | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 6: 6 hours postdose | 0.02 beats/minute | Standard Deviation 8.79 |
| Placebo | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 6: predose | -2.85 beats/minute | Standard Deviation 4.93 |
| Placebo | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 48: predose | -1.06 beats/minute | Standard Deviation 10.06 |
| Placebo | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 13: 6 hours postdose | 2.19 beats/minute | Standard Deviation 9.13 |
| Placebo | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 1: 6 hours postdose | 1.77 beats/minute | Standard Deviation 7.2 |
| MEDI0382 100 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 13: 6 hours postdose | 6.40 beats/minute | Standard Deviation 11.41 |
| MEDI0382 100 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 20: 6 hours postdose | 5.09 beats/minute | Standard Deviation 9.37 |
| MEDI0382 100 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 20: predose | 6.24 beats/minute | Standard Deviation 8.02 |
| MEDI0382 100 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 6: predose | 1.84 beats/minute | Standard Deviation 8.56 |
| MEDI0382 100 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 1: 6 hours postdose | 4.24 beats/minute | Standard Deviation 5 |
| MEDI0382 100 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 6: 6 hours postdose | 4.62 beats/minute | Standard Deviation 9.11 |
| MEDI0382 100 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 48: 6 hours postdose | 1.16 beats/minute | Standard Deviation 10.21 |
| MEDI0382 100 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 48: predose | 7.20 beats/minute | Standard Deviation 5.88 |
| MEDI0382 100 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 13: predose | 6.91 beats/minute | Standard Deviation 8.83 |
| MEDI0382 200 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 13: 6 hours postdose | 16.62 beats/minute | Standard Deviation 7.14 |
| MEDI0382 200 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 1: 6 hours postdose | 2.18 beats/minute | Standard Deviation 8.62 |
| MEDI0382 200 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 6: predose | 7.69 beats/minute | Standard Deviation 7.11 |
| MEDI0382 200 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 6: 6 hours postdose | 8.88 beats/minute | Standard Deviation 6.06 |
| MEDI0382 200 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 13: predose | 8.93 beats/minute | Standard Deviation 6.84 |
| MEDI0382 200 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 20: predose | 11.97 beats/minute | Standard Deviation 8.12 |
| MEDI0382 200 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 20: 6 hours postdose | 16.79 beats/minute | Standard Deviation 6.21 |
| MEDI0382 200 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 48: predose | 10.20 beats/minute | Standard Deviation 9.7 |
| MEDI0382 200 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 48: 6 hours postdose | 15.43 beats/minute | Standard Deviation 12.15 |
| MEDI0382 300 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 20: 6 hours postdose | 16.94 beats/minute | Standard Deviation 8.86 |
| MEDI0382 300 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 13: predose | 11.74 beats/minute | Standard Deviation 7.92 |
| MEDI0382 300 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 6: 6 hours postdose | 10.67 beats/minute | Standard Deviation 7.59 |
| MEDI0382 300 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 48: 6 hours postdose | 12.70 beats/minute | Standard Deviation 5.95 |
| MEDI0382 300 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 48: predose | 17.06 beats/minute | Standard Deviation 6.12 |
| MEDI0382 300 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 6: predose | 10.79 beats/minute | Standard Deviation 5.87 |
| MEDI0382 300 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 20: predose | 13.03 beats/minute | Standard Deviation 8.65 |
| MEDI0382 300 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 13: 6 hours postdose | 13.31 beats/minute | Standard Deviation 9.45 |
| MEDI0382 300 mcg | Mean Change From Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. | Day 1: 6 hours postdose | 6.27 beats/minute | Standard Deviation 7.91 |
Primary
Mean Percentage Change From Baseline in Body Weight at Day 48
The mean percentage change from baseline in body weight at Day 48 was analysed using an ANCOVA model with treatment group as a factor and baseline as a covariate. For patients who prematurely discontinued IP, the last on-treatment measurement, regardless of rescue medication, was used (last observation carried forward \[LOCF\]).
Time frame: Baseline (Day -1) and Day 48.
Population: The Full Analysis Set included all randomised patients who received at least 1 dose of IP, analysed according to their randomised treatment group. Patients with data available are presented.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Mean Percentage Change From Baseline in Body Weight at Day 48 | -0.82 Percentage change |
| MEDI0382 100 mcg | Mean Percentage Change From Baseline in Body Weight at Day 48 | -2.12 Percentage change |
| MEDI0382 200 mcg | Mean Percentage Change From Baseline in Body Weight at Day 48 | -3.34 Percentage change |
| MEDI0382 300 mcg | Mean Percentage Change From Baseline in Body Weight at Day 48 | -3.34 Percentage change |
Comparison: Pair-wise comparison of MEDI0382 100 mcg versus Placebo.p-value: 0.147695% CI: [-3.08, 0.47]ANCOVA
Comparison: Pair-wise comparison of MEDI0382 200 mcg versus Placebo.p-value: 0.00895% CI: [-4.37, -0.69]ANCOVA
Comparison: Pair-wise comparison of MEDI0382 300 mcg versus Placebo.p-value: 0.006395% CI: [-4.3, -0.74]ANCOVA
Primary
Mean Percentage Change From Baseline in Glucose Area Under the Plasma Concentration Curve (AUC[0-4h]) as Measured by a Standardised Mixed-Meal Test (MMT) at Day 48
The MMT was conducted following a minimum 8-hour fast. Blood samples for glucose monitoring were taken 15 minutes before the patient consumed a standardised meal, and samples were taken at intervals after the meal, up to 4 hours. The MMT glucose AUC(0-4h) was calculated using a trapezoidal method, and the mean percentage change from baseline at Day 48 was analysed using an analysis of covariance (ANCOVA) model with treatment group as a factor and baseline as a covariate.
Time frame: Baseline (Day -1) and Day 48: 15 minutes before standardised meal, and then at 15, 30, 45, 60, 90, 120, 180 and 240 minutes (+/-5 minutes) after consumption of the standardised meal.
Population: The Full Analysis Set included all randomised patients who received at least 1 dose of IP, analysed according to their randomised treatment group. MMTs were not conducted on patients who prematurely discontinued IP.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Mean Percentage Change From Baseline in Glucose Area Under the Plasma Concentration Curve (AUC[0-4h]) as Measured by a Standardised Mixed-Meal Test (MMT) at Day 48 | 2.45 Percentage change |
| MEDI0382 100 mcg | Mean Percentage Change From Baseline in Glucose Area Under the Plasma Concentration Curve (AUC[0-4h]) as Measured by a Standardised Mixed-Meal Test (MMT) at Day 48 | -39.66 Percentage change |
| MEDI0382 200 mcg | Mean Percentage Change From Baseline in Glucose Area Under the Plasma Concentration Curve (AUC[0-4h]) as Measured by a Standardised Mixed-Meal Test (MMT) at Day 48 | -31.16 Percentage change |
| MEDI0382 300 mcg | Mean Percentage Change From Baseline in Glucose Area Under the Plasma Concentration Curve (AUC[0-4h]) as Measured by a Standardised Mixed-Meal Test (MMT) at Day 48 | -37.86 Percentage change |
Comparison: Pair-wise comparison of MEDI0382 100 mcg versus Placebo.p-value: <0.000195% CI: [-50.47, -33.75]ANCOVA
Comparison: Pair-wise comparison of MEDI0382 200 mcg versus Placebo.p-value: <0.000195% CI: [-43.04, -24.18]ANCOVA
Comparison: Pair-wise comparison of MEDI0382 300 mcg versus Placebo.p-value: <0.000195% CI: [-49.49, -31.12]ANCOVA
Primary
Number of Patients Who Experienced Adverse Events (AEs)
AEs were collected from Day 1 of treatment up to 14 days after the last dose of IP. Serious AEs (SAEs) were collected from signing of informed consent. The numbers of patients who experienced any AE, any SAE (including events with an outcome of death), and any AE leading to discontinuation of IP are presented.
Time frame: Day 1 up to 14 days after the last dose of IP (approximately 9 weeks).
Population: The Safety Analysis Set included all randomised patients who received at least 1 dose of IP, analysed according to the treatment received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Patients Who Experienced Adverse Events (AEs) | Any AE leading to discontinuation of IP | 0 Participants |
| Placebo | Number of Patients Who Experienced Adverse Events (AEs) | Any AE | 6 Participants |
| Placebo | Number of Patients Who Experienced Adverse Events (AEs) | Any SAE | 0 Participants |
| MEDI0382 100 mcg | Number of Patients Who Experienced Adverse Events (AEs) | Any AE leading to discontinuation of IP | 0 Participants |
| MEDI0382 100 mcg | Number of Patients Who Experienced Adverse Events (AEs) | Any SAE | 0 Participants |
| MEDI0382 100 mcg | Number of Patients Who Experienced Adverse Events (AEs) | Any AE | 6 Participants |
| MEDI0382 200 mcg | Number of Patients Who Experienced Adverse Events (AEs) | Any AE | 11 Participants |
| MEDI0382 200 mcg | Number of Patients Who Experienced Adverse Events (AEs) | Any SAE | 0 Participants |
| MEDI0382 200 mcg | Number of Patients Who Experienced Adverse Events (AEs) | Any AE leading to discontinuation of IP | 4 Participants |
| MEDI0382 300 mcg | Number of Patients Who Experienced Adverse Events (AEs) | Any AE leading to discontinuation of IP | 1 Participants |
| MEDI0382 300 mcg | Number of Patients Who Experienced Adverse Events (AEs) | Any AE | 9 Participants |
| MEDI0382 300 mcg | Number of Patients Who Experienced Adverse Events (AEs) | Any SAE | 0 Participants |
Secondary
Mean Change From Baseline in Fasting Plasma Glucose at Day 48
The mean change from baseline in fasting plasma glucose at Day 48 was analysed using an ANCOVA model with treatment group as a factor and baseline as a covariate. For patients who prematurely discontinued IP, or for patients who did not have a measurement taken on Day 48, the last post-baseline measurement, regardless of rescue medication, was used (LOCF).
Time frame: Baseline (Day -1) and Day 48 (predose).
Population: The Full Analysis Set included all randomised patients who received at least 1 dose of IP, analysed according to their randomised treatment group. Patients with data available are presented.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Mean Change From Baseline in Fasting Plasma Glucose at Day 48 | -0.40 milligrams per decilitre (mg/dL) |
| MEDI0382 100 mcg | Mean Change From Baseline in Fasting Plasma Glucose at Day 48 | -57.10 milligrams per decilitre (mg/dL) |
| MEDI0382 200 mcg | Mean Change From Baseline in Fasting Plasma Glucose at Day 48 | -60.98 milligrams per decilitre (mg/dL) |
| MEDI0382 300 mcg | Mean Change From Baseline in Fasting Plasma Glucose at Day 48 | -55.47 milligrams per decilitre (mg/dL) |
Comparison: Pair-wise comparison of MEDI0382 100 mcg versus Placebo.p-value: <0.000195% CI: [-74.3, -39.09]ANCOVA
Comparison: Pair-wise comparison of MEDI0382 200 mcg versus Placebo.p-value: <0.000195% CI: [-80.53, -40.63]ANCOVA
Comparison: Pair-wise comparison of MEDI0382 300 mcg versus Placebo.p-value: <0.000195% CI: [-74.28, -35.86]ANCOVA
Secondary
Mean Change From Baseline in Fructosamine at Day 48
The mean change from baseline in fructosamine at Day 48 was analysed using an ANCOVA model with treatment group as a factor and baseline as a covariate. For patients who prematurely discontinued IP, the last on-treatment measurement, regardless of rescue medication, was used (LOCF).
Time frame: Baseline (Day -1) and Day 48 (predose).
Population: The Full Analysis Set included all randomised patients who received at least 1 dose of IP, analysed according to their randomised treatment group. Patients with data available are presented.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Mean Change From Baseline in Fructosamine at Day 48 | -0.012 millimoles per litre (mmol/L) |
| MEDI0382 100 mcg | Mean Change From Baseline in Fructosamine at Day 48 | -0.083 millimoles per litre (mmol/L) |
| MEDI0382 200 mcg | Mean Change From Baseline in Fructosamine at Day 48 | -0.066 millimoles per litre (mmol/L) |
| MEDI0382 300 mcg | Mean Change From Baseline in Fructosamine at Day 48 | -0.061 millimoles per litre (mmol/L) |
Comparison: Pair-wise comparison of MEDI0382 100 mcg versus Placebo.p-value: <0.000195% CI: [-0.094, -0.047]ANCOVA
Comparison: Pair-wise comparison of MEDI0382 200 mcg versus Placebo.p-value: <0.000195% CI: [-0.077, -0.03]ANCOVA
Comparison: Pair-wise comparison of MEDI0382 300 mcg versus Placebo.p-value: 0.000295% CI: [-0.074, -0.024]ANCOVA
Secondary
Mean Change From Baseline in HbA1c at Day 48
The mean change from baseline in HbA1c at Day 48 was analysed using an ANCOVA model with treatment group as a factor and baseline as a covariate. For patients who prematurely discontinued IP, or for patients who did not have a measurement taken on Day 48, the last post-baseline measurement, regardless of rescue medication, was used (LOCF).
Time frame: Baseline (Day -1) and Day 48 (predose).
Population: The Full Analysis Set included all randomised patients who received at least 1 dose of IP, analysed according to their randomised treatment group. Patients with data available are presented.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Mean Change From Baseline in HbA1c at Day 48 | -0.14 Percent glycated haemoglobin |
| MEDI0382 100 mcg | Mean Change From Baseline in HbA1c at Day 48 | -1.23 Percent glycated haemoglobin |
| MEDI0382 200 mcg | Mean Change From Baseline in HbA1c at Day 48 | -1.24 Percent glycated haemoglobin |
| MEDI0382 300 mcg | Mean Change From Baseline in HbA1c at Day 48 | -0.90 Percent glycated haemoglobin |
Comparison: Pair-wise comparison of MEDI0382 100 mcg versus Placebo.p-value: <0.000195% CI: [-1.48, -0.7]ANCOVA
Comparison: Pair-wise comparison of MEDI0382 200 mcg versus Placebo.p-value: <0.000195% CI: [-1.49, -0.71]ANCOVA
Comparison: Pair-wise comparison of MEDI0382 300 mcg versus Placebo.p-value: 0.000295% CI: [-1.15, -0.38]ANCOVA
Secondary
Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47
Hyperglycaemia was defined as blood glucose \>7.8 mmol/L or \>140 mg/dL. Continuous glucose monitoring used a device fitted to the upper arm by trained study site staff to measure and record interstitial glucose levels every 15 minutes. Analysis was based on 24-hour readings defined as the first available time point with a valid continuous glucose monitoring glucose reading. The change in the percentage time in hyperglycaemia from the last day of baseline continuous glucose monitoring over 24 hours to the end of dosing at each dose level for the indicated timepoints is presented.
Time frame: Baseline (Day -8 to -2) and Days 5, 12, 19 and 47.
Population: The Full Analysis Set included all randomised patients who received at least 1 dose of IP, analysed according to their randomised treatment group. Patients with data available at each time point are presented.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 5 | -3.23 Percentage of time | Standard Deviation 12.59 |
| Placebo | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 12 | -11.72 Percentage of time | Standard Deviation 28.58 |
| Placebo | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 19 | -12.08 Percentage of time | Standard Deviation 17.61 |
| Placebo | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 47 | -6.15 Percentage of time | Standard Deviation 22.8 |
| MEDI0382 100 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 12 | -57.74 Percentage of time | Standard Deviation 24.59 |
| MEDI0382 100 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 19 | -59.57 Percentage of time | Standard Deviation 16.98 |
| MEDI0382 100 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 47 | -47.99 Percentage of time | Standard Deviation 20.63 |
| MEDI0382 100 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 5 | -48.35 Percentage of time | Standard Deviation 21.27 |
| MEDI0382 200 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 19 | -43.85 Percentage of time | Standard Deviation 28.96 |
| MEDI0382 200 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 12 | -53.36 Percentage of time | Standard Deviation 21.59 |
| MEDI0382 200 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 47 | -48.96 Percentage of time | Standard Deviation 20.28 |
| MEDI0382 200 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 5 | -33.71 Percentage of time | Standard Deviation 24.67 |
| MEDI0382 300 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 47 | -57.59 Percentage of time | Standard Deviation 21.86 |
| MEDI0382 300 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 12 | -55.78 Percentage of time | Standard Deviation 25.19 |
| MEDI0382 300 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 5 | -51.33 Percentage of time | Standard Deviation 30.04 |
| MEDI0382 300 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 19 | -60.68 Percentage of time | Standard Deviation 24.93 |
Secondary
Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels
Hyperglycaemia was defined as blood glucose \>7.8 mmol/L or \>140 mg/dL. Continuous glucose monitoring used a device fitted to the upper arm by trained study site staff to measure and record interstitial glucose levels every 15 minutes. Analysis was based on 24-hour readings defined as the first available time point with a valid continuous glucose monitoring glucose reading. The change in the percentage time in hyperglycaemia from the last day of baseline continuous glucose monitoring over 5 days for 50 mcg MEDI0382 and 7 days for each of the dose levels (during titration) is presented, up to Day 47, per randomised group.
Time frame: Baseline (Day -8 to -2) and Days 1 to 5, 6 to 12, 13 to 19 and 41 to 47.
Population: The Full Analysis Set included all randomised patients who received at least 1 dose of IP, analysed according to their randomised treatment group. Patients with data available at each time point are presented.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 13 to 19 | -6.09 Percentage of time | Standard Deviation 19.1 |
| Placebo | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 41 to 47 | -0.40 Percentage of time | Standard Deviation 22.7 |
| Placebo | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 1 to 5 | -1.43 Percentage of time | Standard Deviation 10.26 |
| Placebo | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 6 to 12 | -8.97 Percentage of time | Standard Deviation 26.12 |
| MEDI0382 100 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 41 to 47 | -42.37 Percentage of time | Standard Deviation 17.22 |
| MEDI0382 100 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 6 to 12 | -48.35 Percentage of time | Standard Deviation 16.01 |
| MEDI0382 100 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 13 to 19 | -53.25 Percentage of time | Standard Deviation 16.47 |
| MEDI0382 100 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 1 to 5 | -42.52 Percentage of time | Standard Deviation 13.46 |
| MEDI0382 200 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 13 to 19 | -52.33 Percentage of time | Standard Deviation 20.96 |
| MEDI0382 200 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 6 to 12 | -50.81 Percentage of time | Standard Deviation 18.97 |
| MEDI0382 200 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 1 to 5 | -38.68 Percentage of time | Standard Deviation 18.97 |
| MEDI0382 200 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 41 to 47 | -43.44 Percentage of time | Standard Deviation 18.26 |
| MEDI0382 300 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 6 to 12 | -51.82 Percentage of time | Standard Deviation 16.73 |
| MEDI0382 300 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 13 to 19 | -47.50 Percentage of time | Standard Deviation 20.67 |
| MEDI0382 300 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 41 to 47 | -51.25 Percentage of time | Standard Deviation 17.12 |
| MEDI0382 300 mcg | Mean Change From Baseline in the Percentage of Time in Hyperglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 1 to 5 | -34.74 Percentage of time | Standard Deviation 18.24 |
Secondary
Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47
Hypoglycaemia was defined as blood glucose \<3 mmol/L or \<54 mg/dL. Continuous glucose monitoring used a device fitted to the upper arm by trained study site staff to measure and record interstitial glucose levels every 15 minutes. Analysis was based on 24-hour readings defined as the first available time point with a valid continuous glucose monitoring glucose reading. The change in the percentage time in hypoglycaemia from the last day of baseline continuous glucose monitoring over 24 hours to the end of dosing at each dose level for the timepoints is presented.
Time frame: Baseline (Day -8 to -2) and Days 5, 12, 19 and 47.
Population: The Full Analysis Set included all randomised patients who received at least 1 dose of IP, analysed according to their randomised treatment group. Patients with data available at each time point are presented.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 19 | 0.00 Percentage of time | Standard Deviation 0 |
| Placebo | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 5 | 0.00 Percentage of time | Standard Deviation 0 |
| Placebo | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 47 | 0.00 Percentage of time | Standard Deviation 0 |
| Placebo | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 12 | 0.00 Percentage of time | Standard Deviation 0 |
| MEDI0382 100 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 5 | 0.00 Percentage of time | Standard Deviation 0 |
| MEDI0382 100 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 47 | 0.00 Percentage of time | Standard Deviation 0 |
| MEDI0382 100 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 19 | 0.00 Percentage of time | Standard Deviation 0 |
| MEDI0382 100 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 12 | 0.00 Percentage of time | Standard Deviation 0 |
| MEDI0382 200 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 12 | 0.00 Percentage of time | Standard Deviation 0 |
| MEDI0382 200 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 5 | 0.00 Percentage of time | Standard Deviation 0 |
| MEDI0382 200 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 19 | 3.68 Percentage of time | Standard Deviation 12.75 |
| MEDI0382 200 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 47 | 0.00 Percentage of time | Standard Deviation 0 |
| MEDI0382 300 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 47 | 0.00 Percentage of time | Standard Deviation 0 |
| MEDI0382 300 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 5 | 6.28 Percentage of time | Standard Deviation 16.61 |
| MEDI0382 300 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 12 | 0.00 Percentage of time | Standard Deviation 0 |
| MEDI0382 300 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 | Day 19 | 0.00 Percentage of time | Standard Deviation 0 |
Secondary
Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels
Hyp0glycaemia was defined as blood glucose \<3 mmol/L or \<54 mg/dL. Continuous glucose monitoring used a device fitted to the upper arm by trained study site staff to measure and record interstitial glucose levels every 15 minutes. Analysis was based on 24-hour readings defined as the first available time point with a valid continuous glucose monitoring glucose reading. The change in the percentage time in hypoglycaemia from the last day of baseline continuous glucose monitoring over 5 days for 50 mcg MEDI0382 and 7 days for each of the randomised dose levels (during titration) is presented, up to Day 47, per randomised group.
Time frame: Baseline (Day -8 to -2) and Days 1 to 5, 6 to 12, 13 to 19 and 41 to 47.
Population: The Full Analysis Set included all randomised patients who received at least 1 dose of IP, analysed according to their randomised treatment group. Patients with data available at each time point are presented.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 1 to 5 | 0.21 Percentage of time | Standard Deviation 0.76 |
| Placebo | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 6 to 12 | 0.06 Percentage of time | Standard Deviation 0.22 |
| Placebo | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 13 to 19 | 0.10 Percentage of time | Standard Deviation 0.3 |
| Placebo | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 41 to 47 | 0.01 Percentage of time | Standard Deviation 0.04 |
| MEDI0382 100 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 6 to 12 | 0.90 Percentage of time | Standard Deviation 2.24 |
| MEDI0382 100 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 13 to 19 | 0.41 Percentage of time | Standard Deviation 1.25 |
| MEDI0382 100 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 41 to 47 | -0.02 Percentage of time | Standard Deviation 0.05 |
| MEDI0382 100 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 1 to 5 | 0.06 Percentage of time | Standard Deviation 0.27 |
| MEDI0382 200 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 13 to 19 | 2.97 Percentage of time | Standard Deviation 5.43 |
| MEDI0382 200 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 6 to 12 | 0.07 Percentage of time | Standard Deviation 0.19 |
| MEDI0382 200 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 41 to 47 | 0.30 Percentage of time | Standard Deviation 0.6 |
| MEDI0382 200 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 1 to 5 | 0.25 Percentage of time | Standard Deviation 0.55 |
| MEDI0382 300 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 41 to 47 | 2.59 Percentage of time | Standard Deviation 7.22 |
| MEDI0382 300 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 6 to 12 | 0.13 Percentage of time | Standard Deviation 0.62 |
| MEDI0382 300 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 1 to 5 | 5.50 Percentage of time | Standard Deviation 16.57 |
| MEDI0382 300 mcg | Mean Change From Baseline in the Percentage of Time in Hypoglycaemia Over 5 Days for 50 mcg Dose Level and 7 Days for Other Dose Levels | Days 13 to 19 | 1.09 Percentage of time | Standard Deviation 1.58 |
Secondary
Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48
To evaluate pharmacokinetics (PK), blood samples were collected predose and Ctrough of MEDI0382 was determined. Results are presented for Days 2, 5, 34 and 48.
Time frame: Blood samples collected predose on Days 1 to 6, 13, 20, 34 and 48.
Population: The PK Analysis Set included all patients who received at least 1 dose of MEDI0382 and had at least 1 post-baseline MEDI0382 PK sample taken that was above the lower limit of quantification. Patients with data available at each timepoint are presented.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48 | Day 2 | 1.20 nanograms per millilitre | Geometric Coefficient of Variation 41.8 |
| Placebo | Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48 | Day 5 | 1.47 nanograms per millilitre | Geometric Coefficient of Variation 36.8 |
| Placebo | Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48 | Day 34 | 2.70 nanograms per millilitre | Geometric Coefficient of Variation 78 |
| Placebo | Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48 | Day 48 | 2.83 nanograms per millilitre | Geometric Coefficient of Variation 77.5 |
| MEDI0382 100 mcg | Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48 | Day 48 | 7.14 nanograms per millilitre | Geometric Coefficient of Variation 23.8 |
| MEDI0382 100 mcg | Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48 | Day 2 | 1.22 nanograms per millilitre | Geometric Coefficient of Variation 22.9 |
| MEDI0382 100 mcg | Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48 | Day 34 | 5.16 nanograms per millilitre | Geometric Coefficient of Variation 81.4 |
| MEDI0382 100 mcg | Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48 | Day 5 | 1.61 nanograms per millilitre | Geometric Coefficient of Variation 26.6 |
| MEDI0382 200 mcg | Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48 | Day 48 | 9.12 nanograms per millilitre | Geometric Coefficient of Variation 24.7 |
| MEDI0382 200 mcg | Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48 | Day 5 | 1.56 nanograms per millilitre | Geometric Coefficient of Variation 25.8 |
| MEDI0382 200 mcg | Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48 | Day 34 | 7.18 nanograms per millilitre | Geometric Coefficient of Variation 39.8 |
| MEDI0382 200 mcg | Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48 | Day 2 | 1.11 nanograms per millilitre | Geometric Coefficient of Variation 26.9 |
Secondary
Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382
The number of patients who were ADA positive at baseline and/or post-baseline are presented. Persistent positive was defined as positive at ≥2 post-baseline assessments (with ≥16 weeks between first and last positive) or positive at the last post-baseline assessment. Transiently positive was defined as having at least 1 post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive. +ve = positive
Time frame: Samples were collected predose on days 1, 13, 20 and 48, and 7 to 14 days after administration of last dose of IP.
Population: The PK Analysis Set included all patients who received at least 1 dose of MEDI0382 and had at least 1 post-baseline MEDI0382 PK sample taken that was above the lower limit of quantification.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | Persistent +ve | 2 Participants |
| Placebo | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | ADA +ve at baseline | 0 Participants |
| Placebo | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | Transient +ve | 2 Participants |
| Placebo | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | ADA +ve post-baseline & +ve at baseline | 0 Participants |
| Placebo | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | ADA not detected post-baseline & +ve baseline | 0 Participants |
| Placebo | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | ADA+ve post-baseline & not detected at baseline | 4 Participants |
| Placebo | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | ADA +ve post-baseline | 4 Participants |
| MEDI0382 100 mcg | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | ADA +ve at baseline | 0 Participants |
| MEDI0382 100 mcg | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | ADA +ve post-baseline & +ve at baseline | 0 Participants |
| MEDI0382 100 mcg | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | ADA+ve post-baseline & not detected at baseline | 5 Participants |
| MEDI0382 100 mcg | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | Persistent +ve | 4 Participants |
| MEDI0382 100 mcg | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | Transient +ve | 1 Participants |
| MEDI0382 100 mcg | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | ADA +ve post-baseline | 5 Participants |
| MEDI0382 100 mcg | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | ADA not detected post-baseline & +ve baseline | 0 Participants |
| MEDI0382 200 mcg | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | ADA not detected post-baseline & +ve baseline | 0 Participants |
| MEDI0382 200 mcg | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | ADA +ve post-baseline | 2 Participants |
| MEDI0382 200 mcg | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | ADA +ve post-baseline & +ve at baseline | 0 Participants |
| MEDI0382 200 mcg | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | ADA+ve post-baseline & not detected at baseline | 2 Participants |
| MEDI0382 200 mcg | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | ADA +ve at baseline | 0 Participants |
| MEDI0382 200 mcg | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | Transient +ve | 0 Participants |
| MEDI0382 200 mcg | Number of Patients With Antidrug Antibody (ADA) Response to MEDI0382 | Persistent +ve | 2 Participants |