Safety and tolerability study of MEDI0382 in Japanese preobese or obese subjects with type 2 diabetes

Study identifier:D5674C00001

ClinicalTrials.gov identifier:NCT03645421

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A Phase IIa, Randomised, Parallel, Double-Blind,Placebo-Controlled Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of MEDI0382 in Japanese Preobese or Obese Subjects with Type 2 Diabetes Who Have Inadequate Glycemic Control with Diet and Exercise

Medical condition

Type 2 Diabetes

Phase

Phase 2

Healthy volunteers

Study drug

MEDI0382 100 μg, MEDI0382 200 μg, MEDI0382 300 μg, PlaceboA, MEDI0382 50 ug, PlaceboB

Sex

All

Actual Enrollment

Study type

Interventional

Age

20 Years - 120 Years

Date

Study Start Date: 10 Aug 2018

Primary Completion Date: 17 Jan 2019

Study Completion Date: 17 Jan 2019

Study design

Allocation: Randomized
Endpoint Classification: -
Intervention Model: Parallel Assignment
Masking: -
Primary Purpose: Treatment

Verification:

Verified 01 Dec 2019 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Location

Research Site

Shinjuku-ku, Japan, 160-0008

Location

Research Site

Suita-shi, Japan, 565-0853

Location

Research Site

Chuo-ku, Japan, 103-0027

Location

Research Site

Chuo-ku, Japan, 104-0031

Location

Research Site

Shinjuku-ku, Japan, 162-0053

Arms	Assigned Interventions
Placebo Comparator: placebo Placebo per day,SC injection on 48 days.	Drug: PlaceboA 1.0 mL liquid formulation per Vial Drug: PlaceboB Solution for injection in 1.0 mL pre-filled syringe.
Experimental: MEDI0382 100μg 50 μg/day,SC injection on the first 5 days and 100 μg/day,SC injection on 43 days	Drug: MEDI0382 100 μg Solution for injection in 1.0 mL pre-filled syringe, 100 μg per dose, 1 dose Drug: MEDI0382 50 ug Solution for injection, 1.0 mL per vial, 50 ug
Experimental: MEDI0382 200μg 50 μg/day,SC injection on the first 5 days, 100 μg/day,SC injection on 7 days and 200 μg/day,SC injection on 36 days.	Drug: MEDI0382 100 μg Solution for injection in 1.0 mL pre-filled syringe, 100 μg per dose, 1 dose Drug: MEDI0382 200 μg Solution for injection in 1.0 mL pre filled syringe 200 μg per dose, 1 dose Drug: MEDI0382 50 ug Solution for injection, 1.0 mL per vial, 50 ug
Experimental: MEDI0382 300μg 50 μg/day,SC injection on the first 5 days, 100 μg/day,SC injection on 7 days, 200 μg/day,SC injection on 7 days and 300 μg/day,SC injection on 29 days	Drug: MEDI0382 100 μg Solution for injection in 1.0 mL pre-filled syringe, 100 μg per dose, 1 dose Drug: MEDI0382 200 μg Solution for injection in 1.0 mL pre filled syringe 200 μg per dose, 1 dose Drug: MEDI0382 300 μg Solution for injection in 1.0 mL pre filled syringe, 300 μg per dose, 1 dose Drug: MEDI0382 50 ug Solution for injection, 1.0 mL per vial, 50 ug

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups

	Description
Placebo	Patients were randomised to receive MEDI0382 matched placebo for 48 days.
MEDI0382 100 mcg	Patients were randomised to receive 100 micrograms (mcg) MEDI0382 per day by subcutaneous (SC) injection, titrated as follows: 50 mcg/day for 5 days and then 100 mcg/day for 43 days.
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.
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.

Participant Flow: Overall Study

	Placebo	MEDI0382 100 mcg	MEDI0382 200 mcg	MEDI0382 300 mcg
STARTED	16	15	15	15
Received investigational product (IP)	16	15	15	15
COMPLETED	16	15	10	11
NOT COMPLETED	0	0	5	4
Adverse Event	0	0	4	1
Withdrawal by patient	0	0	0	3
Study specific withdrawal criteria	0	0	1	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Baseline characteristics are presented for the Full Analysis Set which included all randomised patients who received at least 1 dose of IP, analysed according to their randomised treatment group.

Reporting Groups

	Description
Placebo	Patients were randomised to receive MEDI0382 matched placebo for 48 days.
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.
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.
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.

Baseline Measures

	Placebo	MEDI0382 100 mcg	MEDI0382 200 mcg	MEDI0382 300 mcg	Total
Number of Participants [units: Participants]	16	15	15	15	61
Age Continuous [units: years] Mean ± Standard Deviation	60.0 ± 8.6	56.7 ± 10.7	58.7 ± 11.3	57.5 ± 9.2	58.2 ± 9.8
Sex: Female, Male [units: participants]
Female	3	7	2	2	14
Male	13	8	13	13	47
Race/Ethnicity, Customized [units: participants]
Asian	16	15	15	15	61
Not Hispanic or Latino	16	15	15	15	61

Outcome Measures

1. Primary Outcome Measure: Mean Change from Baseline in 24-Hour Heart Rate at Days 20 and 48 [ Time Frame: Baseline (Day -1) and Days 20 and 48. ]

Measure Type	Primary
Measure Name	Mean Change from Baseline in 24-Hour Heart Rate at Days 20 and 48
Measure Description	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.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Patients were randomised to receive MEDI0382 matched placebo for 48 days.
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.
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.
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.

Measured Values

	Placebo	MEDI0382 100 mcg	MEDI0382 200 mcg	MEDI0382 300 mcg
Number of Participants Analyzed [units:participants]	16	15	15	15
Mean Change from Baseline in 24-Hour Heart Rate at Days 20 and 48 [units: beats/minute] Mean (Standard Deviation)
Day 20	-1.86 (7.43)	6.65 (7.46)	13.50 (5.86)	15.80 (7.86)
Day 48	-0.25 (7.24)	7.87 (8.60)	12.81 (4.93)	15.22 (5.50)

No statistical analysis provided for Mean Change from Baseline in 24-Hour Heart Rate at Days 20 and 48

2. Primary Outcome Measure: Mean Change from Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 [ Time Frame: Baseline (Day -1) and Days 20 and 48. ]

Measure Type	Primary
Measure Name	Mean Change from Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48
Measure Description	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.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Patients were randomised to receive MEDI0382 matched placebo for 48 days.
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.
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.
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.

Measured Values

	Placebo	MEDI0382 100 mcg	MEDI0382 200 mcg	MEDI0382 300 mcg
Number of Participants Analyzed [units:participants]	16	15	15	15
Mean Change from Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48 [units: millimetres of mercury] Mean (Standard Deviation)
24-hour Systolic BP: Day 20	2.98 (9.00)	-4.09 (8.93)	-7.24 (10.54)	-2.48 (9.28)
24-hour Systolic BP: Day 48	0.08 (14.32)	-2.27 (12.42)	-5.17 (19.35)	-6.97 (7.48)
24-hour Diastolic BP: Day 20	0.98 (4.34)	-0.62 (3.42)	-1.41 (4.56)	0.81 (5.58)
24-hour Diastolic BP: Day 48	-0.06 (6.82)	-0.66 (4.56)	-0.27 (9.17)	-0.68 (3.88)

No statistical analysis provided for Mean Change from Baseline in 24-Hour Systolic and Diastolic Blood Pressure (BP) at Days 20 and 48

3. Primary Outcome Measure: 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 [ 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. ]

Measure Type	Primary
Measure Name	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
Measure Description	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.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Patients were randomised to receive MEDI0382 matched placebo for 48 days.
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.
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.
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.

Measured Values

	Placebo	MEDI0382 100 mcg	MEDI0382 200 mcg	MEDI0382 300 mcg
Number of Participants Analyzed [units:participants]	16	15	15	15
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 [units: Percentage change] Least Squares Mean (95% Confidence Interval)	2.45 (-3.37 to 8.26)	-39.66 (-45.67 to -33.66)	-31.16 (-38.61 to -23.71)	-37.86 (-44.95 to -30.76)

Statistical Analysis 1 for 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

Groups^[1]	Placebo, MEDI0382 100 mcg
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	-42.11
Standard Error of the mean	± 4.16
95% Confidence Interval	( -50.47 to -33.75 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Pair-wise comparison of MEDI0382 100 mcg versus Placebo.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Analysis used treatment group as a factor and baseline as a covariate.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Treatment difference = MEDI0382 100 mcg - Placebo

Statistical Analysis 2 for 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

Groups^[1]	Placebo, MEDI0382 200 mcg
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	-33.61
Standard Error of the mean	± 4.69
95% Confidence Interval	( -43.04 to -24.18 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Pair-wise comparison of MEDI0382 200 mcg versus Placebo.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Analysis used treatment group as a factor and baseline as a covariate.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Treatment difference = MEDI0382 200 mcg - Placebo

Statistical Analysis 3 for 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

Groups^[1]	Placebo, MEDI0382 300 mcg
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	-40.30
Standard Error of the mean	± 4.57
95% Confidence Interval	( -49.49 to -31.12 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Pair-wise comparison of MEDI0382 300 mcg versus Placebo.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Analysis used treatment group as a factor and baseline as a covariate.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Treatment difference = MEDI0382 300 mcg - Placebo

4. Primary Outcome Measure: Mean Percentage Change from Baseline in Body Weight at Day 48 [ Time Frame: Baseline (Day -1) and Day 48. ]

Measure Type	Primary
Measure Name	Mean Percentage Change from Baseline in Body Weight at Day 48
Measure Description	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.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Patients were randomised to receive MEDI0382 matched placebo for 48 days.
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.
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.
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.

Measured Values

	Placebo	MEDI0382 100 mcg	MEDI0382 200 mcg	MEDI0382 300 mcg
Number of Participants Analyzed [units:participants]	16	15	15	15
Mean Percentage Change from Baseline in Body Weight at Day 48 [units: Percentage change] Least Squares Mean (95% Confidence Interval)	-0.82 (-2.06 to 0.43)	-2.12 (-3.40 to -0.84)	-3.34 (-4.68 to -2.01)	-3.34 (-4.61 to -2.06)

Statistical Analysis 1 for Mean Percentage Change from Baseline in Body Weight at Day 48

Groups^[1]	Placebo, MEDI0382 100 mcg
Method^[3]	ANCOVA
P-Value^[4]	0.1476
Other^[5]	-1.30
Standard Error of the mean	± 0.89
95% Confidence Interval	( -3.08 to 0.47 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Pair-wise comparison of MEDI0382 100 mcg versus Placebo.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Analysis used treatment group as a factor and baseline as a covariate.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Treatment difference = MEDI0382 100 mcg - Placebo

Statistical Analysis 2 for Mean Percentage Change from Baseline in Body Weight at Day 48

Groups^[1]	Placebo, MEDI0382 200 mcg
Method^[3]	ANCOVA
P-Value^[4]	0.0080
Other^[5]	-2.53
Standard Error of the mean	± 0.92
95% Confidence Interval	( -4.37 to -0.69 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Pair-wise comparison of MEDI0382 200 mcg versus Placebo.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Analysis used treatment group as a factor and baseline as a covariate.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Treatment difference = MEDI0382 200 mcg - Placebo

Statistical Analysis 3 for Mean Percentage Change from Baseline in Body Weight at Day 48

Groups^[1]	Placebo, MEDI0382 300 mcg
Method^[3]	ANCOVA
P-Value^[4]	0.0063
Other^[5]	-2.52
Standard Error of the mean	± 0.89
95% Confidence Interval	( -4.30 to -0.74 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Pair-wise comparison of MEDI0382 300 mcg versus Placebo.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Analysis used treatment group as a factor and baseline as a covariate.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Treatment difference = MEDI0382 300 mcg - Placebo

5. Primary Outcome Measure: Mean Change from Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. [ Time Frame: Baseline (Day -1) and Days 1, 6, 13, 20 and 48: predose and 6 hours (+/-15 minutes) postdose. ]

Measure Type	Primary
Measure Name	Mean Change from Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48.
Measure Description	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.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Patients were randomised to receive MEDI0382 matched placebo for 48 days.
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.
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.
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.

Measured Values

	Placebo	MEDI0382 100 mcg	MEDI0382 200 mcg	MEDI0382 300 mcg
Number of Participants Analyzed [units:participants]	16	15	15	15
Mean Change from Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48. [units: beats/minute] Mean (Standard Deviation)
Day 1: 6 hours postdose	1.77 (7.20)	4.24 (5.00)	2.18 (8.62)	6.27 (7.91)
Day 6: predose	-2.85 (4.93)	1.84 (8.56)	7.69 (7.11)	10.79 (5.87)
Day 6: 6 hours postdose	0.02 (8.79)	4.62 (9.11)	8.88 (6.06)	10.67 (7.59)
Day 13: predose	-2.63 (5.58)	6.91 (8.83)	8.93 (6.84)	11.74 (7.92)
Day 13: 6 hours postdose	2.19 (9.13)	6.40 (11.41)	16.62 (7.14)	13.31 (9.45)
Day 20: predose	-1.85 (7.52)	6.24 (8.02)	11.97 (8.12)	13.03 (8.65)
Day 20: 6 hours postdose	0.29 (9.15)	5.09 (9.37)	16.79 (6.21)	16.94 (8.86)
Day 48: predose	-1.06 (10.06)	7.20 (5.88)	10.20 (9.70)	17.06 (6.12)
Day 48: 6 hours postdose	-6.25 (10.34)	1.16 (10.21)	15.43 (12.15)	12.70 (5.95)

No statistical analysis provided for Mean Change from Baseline in Heart Rate Measured by Electrocardiogram (ECG) at Day 48.

6. Primary Outcome Measure: Number of Patients who Experienced Adverse Events (AEs) [ Time Frame: Day 1 up to 14 days after the last dose of IP (approximately 9 weeks). ]

Measure Type	Primary
Measure Name	Number of Patients who Experienced Adverse Events (AEs)
Measure Description	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).
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Safety Analysis Set included all randomised patients who received at least 1 dose of IP, analysed according to the treatment received.

Reporting Groups

	Description
Placebo	Patients were randomised to receive MEDI0382 matched placebo for 48 days.
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.
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.
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.

Measured Values

	Placebo	MEDI0382 100 mcg	MEDI0382 200 mcg	MEDI0382 300 mcg
Number of Participants Analyzed [units:participants]	16	15	15	15
Number of Patients who Experienced Adverse Events (AEs) [units: Participants]
Any AE	6	6	11	9
Any SAE	0	0	0	0
Any AE leading to discontinuation of IP	0	0	4	1

No statistical analysis provided for Number of Patients who Experienced Adverse Events (AEs)

7. Secondary Outcome Measure: Mean Change from Baseline in HbA1c at Day 48 [ Time Frame: Baseline (Day -1) and Day 48 (predose). ]

Measure Type	Secondary
Measure Name	Mean Change from Baseline in HbA1c at Day 48
Measure Description	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).
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Patients were randomised to receive MEDI0382 matched placebo for 48 days.
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.
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.
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.

Measured Values

	Placebo	MEDI0382 100 mcg	MEDI0382 200 mcg	MEDI0382 300 mcg
Number of Participants Analyzed [units:participants]	16	15	15	15
Mean Change from Baseline in HbA1c at Day 48 [units: Percent glycated haemoglobin] Least Squares Mean (95% Confidence Interval)	-0.14 (-0.41 to 0.12)	-1.23 (-1.51 to -0.96)	-1.24 (-1.53 to -0.96)	-0.90 (-1.18 to -0.63)

Statistical Analysis 1 for Mean Change from Baseline in HbA1c at Day 48

Groups^[1]	Placebo, MEDI0382 100 mcg
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	-1.09
Standard Error of the mean	± 0.19
95% Confidence Interval	( -1.48 to -0.70 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Pair-wise comparison of MEDI0382 100 mcg versus Placebo.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Analysis used treatment group as a factor and baseline as a covariate.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Treatment difference = MEDI0382 100 mcg – Placebo

Statistical Analysis 2 for Mean Change from Baseline in HbA1c at Day 48

Groups^[1]	Placebo, MEDI0382 200 mcg
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	-1.10
Standard Error of the mean	± 0.19
95% Confidence Interval	( -1.49 to -0.71 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Pair-wise comparison of MEDI0382 200 mcg versus Placebo.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Analysis used treatment group as a factor and baseline as a covariate.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Treatment difference = MEDI0382 200 mcg – Placebo

Statistical Analysis 3 for Mean Change from Baseline in HbA1c at Day 48

Groups^[1]	Placebo, MEDI0382 300 mcg
Method^[3]	ANCOVA
P-Value^[4]	0.0002
Other^[5]	-0.76
Standard Error of the mean	± 0.19
95% Confidence Interval	( -1.15 to -0.38 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Pair-wise comparison of MEDI0382 300 mcg versus Placebo.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Analysis used treatment group as a factor and baseline as a covariate.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Treatment difference = MEDI0382 300 mcg – Placebo

8. Secondary Outcome Measure: Mean Change from Baseline in Fasting Plasma Glucose at Day 48 [ Time Frame: Baseline (Day -1) and Day 48 (predose). ]

Measure Type	Secondary
Measure Name	Mean Change from Baseline in Fasting Plasma Glucose at Day 48
Measure Description	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).
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Patients were randomised to receive MEDI0382 matched placebo for 48 days.
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.
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.
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.

Measured Values

	Placebo	MEDI0382 100 mcg	MEDI0382 200 mcg	MEDI0382 300 mcg
Number of Participants Analyzed [units:participants]	16	15	15	15
Mean Change from Baseline in Fasting Plasma Glucose at Day 48 [units: milligrams per decilitre (mg/dL)] Least Squares Mean (95% Confidence Interval)	-0.40 (-12.60 to 11.80)	-57.10 (-69.77 to -44.42)	-60.98 (-76.82 to -45.15)	-55.47 (-70.28 to -40.66)

Statistical Analysis 1 for Mean Change from Baseline in Fasting Plasma Glucose at Day 48

Groups^[1]	Placebo, MEDI0382 100 mcg
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	-56.69
Standard Error of the mean	± 8.75
95% Confidence Interval	( -74.30 to -39.09 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Pair-wise comparison of MEDI0382 100 mcg versus Placebo.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Analysis used treatment group as a factor and baseline as a covariate.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Treatment difference = MEDI0382 100 mcg – Placebo

Statistical Analysis 2 for Mean Change from Baseline in Fasting Plasma Glucose at Day 48

Groups^[1]	Placebo, MEDI0382 200 mcg
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	-60.58
Standard Error of the mean	± 9.92
95% Confidence Interval	( -80.53 to -40.63 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Pair-wise comparison of MEDI0382 200 mcg versus Placebo.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Analysis used treatment group as a factor and baseline as a covariate.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Treatment difference = MEDI0382 200 mcg – Placebo

Statistical Analysis 3 for Mean Change from Baseline in Fasting Plasma Glucose at Day 48

Groups^[1]	Placebo, MEDI0382 300 mcg
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	-55.07
Standard Error of the mean	± 9.55
95% Confidence Interval	( -74.28 to -35.86 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Pair-wise comparison of MEDI0382 300 mcg versus Placebo.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Analysis used treatment group as a factor and baseline as a covariate.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Treatment difference = MEDI0382 300 mcg – Placebo

9. Secondary Outcome Measure: Mean Change from Baseline in Fructosamine at Day 48 [ Time Frame: Baseline (Day -1) and Day 48 (predose). ]

Measure Type	Secondary
Measure Name	Mean Change from Baseline in Fructosamine at Day 48
Measure Description	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).
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Patients were randomised to receive MEDI0382 matched placebo for 48 days.
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.
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.
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.

Measured Values

	Placebo	MEDI0382 100 mcg	MEDI0382 200 mcg	MEDI0382 300 mcg
Number of Participants Analyzed [units:participants]	16	15	15	15
Mean Change from Baseline in Fructosamine at Day 48 [units: millimoles per litre (mmol/L)] Least Squares Mean (95% Confidence Interval)	-0.012 (-0.029 to 0.004)	-0.083 (-0.100 to -0.066)	-0.066 (-0.083 to -0.048)	-0.061 (-0.079 to -0.044)

Statistical Analysis 1 for Mean Change from Baseline in Fructosamine at Day 48

Groups^[1]	Placebo, MEDI0382 100 mcg
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	-0.071
Standard Error of the mean	± 0.012
95% Confidence Interval	( -0.094 to -0.047 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Pair-wise comparison of MEDI0382 100 mcg versus Placebo.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Analysis used treatment group as a factor and baseline as a covariate.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Treatment difference = MEDI0382 100 mcg – Placebo

Statistical Analysis 2 for Mean Change from Baseline in Fructosamine at Day 48

Groups^[1]	Placebo, MEDI0382 200 mcg
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	-0.053
Standard Error of the mean	± 0.012
95% Confidence Interval	( -0.077 to -0.030 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Pair-wise comparison of MEDI0382 200 mcg versus Placebo.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Analysis used treatment group as a factor and baseline as a covariate.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Treatment difference = MEDI0382 200 mcg – Placebo

Statistical Analysis 3 for Mean Change from Baseline in Fructosamine at Day 48

Groups^[1]	Placebo, MEDI0382 300 mcg
Method^[3]	ANCOVA
P-Value^[4]	0.0002
Other^[5]	-0.049
Standard Error of the mean	± 0.012
95% Confidence Interval	( -0.074 to -0.024 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Pair-wise comparison of MEDI0382 300 mcg versus Placebo.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Analysis used treatment group as a factor and baseline as a covariate.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	Treatment difference = MEDI0382 300 mcg – Placebo

10. Secondary Outcome Measure: Mean Change from Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 [ Time Frame: Baseline (Day -8 to -2) and Days 5, 12, 19 and 47. ]

Measure Type	Secondary
Measure Name	Mean Change from Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47
Measure Description	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.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Patients were randomised to receive MEDI0382 matched placebo for 48 days.
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.
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.
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.

Measured Values

	Placebo	MEDI0382 100 mcg	MEDI0382 200 mcg	MEDI0382 300 mcg
Number of Participants Analyzed [units:participants]	16	15	15	15
Mean Change from Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47 [units: Percentage of time] Mean (Standard Deviation)
Day 5	-3.23 (12.59)	-48.35 (21.27)	-33.71 (24.67)	-51.33 (30.04)
Day 12	-11.72 (28.58)	-57.74 (24.59)	-53.36 (21.59)	-55.78 (25.19)
Day 19	-12.08 (17.61)	-59.57 (16.98)	-43.85 (28.96)	-60.68 (24.93)
Day 47	-6.15 (22.80)	-47.99 (20.63)	-48.96 (20.28)	-57.59 (21.86)

No statistical analysis provided for Mean Change from Baseline in the Percentage of Time in Hyperglycaemia Over 24 Hours at Days 5, 12, 19 and 47

11. Secondary Outcome Measure: Mean Change from Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 [ Time Frame: Baseline (Day -8 to -2) and Days 5, 12, 19 and 47. ]

Measure Type	Secondary
Measure Name	Mean Change from Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47
Measure Description	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.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Patients were randomised to receive MEDI0382 matched placebo for 48 days.
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.
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.
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.

Measured Values

	Placebo	MEDI0382 100 mcg	MEDI0382 200 mcg	MEDI0382 300 mcg
Number of Participants Analyzed [units:participants]	16	15	15	15
Mean Change from Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47 [units: Percentage of time] Mean (Standard Deviation)
Day 5	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	6.28 (16.61)
Day 12	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
Day 19	0.00 (0.00)	0.00 (0.00)	3.68 (12.75)	0.00 (0.00)
Day 47	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)

No statistical analysis provided for Mean Change from Baseline in the Percentage of Time in Hypoglycaemia Over 24 Hours at Days 5, 12, 19 and 47

12. Secondary Outcome Measure: 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 [ Time Frame: Baseline (Day -8 to -2) and Days 1 to 5, 6 to 12, 13 to 19 and 41 to 47. ]

Measure Type	Secondary
Measure Name	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
Measure Description	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.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Patients were randomised to receive MEDI0382 matched placebo for 48 days.
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.
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.
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.

Measured Values

	Placebo	MEDI0382 100 mcg	MEDI0382 200 mcg	MEDI0382 300 mcg
Number of Participants Analyzed [units:participants]	16	15	15	15
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 [units: Percentage of time] Mean (Standard Deviation)
Days 1 to 5	-1.43 (10.26)	-42.52 (13.46)	-38.68 (18.97)	-34.74 (18.24)
Days 6 to 12	-8.97 (26.12)	-48.35 (16.01)	-50.81 (18.97)	-51.82 (16.73)
Days 13 to 19	-6.09 (19.10)	-53.25 (16.47)	-52.33 (20.96)	-47.50 (20.67)
Days 41 to 47	-0.40 (22.70)	-42.37 (17.22)	-43.44 (18.26)	-51.25 (17.12)

No statistical analysis provided for 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

13. Secondary Outcome Measure: 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 [ Time Frame: Baseline (Day -8 to -2) and Days 1 to 5, 6 to 12, 13 to 19 and 41 to 47. ]

Measure Type	Secondary
Measure Name	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
Measure Description	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.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Placebo	Patients were randomised to receive MEDI0382 matched placebo for 48 days.
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.
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.
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.

Measured Values

	Placebo	MEDI0382 100 mcg	MEDI0382 200 mcg	MEDI0382 300 mcg
Number of Participants Analyzed [units:participants]	16	15	15	15
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 [units: Percentage of time] Mean (Standard Deviation)
Days 1 to 5	0.21 (0.76)	0.06 (0.27)	0.25 (0.55)	5.50 (16.57)
Days 6 to 12	0.06 (0.22)	0.90 (2.24)	0.07 (0.19)	0.13 (0.62)
Days 13 to 19	0.10 (0.30)	0.41 (1.25)	2.97 (5.43)	1.09 (1.58)
Days 41 to 47	0.01 (0.04)	-0.02 (0.05)	0.30 (0.60)	2.59 (7.22)

No statistical analysis provided for 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

14. Secondary Outcome Measure: Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48 [ Time Frame: Blood samples collected predose on Days 1 to 6, 13, 20, 34 and 48. ]

Measure Type	Secondary
Measure Name	Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48
Measure Description	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.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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.
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.
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.

Measured Values

	MEDI0382 100 mcg	MEDI0382 200 mcg	MEDI0382 300 mcg
Number of Participants Analyzed [units:participants]	15	15	15
Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48 [units: nanograms per millilitre] Geometric Mean (Geometric Coefficient of Variation)
Day 2	1.20 (41.8%)	1.22 (22.9%)	1.11 (26.9%)
Day 5	1.47 (36.8%)	1.61 (26.6%)	1.56 (25.8%)
Day 34	2.70 (78.0%)	5.16 (81.4%)	7.18 (39.8%)
Day 48	2.83 (77.5%)	7.14 (23.8%)	9.12 (24.7%)

No statistical analysis provided for Mean Trough Plasma Concentration (Ctrough) of MEDI0382 up to Day 48

15. Secondary Outcome Measure: Number of Patients with Antidrug Antibody (ADA) Response to MEDI0382 [ 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. ]

Measure Type	Secondary
Measure Name	Number of Patients with Antidrug Antibody (ADA) Response to MEDI0382
Measure Description	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.
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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.
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.
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.

Measured Values

	MEDI0382 100 mcg	MEDI0382 200 mcg	MEDI0382 300 mcg
Number of Participants Analyzed [units:participants]	15	15	15
Number of Patients with Antidrug Antibody (ADA) Response to MEDI0382 [units: Participants]
ADA +ve at baseline	0	0	0
ADA +ve post-baseline	4	5	2
ADA +ve post-baseline & +ve at baseline	0	0	0
ADA+ve post-baseline & not detected at baseline	4	5	2
Persistent +ve	2	4	2
Transient +ve	2	1	0
ADA not detected post-baseline & +ve baseline	0	0	0

No statistical analysis provided for Number of Patients with Antidrug Antibody (ADA) Response to MEDI0382

Serious Adverse Events

Time Frame	Treatment-emergent AEs were collected from Day 1 of treatment up to 14 days after the last dose of IP (approximately 9 weeks).
Additional Description	AEs are presented for the Safety Analysis Set which included all randomised patients who received at least 1 dose of IP, analysed according to the treatment received.

Reporting Groups

	Description
Placebo	Patients were randomised to receive MEDI0382 matched placebo for 48 days.
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.
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.
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.

Serious Adverse Events

	Placebo	MEDI0382 100 mcg	MEDI0382 200 mcg	MEDI0382 300 mcg
Total, serious adverse events
# participants affected / at risk	0/16 (0.00%)	0/15 (0.00%)	0/15 (0.00%)	0/15 (0.00%)

Other Adverse Events

Time Frame	Treatment-emergent AEs were collected from Day 1 of treatment up to 14 days after the last dose of IP (approximately 9 weeks).
Additional Description	AEs are presented for the Safety Analysis Set which included all randomised patients who received at least 1 dose of IP, analysed according to the treatment received.

Frequency Threshold

Threshold above which other adverse events are reported	0%

Reporting Groups

	Description
Placebo	Patients were randomised to receive MEDI0382 matched placebo for 48 days.
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.
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.
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.

Other Adverse Events

Placebo

MEDI0382 100 mcg

MEDI0382 200 mcg

MEDI0382 300 mcg

Total, other (not including serious) adverse events

# participants affected / at risk

6/16 (37.50%)

6/15 (40.00%)

11/15 (73.33%)

9/15 (60.00%)

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

1/16 (6.25%)

2/15 (13.33%)

7/15 (46.67%)

4/15 (26.67%)

Gastrointestinal disorders

Vomiting¹,^†

# participants affected / at risk

0/16 (0.00%)

3/15 (20.00%)

5/15 (33.33%)

3/15 (20.00%)

Gastrointestinal disorders

Abdominal distension¹,^†

# participants affected / at risk

0/16 (0.00%)

0/15 (0.00%)

1/15 (6.67%)

Gastrointestinal disorders

Abdominal pain¹,^†

# participants affected / at risk

0/16 (0.00%)

0/15 (0.00%)

1/15 (6.67%)

Gastrointestinal disorders

Faeces hard¹,^†

# participants affected / at risk

0/16 (0.00%)

0/15 (0.00%)

1/15 (6.67%)

Gastrointestinal disorders

Gastrointestinal motility disorder¹,^†

# participants affected / at risk

0/16 (0.00%)

0/15 (0.00%)

1/15 (6.67%)

Gastrointestinal disorders

Gastrooesophageal reflux disease¹,^†

# participants affected / at risk

0/16 (0.00%)

0/15 (0.00%)

1/15 (6.67%)

Gastrointestinal disorders

Abdominal pain upper¹,^†

# participants affected / at risk

0/16 (0.00%)

1/15 (6.67%)

0/15 (0.00%)

Gastrointestinal disorders

Constipation¹,^†

# participants affected / at risk

0/16 (0.00%)

1/15 (6.67%)

0/15 (0.00%)

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

0/16 (0.00%)

1/15 (6.67%)

0/15 (0.00%)

General disorders

Malaise¹,^†

# participants affected / at risk

0/16 (0.00%)

0/15 (0.00%)

3/15 (20.00%)

General disorders

Injection site bruising¹,^†

# participants affected / at risk

1/16 (6.25%)

0/15 (0.00%)

General disorders

Injection site erythema¹,^†

# participants affected / at risk

0/16 (0.00%)

1/15 (6.67%)

0/15 (0.00%)

General disorders

Injection site pruritus¹,^†

# participants affected / at risk

0/16 (0.00%)

1/15 (6.67%)

0/15 (0.00%)

Metabolism and nutrition disorders

Decreased appetite¹,^†

# participants affected / at risk

0/16 (0.00%)

0/15 (0.00%)

3/15 (20.00%)

2/15 (13.33%)

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

2/16 (12.50%)

2/15 (13.33%)

0/15 (0.00%)

1/15 (6.67%)

Infections and infestations

Folliculitis¹,^†

# participants affected / at risk

0/16 (0.00%)

0/15 (0.00%)

1/15 (6.67%)

0/15 (0.00%)

Infections and infestations

Tonsillitis¹,^†

# participants affected / at risk

0/16 (0.00%)

0/15 (0.00%)

1/15 (6.67%)

0/15 (0.00%)

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

0/16 (0.00%)

0/15 (0.00%)

1/15 (6.67%)

Skin and subcutaneous tissue disorders

Urticaria¹,^†

# participants affected / at risk

0/16 (0.00%)

0/15 (0.00%)

1/15 (6.67%)

Skin and subcutaneous tissue disorders

Haemorrhage subcutaneous¹,^†

# participants affected / at risk

2/16 (12.50%)

0/15 (0.00%)

1/15 (6.67%)

0/15 (0.00%)

Eye disorders

Dry eye¹,^†

# participants affected / at risk

0/16 (0.00%)

0/15 (0.00%)

1/15 (6.67%)

0/15 (0.00%)

Psychiatric disorders

Insomnia¹,^†

# participants affected / at risk

0/16 (0.00%)

1/15 (6.67%)

0/15 (0.00%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 21.1

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: PI needs to provide sponsor with the draft to review no later than 30 days prior to the date of publication of trial results.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	Global Clinical Lead
Organization:	AstraZeneca
Phone	+13028851180
E-mail:	[email protected]

Documents available

d5674c00001 CSP redacted
Download
Statistical Analysis Plan (SAP) redacted
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

d5674c00001 CSP redacted

Statistical Analysis Plan (SAP) redacted

Trial Results Summaries