A Study to Look at the Effect MEDI0382 Has on Blood Sugar in People With Type 2 Diabetes and Kidney Problems and Also to Check That MEDI0382 is Well Tolerated

• Sponsor: MedImmune LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03550378
• Collaborator: (none)
• Enrollment: 41
• Locations: 7
• Arms: 2
• Actual Duration (Months): 7.2
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

A study to look at the effect MEDI0382 has on blood sugar in people with type 2 diabetes and kidney problems and also to check that MEDI0382 is well tolerated.

Condition or Disease	Intervention/Treatment	Phase
Type II Diabetes Mellitus; Renal Insufficiency	Drug: MEDI0382; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomised, Double-Blind, Placebo-ControlledRandomised, Double-Blind, Placebo-Controlled
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of MEDI0382 in Subjects With Type 2 Diabetes Mellitus and Renal Impairment
• Actual Study Start Date: Jun 29, 2018
• Actual Primary Completion Date: Feb 4, 2019
• Actual Study Completion Date: Feb 4, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MEDI0382 Participants will receive subcutaneous (SC) dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.	Drug: MEDI0382; Participants will receive subcutaneous MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Placebo Comparator: Placebo Participants will receive SC dose of placebo matched to MEDI0382 once daily for 32 days.	Drug: Placebo; Participants will receive SC placebo matched to MEDI0382 once daily for 32 days.

Outcome Measures

Primary Outcome Measures

1. Percent Change From Baseline in Plasma Glucose Area Under the Concentration Time-curve From Time 0 to 4 Hours (AUC0-4 Hrs) as Measured by Mixed-meal Tolerance Test (MMTT) to Day 32 [Zero minutes before and 15, 30, 45, 60, 90, 120, 180, and 240 minutes after consumption of the standardised meal on Day -5 (Baseline) and Day 32]

   The MMTT involved the consumption of a standardised liquid meal (a nutritional supplement containing the components of fat, carbohydrate, and protein, which make up a standard MMTT) within 15 minutes, and timed serial blood samples obtained for measurement of glucose and parameters related to glucose metabolism through 240 minutes after consumption of the standardized meal (with no additional food intake during this time).

Secondary Outcome Measures

1. Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [Day 1 through Day 60]

   An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.

2. Number of Participants With Abnormal Vital Signs Reported as TEAEs [Day 1 through Day 60]

   Number of participants with abnormal vital signs reported as TEAEs is reported. Vital sign measurements were obtained after the participant had rested in the supine position for at least 10 minutes at the recording time. Abnormal vital signs is defined as any abnormal finding in the vital sign parameters (blood pressure, pulse rate, body temperature, and respiratory rate).

3. Change From Baseline in Postural Blood Pressure [Baseline (Day 1) through Day 32]

   The change difference is the change from Day 1 to Day 32 in the difference between systolic blood pressure (SBP) or diastolic blood pressure (DBP) values in standing and supine positions. For this outcome measure, participants with difference (standing-supine) in DBP or SBP on Day 1 and Day 32 were analyzed. For few participants either DBP or SBP was recorded eg, standing DBP was not recorded on Day 1 for 2 participants in Placebo arm and 1 participant in MEDI0382 arm; standing SBP was not recorded on Day 32 for a participant in the Placebo arm.

4. Number of Participants With Abnormal Electrocardiograms (ECGs) Reported as TEAEs [Day 1 through Day 60]

   Number of participants with abnormal ECGs reported as TEAEs is reported. Abnormal ECGs is defined as any abnormal findings in heart rate, RR interval, PR interval, QRS, axis, ST-T morphology, and QT intervals from the primary lead of the digital 12-lead ECG.

5. Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs [Day 1 through Day 60]

   Number of participants with abnormal clinical laboratory parameters reported as TEAEs is reported. Abnormal clinical laboratory parameters defined as any abnormal finding during analysis of serum chemistry, hematology, and urine.

6. Number of Participants With Treatment-emergent Adverse Events of Special Interest (TEAESIs) [Day 1 through Day 60]

   An adverse event of special interest (AESI) was one of scientific and medical interest specific to understanding of the study drug and may require close monitoring and rapid communication by the investigator to the sponsor.

7. Change From Baseline in Mean 24-hrs Pulse Rate to the End of Each Dosing Level [Day -5 (Baseline) and on Days 5, 12, 19, and 32]

   Change from baseline in mean 24-hrs pulse rate to the end of each dosing levels: Day 5 for 50 μg; Day 12 for 100 μg, Day 19 for 200 μg, and Day 32 for 300 μg.

8. Change From Baseline in Mean 24-hrs Systolic and Diastolic Blood Pressure to the End of Each Dosing Level [Day -5 (Baseline) and on Days 5, 12, 19, and 32]

   Change from baseline in mean 24-hrs systolic and diastolic blood pressure to the end of each dosing levels: Day 5 for 50 μg, Day 12 for 100 μg, Day 19 for 200 μg, and Day 32 for 300 μg.

9. Change From Baseline in Haemoglobin A1c (HbA1c) to Day 32 [Day 1 (Baseline) and Day 32]

   Change from baseline in haemoglobin A1c (HbA1c) is reported.

10. Change From Baseline in Fasting Glucose to Day 32 [Day 1 (Baseline) and Day 32]

    Change from baseline in fasting glucose is reported.

11. Change From Baseline in Percentage of Time Spent Within a Target Glucose Range Over a 7-day Period to the Final Week of Treatment [Baseline (Days -8 to -2), Days 5 to 11, Days 12 to 18, Days 19 to 25, and Days 26 to 32 (final week of treatment)]

    Change from baseline in percentage of time spent within a target glucose range over a 7-day period to the final week of treatment is reported. Target glucose range was considered as 70 mg/dL (3.9 mmol/L) to 180 mg/dL (10 mmol/L).

12. Percent Change Frome Baseline in Body Weight to Day 33 [Day 1 (Baseline) and Day 33]

    Percent change from baseline in body weight is reported.

13. Change From Baseline in Absolute Body Weight to Day 33 [Day 1 (Baseline) and Day 33]

    Change from baseline in absolute body weight is reported.

14. Area Under the Plasma Concentration Time Curve Over a Dosing Duration (AUCτ) of MEDI0382 at 300 μg [Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose on Day 32]

    Area under the plasma concentration time curve over a dosing duration (AUCτ) of MEDI0382 at 300 μg is reported.

15. Maximum Observed Serum Concentration (Cmax) of MEDI0382 at 300 μg [Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose on Day 32]

    Maximum observed serum concentration (Cmax) of MEDI0382 at 300 μg is reported.

16. Time to Observed Maximum Serum Concentration (Tmax) of MEDI0382 at 300 μg [Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose on Day 32]

    Time to observed maximum serum concentration (Tmax) of MEDI0382 at 300 μg is reported.

17. Trough Plasma Concentration (Ctrough) of MEDI0382 [Days 1, 5, 12, and 19: Predose; and Day 32: Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose (Day 33)]

    Trough concentration is the lowest concentration reached by a drug before the next dose is administered. Trough plasma concentration of MEDI0382 is reported.

18. Number of Participants With Positive Anti-drug Antibodies (ADA) Titre to MEDI0382 [Pre-dose on Days 1, 12, and 32 and on Day 60]

    Number of participants with positive Anti-drug antibodies (ADA) Titre to MEDI0382 is reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 84 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age ≥ 18 and < 85 years at screening.

2. Signed and dated written informed consent (with the exception of consent for genetic and nongenetic research) prior to performing any protocol-related procedures, including screening evaluations.

3. Diagnosed with type 2 diabetes mellitus (T2DM) with glucose control managed with any insulin and/or oral therapy combination where no significant dose changes of oral therapy of more than 50% have occurred in the 3 months prior to screening

4. Body mass index (BMI) between 25 and 45 kg/m^2 (inclusive) at screening

5. Haemoglobin A1c (HbA1c) range of 6.5 % to 10.5% (inclusive) at screening

6. Renal impairment with estimated glomerular filtration rate (eGFR) ≥ 30 and < 60 mL/min/1.73 m^{2 at screening. Approximately 16 participants (40%) are required to have a screening eGFR ≥30 and < 45 mL/min/1.73 m}2 and at least 16 participants (40%) are required to have screening eGFR ≥45 and < 60 mL/min/1.73 m^2.

7. Females of childbearing potential must have a negative pregnancy test at screening and randomisation, and must not be lactating. Women of childbearing potential who are sexually active with a non-sterilized male partner must be using at least one highly effective method of contraception from screening and up to 4 weeks after the last dose study drug.

Exclusion Criteria:

1. History or presence of significant medical or psychological conditions, including substance dependence/abuse, or significant abnormalities in laboratory parameters or vital signs including electrocardiogram (ECG), which in the opinion of the investigator, would compromise the participant's safety or successful participation in the study. As an example, severe anaemia (haemoglobin < 7.0 g/dL) could be exclusionary due to blood sampling required by the protocol, at the discretion of investigator.

2. Concurrent participation in another interventional study of any kind and repeat randomisation in this study is prohibited.

3. Any participant who has received another study drug as part of a clinical study or a glucagon-like peptide-1 (GLP-1) analogue-containing preparation within the last 30 days or 5 half-lives of the drug (if known; whichever is longer) at the time of Visit

5. Any participant who has received any of the following medications within the specified timeframe prior to the start of the study (Visit 2)

• Herbal preparations within 1 week prior to the start of dosing (Visit 4) or drugs licensed for control of body weight or appetite (eg, orlistat, bupropion-naltrexone, phentermine-topiramate, phentermine, lorcaserin) within 30 days (or 5 half-lives of the drug) prior to the start of dosing (Visit 4)

• Aspirin (acetylsalicylic acid) at a dose greater than 150 mg once daily and within the last 3 days prior to the start of the run-in period (Visit 2)

• Paracetamol (acetaminophen) or paracetamol-containing preparations at a total daily dose of greater than 3000 mg and within the last 3 days prior to the start of the run-in period (Visit 2)

• Ascorbic acid (vitamin C) supplements at a total daily dose of greater than 1000 mg and within the last 3 days prior to the start of the run-in period (Visit 2)

• Opiates, domperidone, metoclopramide, or other drugs known to alter gastric emptying and within 2 weeks prior to the start of dosing (Visit 4)

1. Severe allergy/hypersensitivity to any of the proposed study treatments or excipients

2. Symptoms of acutely decompensated blood glucose control (eg, thirst, polyuria, weight loss), a history of type 1 diabetes mellitus or diabetic ketoacidosis

3. Participants who have undergone a renal transplant

4. Participants with suspicion of acute or subacute renal function deterioration (eg, participants with large fluctuations of creatinine values documented within the 6 months prior to screening)

5. Significant inflammatory bowel disease, gastroparesis, or other severe disease or surgery affecting the upper gastrointestinal (GI) tract including weight-reducing surgery and procedures) which may affect gastric emptying or could affect the interpretation of safety and tolerability data

6. History of acute or chronic pancreatitis

7. Significant hepatic disease (except for non-alcoholic steatohepatitis or nonalcoholic fatty liver disease without portal hypertension or cirrhosis) and/or participants with any of the following results:

• Aspartate transaminase (AST) ≥ 3 × upper limit of normal (ULN)

• Alanine transaminase (ALT) ≥ 3 × ULN

• Total bilirubin ≥ 2 × ULN

1. Poorly controlled hypertension defined as:

• Systolic blood pressure (BP) > 180 mm Hg

• Diastolic BP ≥ 100 mm Hg Participants who fail BP screening criteria may be considered for 24-hour ambulatory blood pressure monitoring (ABPM) at the discretion of the investigator. Participants who maintain a mean 24-hour systolic BP ≤ 180 or diastolic BP < 100 mm Hg with a preserved nocturnal dip of > 15% will be considered eligible

1. Unstable angina pectoris, myocardial infarction, transient ischemic attack or stroke within 3 months prior to screening, or participants who have undergone percutaneous coronary intervention or a coronary artery bypass graft within the past 6 months or who are due to undergo these procedures at the time of screening

2. Severe congestive heart failure (New York Heart Association Class III or IV)

3. Basal calcitonin level > 50 ng/L at screening or history/family history of medullary thyroid carcinoma or multiple endocrine neoplasia

4. History of neoplastic disease within 5 years prior to screening, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer

5. Any positive results for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody, and human immunodeficiency virus (HIV) antibody

6. Nephrotic range proteinuria defined as spot urine albumin creatinine ratio (ACR) > 250 mg/mmol at screening

7. History of substance dependence, alcohol abuse, or excessive alcohol intake (defined as an average weekly intake of > 21 alcoholic drinks for men or > 10 alcoholic drinks for women) within 3 years prior to screening, and/or a positive screen for drugs of abuse or alcohol at screening or on Day -5. Participants who use tricyclic antidepressants or benzodiazepines for an established clinical indication may be permitted to enter the study based upon the judgement of the investigator

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Berlin		Germany	10117
2	Research Site	Magdeburg		Germany	39120
3	Research Site	Munster		Germany	48145
4	Research Site	München		Germany	81241
5	Research Site	Dundee		United Kingdom	DD1 9SY
6	Research Site	Edinburgh		United Kingdom	EH16 4SA
7	Research Site	Edinburgh		United Kingdom	EH4 2XU

Sponsors and Collaborators

• MedImmune LLC

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Nov 12, 2018
• Statistical Analysis Plan - Jun 8, 2018

More Information

Additional Information:

• D5670C00013 CSP redacted
• D5670C00013 - SAP_Redacted

Publications

None provided.

• Responsible Party: MedImmune LLC
• ClinicalTrials.gov Identifier: NCT03550378
• Other Study ID Numbers: D5670C00013; 2018-000019-26
• First Posted: Jun 8, 2018
• Last Update Posted: Apr 13, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by MedImmune LLC: Type 2 Diabetes Mellitus; MEDI0382; Renal Impairment; Glucose concentration; Hemoglobin A1c
• Additional relevant MeSH terms: Renal Insufficiency; Diabetes Mellitus; Diabetes Mellitus, Type 2

Study Results

Participant Flow

Recruitment Details	The study was conducted in the United Kingdom and Germany between 29Jun2018 and 04Feb2019.
Pre-assignment Detail	A total of 41 participants were randomized to the study.

Arm/Group Title	Placebo	MEDI0382
Arm/Group Description	Participants received subcutaneous dose (SC) of placebo matched to MEDI0382 once daily for 32 days.	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Period Title: Overall Study
STARTED	20	21
COMPLETED	20	20
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Placebo	MEDI0382	Total
Arm/Group Description	Participants received subcutaneous dose (SC) of placebo matched to MEDI0382 once daily for 32 days.	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.	Total of all reporting groups
Overall Participants	20	21	41
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	70.9 (4.7)	71.1 (7.4)	71.0 (6.1)
Sex: Female, Male (Count of Participants)
Female	11 55%	9 42.9%	20 48.8%
Male	9 45%	12 57.1%	21 51.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	20 100%	21 100%	41 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	1 4.8%	1 2.4%
Black or African American	0 0%	0 0%	0 0%
White	20 100%	20 95.2%	40 97.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in Plasma Glucose Area Under the Concentration Time-curve From Time 0 to 4 Hours (AUC0-4 Hrs) as Measured by Mixed-meal Tolerance Test (MMTT) to Day 32
Description	The MMTT involved the consumption of a standardised liquid meal (a nutritional supplement containing the components of fat, carbohydrate, and protein, which make up a standard MMTT) within 15 minutes, and timed serial blood samples obtained for measurement of glucose and parameters related to glucose metabolism through 240 minutes after consumption of the standardized meal (with no additional food intake during this time).
Time Frame	Zero minutes before and 15, 30, 45, 60, 90, 120, 180, and 240 minutes after consumption of the standardised meal on Day -5 (Baseline) and Day 32

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population included all participants who received any dose of study drug and analyzed according to their randomized treatment group. Here, "N" signifies only the participants with available data were analyzed for the outcome measure.

Arm/Group Title	Placebo	MEDI0382
Arm/Group Description	Participants received subcutaneous dose (SC) of placebo matched to MEDI0382 once daily for 32 days.	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	20	18
Least Squares Mean (90% Confidence Interval) [Percent change in plasma glucose]	3.678	-26.706

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, MEDI0382
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-30.384
	Confidence Interval	(2-Sided) 90%; -41.270 to -19.498
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
Description	An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Time Frame	Day 1 through Day 60

Outcome Measure Data

Analysis Population Description

As-treated population included all participants who received any dose of study drug and analyzed according to the treatment they actually received.

Arm/Group Title	Placebo	MEDI0382
Arm/Group Description	Participants received subcutaneous dose (SC) of placebo matched to MEDI0382 once daily for 32 days.	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	20	21
TEAEs	13 65%	20 95.2%
TESAEs	2 10%	2 9.5%

3. Secondary Outcome

Title	Number of Participants With Abnormal Vital Signs Reported as TEAEs
Description	Number of participants with abnormal vital signs reported as TEAEs is reported. Vital sign measurements were obtained after the participant had rested in the supine position for at least 10 minutes at the recording time. Abnormal vital signs is defined as any abnormal finding in the vital sign parameters (blood pressure, pulse rate, body temperature, and respiratory rate).
Time Frame	Day 1 through Day 60

Outcome Measure Data

Analysis Population Description

As-treated population included all participants who received any dose of study drug and analyzed according to the treatment they actually received.

Arm/Group Title	Placebo	MEDI0382
Arm/Group Description	Participants received subcutaneous dose (SC) of placebo matched to MEDI0382 once daily for 32 days.	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	20	21
Count of Participants [Participants]	0 0%	0 0%

4. Secondary Outcome

Title	Change From Baseline in Postural Blood Pressure
Description	The change difference is the change from Day 1 to Day 32 in the difference between systolic blood pressure (SBP) or diastolic blood pressure (DBP) values in standing and supine positions. For this outcome measure, participants with difference (standing-supine) in DBP or SBP on Day 1 and Day 32 were analyzed. For few participants either DBP or SBP was recorded eg, standing DBP was not recorded on Day 1 for 2 participants in Placebo arm and 1 participant in MEDI0382 arm; standing SBP was not recorded on Day 32 for a participant in the Placebo arm.
Time Frame	Baseline (Day 1) through Day 32

Outcome Measure Data

Analysis Population Description

As-treated population included all participants who received any dose of study drug and analyzed according to the treatment they actually received. Participants with difference (standing-supine) in DBP or SBP on Day 1 and the participants with difference (standing-supine) in DBP or SBP on Day 32 were analyzed.

Arm/Group Title	Placebo	MEDI0382
Arm/Group Description	Participants received subcutaneous dose (SC) of placebo matched to MEDI0382 once daily for 32 days.	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	20	21
Systolic Blood Pressure	0.1 (9.3)	8.9 (14.2)
Diastolic Blood Pressure	1.8 (6.3)	0.8 (5.2)

5. Secondary Outcome

Title	Number of Participants With Abnormal Electrocardiograms (ECGs) Reported as TEAEs
Description	Number of participants with abnormal ECGs reported as TEAEs is reported. Abnormal ECGs is defined as any abnormal findings in heart rate, RR interval, PR interval, QRS, axis, ST-T morphology, and QT intervals from the primary lead of the digital 12-lead ECG.
Time Frame	Day 1 through Day 60

Outcome Measure Data

Analysis Population Description

As-treated population included all participants who received any dose of study drug and analyzed according to the treatment they actually received.

Arm/Group Title	Placebo	MEDI0382
Arm/Group Description	Participants received subcutaneous dose (SC) of placebo matched to MEDI0382 once daily for 32 days.	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	20	21
Bradyarrhythmia	1 5%	0 0%
Bundle branch block left	1 5%	0 0%
Bundle branch block right	0 0%	1 4.8%

6. Secondary Outcome

Title	Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs
Description	Number of participants with abnormal clinical laboratory parameters reported as TEAEs is reported. Abnormal clinical laboratory parameters defined as any abnormal finding during analysis of serum chemistry, hematology, and urine.
Time Frame	Day 1 through Day 60

Outcome Measure Data

Analysis Population Description

As-treated population included all participants who received any dose of study drug and analyzed according to the treatment they actually received.

Arm/Group Title	Placebo	MEDI0382
Arm/Group Description	Participants received subcutaneous dose (SC) of placebo matched to MEDI0382 once daily for 32 days.	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	20	21
Hypoglycaemia	1 5%	3 14.3%
Alanine aminotransferase increased	1 5%	0 0%
Aspartate aminotransferase increased	1 5%	0 0%
Glomerular filtration rate decreased	0 0%	1 4.8%

7. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events of Special Interest (TEAESIs)
Description	An adverse event of special interest (AESI) was one of scientific and medical interest specific to understanding of the study drug and may require close monitoring and rapid communication by the investigator to the sponsor.
Time Frame	Day 1 through Day 60

Outcome Measure Data

Analysis Population Description

As-treated population included all participants who received any dose of study drug and analyzed according to the treatment they actually received.

Arm/Group Title	Placebo	MEDI0382
Arm/Group Description	Participants received subcutaneous dose (SC) of placebo matched to MEDI0382 once daily for 32 days.	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	20	21
Count of Participants [Participants]	0 0%	0 0%

8. Secondary Outcome

Title	Change From Baseline in Mean 24-hrs Pulse Rate to the End of Each Dosing Level
Description	Change from baseline in mean 24-hrs pulse rate to the end of each dosing levels: Day 5 for 50 μg; Day 12 for 100 μg, Day 19 for 200 μg, and Day 32 for 300 μg.
Time Frame	Day -5 (Baseline) and on Days 5, 12, 19, and 32

Outcome Measure Data

Analysis Population Description

As-treated population included all participants who received any dose of study drug and analyzed according to the treatment they actually received. Here, "n" signifies only the participants with available data were analyzed for the specified time points.

Arm/Group Title	Placebo	MEDI0382
Arm/Group Description	Participants received subcutaneous dose (SC) of placebo matched to MEDI0382 once daily for 32 days.	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	20	21
Day 5	-0.73 (4.13)	6.40 (5.53)
Day 12	1.04 (5.07)	9.01 (7.73)
Day 19	1.32 (5.28)	12.72 (8.93)
Day 32	-0.92 (4.51)	11.85 (8.82)

9. Secondary Outcome

Title	Change From Baseline in Mean 24-hrs Systolic and Diastolic Blood Pressure to the End of Each Dosing Level
Description	Change from baseline in mean 24-hrs systolic and diastolic blood pressure to the end of each dosing levels: Day 5 for 50 μg, Day 12 for 100 μg, Day 19 for 200 μg, and Day 32 for 300 μg.
Time Frame	Day -5 (Baseline) and on Days 5, 12, 19, and 32

Outcome Measure Data

Analysis Population Description

As-treated population included all participants who received any dose of study drug and analyzed according to the treatment they actually received. Here, "n" signifies only the participants with available data were analyzed for the specified time points.

Arm/Group Title	Placebo	MEDI0382
Arm/Group Description	Participants received subcutaneous dose (SC) of placebo matched to MEDI0382 once daily for 32 days.	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	20	21
Day 5: Systolic Blood Pressure	-3.11 (9.97)	-1.69 (9.06)
Day 12: Systolic Blood Pressure	-2.67 (12.30)	-4.34 (11.46)
Day 19: Systolic Blood Pressure	-3.56 (10.15)	-4.72 (11.65)
Day 32: Systolic Blood Pressure	2.21 (7.24)	-1.15 (18.43)
Day 5: Diastolic Blood Pressure	-0.07 (3.19)	1.15 (3.64)
Day 12: Diastolic Blood Pressure	-0.55 (5.17)	1.28 (5.22)
Day 19: Diastolic Blood Pressure	-0.44 (3.85)	0.76 (3.75)
Day 32: Diastolic Blood Pressure	1.84 (1.79)	2.54 (5.34)

10. Secondary Outcome

Title	Change From Baseline in Haemoglobin A1c (HbA1c) to Day 32
Description	Change from baseline in haemoglobin A1c (HbA1c) is reported.
Time Frame	Day 1 (Baseline) and Day 32

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population included all participants who received any dose of study drug and analyzed according to their randomized treatment group. Here, "N" signifies only the participants with available data were analyzed for the outcome measure.

Arm/Group Title	Placebo	MEDI0382
Arm/Group Description	Participants received subcutaneous dose (SC) of placebo matched to MEDI0382 once daily for 32 days.	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	20	19
Least Squares Mean (90% Confidence Interval) [Percent]	0.01	-0.65

11. Secondary Outcome

Title	Change From Baseline in Fasting Glucose to Day 32
Description	Change from baseline in fasting glucose is reported.
Time Frame	Day 1 (Baseline) and Day 32

Outcome Measure Data

Analysis Population Description

An ITT population included all participants who received any dose of study drug and analyzed according to their randomized treatment group. Here, "N" signifies only the participants with available data were analyzed for the outcome measure.

Arm/Group Title	Placebo	MEDI0382
Arm/Group Description	Participants received subcutaneous dose (SC) of placebo matched to MEDI0382 once daily for 32 days.	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	20	19
Least Squares Mean (90% Confidence Interval) [mg/dL]	0.60	-19.55

12. Secondary Outcome

Title	Change From Baseline in Percentage of Time Spent Within a Target Glucose Range Over a 7-day Period to the Final Week of Treatment
Description	Change from baseline in percentage of time spent within a target glucose range over a 7-day period to the final week of treatment is reported. Target glucose range was considered as 70 mg/dL (3.9 mmol/L) to 180 mg/dL (10 mmol/L).
Time Frame	Baseline (Days -8 to -2), Days 5 to 11, Days 12 to 18, Days 19 to 25, and Days 26 to 32 (final week of treatment)

Outcome Measure Data

Analysis Population Description

An ITT population included all participants who received any dose of study drug and analyzed according to their randomized treatment group. Here, "n" signifies only the participants with available data were analyzed for the specified time points.

Arm/Group Title	Placebo	MEDI0382
Arm/Group Description	Participants received subcutaneous dose (SC) of placebo matched to MEDI0382 once daily for 32 days.	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	20	21
Days 5 - 11	-10.49	12.25
Days 12 - 18	-5.34	15.62
Days 19 - 25	-16.05	19.18
Days 26 - 32	-21.23	14.79

13. Secondary Outcome

Title	Percent Change Frome Baseline in Body Weight to Day 33
Description	Percent change from baseline in body weight is reported.
Time Frame	Day 1 (Baseline) and Day 33

Outcome Measure Data

Analysis Population Description

An ITT population included all participants who received any dose of study drug and analyzed according to their randomized treatment group. Here, "N" signifies only the participants with available data were analyzed for the outcome measure.

Arm/Group Title	Placebo	MEDI0382
Arm/Group Description	Participants received subcutaneous dose (SC) of placebo matched to MEDI0382 once daily for 32 days.	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	20	19
Least Squares Mean (90% Confidence Interval) [Percent change in body weight]	-0.21	-3.69

14. Secondary Outcome

Title	Change From Baseline in Absolute Body Weight to Day 33
Description	Change from baseline in absolute body weight is reported.
Time Frame	Day 1 (Baseline) and Day 33

Outcome Measure Data

Analysis Population Description

An ITT population included all participants who received any dose of study drug and analyzed according to their randomized treatment group. Here, "N" signifies only the participants with available data were analyzed for the outcome measure.

Arm/Group Title	Placebo	MEDI0382
Arm/Group Description	Participants received subcutaneous dose (SC) of placebo matched to MEDI0382 once daily for 32 days.	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	20	19
Mean (Standard Deviation) [Kg]	-0.15 (1.84)	-3.39 (2.16)

15. Secondary Outcome

Title	Area Under the Plasma Concentration Time Curve Over a Dosing Duration (AUCτ) of MEDI0382 at 300 μg
Description	Area under the plasma concentration time curve over a dosing duration (AUCτ) of MEDI0382 at 300 μg is reported.
Time Frame	Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose on Day 32

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) population included all participants who received at least 1 dose of study drug and had at least one PK sample collected with a value above the lower limit of quantitation.

Arm/Group Title	MEDI0382
Arm/Group Description	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	16
Geometric Mean (Full Range) [ng.hr/mL]	285.93

16. Secondary Outcome

Title	Maximum Observed Serum Concentration (Cmax) of MEDI0382 at 300 μg
Description	Maximum observed serum concentration (Cmax) of MEDI0382 at 300 μg is reported.
Time Frame	Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose on Day 32

Outcome Measure Data

Analysis Population Description

The PK population included all participants who received at least 1 dose of study drug and had at least one PK sample collected with a value above the lower limit of quantitation.

Arm/Group Title	MEDI0382
Arm/Group Description	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	18
Geometric Mean (Full Range) [ng/mL]	16.93

17. Secondary Outcome

Title	Time to Observed Maximum Serum Concentration (Tmax) of MEDI0382 at 300 μg
Description	Time to observed maximum serum concentration (Tmax) of MEDI0382 at 300 μg is reported.
Time Frame	Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose on Day 32

Outcome Measure Data

Analysis Population Description

The PK population included all participants who received at least 1 dose of study drug and had at least one PK sample collected with a value above the lower limit of quantitation.

Arm/Group Title	MEDI0382
Arm/Group Description	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	18
Median (Full Range) [Hours]	5.6

18. Secondary Outcome

Title	Trough Plasma Concentration (Ctrough) of MEDI0382
Description	Trough concentration is the lowest concentration reached by a drug before the next dose is administered. Trough plasma concentration of MEDI0382 is reported.
Time Frame	Days 1, 5, 12, and 19: Predose; and Day 32: Predose and at 0.5, 1, 2, 4, 6, 8, and 24 hrs postdose (Day 33)

Outcome Measure Data

Analysis Population Description

The PK population included all participants who received at least 1 dose of study drug and had at least one PK sample collected with a value above the lower limit of quantitation. Here, "n" signifies only the participants with available data were analyzed for the specified time points.

Arm/Group Title	MEDI0382
Arm/Group Description	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	21
Day 5	1.44
Day 12	2.03
Day 19	3.68
Day 32	5.86
Day 33	5.96

19. Secondary Outcome

Title	Number of Participants With Positive Anti-drug Antibodies (ADA) Titre to MEDI0382
Description	Number of participants with positive Anti-drug antibodies (ADA) Titre to MEDI0382 is reported.
Time Frame	Pre-dose on Days 1, 12, and 32 and on Day 60

Outcome Measure Data

Analysis Population Description

As-treated population included all participants who received any dose of study drug and analyzed according to the treatment they actually received.

Arm/Group Title	Placebo	MEDI0382
Arm/Group Description	Participants received subcutaneous dose (SC) of placebo matched to MEDI0382 once daily for 32 days.	Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
Measure Participants	20	21
Positive at baseline	0 0%	0 0%
Positive post-baseline	0 0%	2 9.5%
Positive at baseline and post-baseline	0 0%	0 0%
Not detected at baseline; positive post-baseline	0 0%	2 9.5%
Positive at baseline; not detected post-baseline	0 0%	0 0%

Adverse Events

Time Frame	Day 1 through Day 60
Arm/Group Title	Placebo		MEDI0382
Arm/Group Description	Participants received subcutaneous dose (SC) of placebo matched to MEDI0382 once daily for 32 days.		Participants received SC dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days.
All Cause Mortality
	Placebo		MEDI0382
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		1/21 (4.8%)
Serious Adverse Events
	Placebo		MEDI0382
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/20 (10%)		2/21 (9.5%)
Metabolism and nutrition disorders
Diabetic ketoacidosis	0/20 (0%)	0	1/21 (4.8%)	1
Nervous system disorders
Carotid artery stenosis	1/20 (5%)	1	0/21 (0%)	0
Syncope	1/20 (5%)	2	0/21 (0%)	0
Vascular disorders
Hypertensive crisis	0/20 (0%)	0	1/21 (4.8%)	1
Other (Not Including Serious) Adverse Events
	Placebo		MEDI0382
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/20 (65%)		19/21 (90.5%)
Cardiac disorders
Bradyarrhythmia	1/20 (5%)	1	0/21 (0%)	0
Bundle branch block left	1/20 (5%)	1	0/21 (0%)	0
Bundle branch block right	0/20 (0%)	0	1/21 (4.8%)	1
Ear and labyrinth disorders
Vertigo	1/20 (5%)	1	0/21 (0%)	0
Vertigo positional	0/20 (0%)	0	1/21 (4.8%)	1
Gastrointestinal disorders
Abdominal distension	0/20 (0%)	0	1/21 (4.8%)	1
Abdominal pain	0/20 (0%)	0	1/21 (4.8%)	1
Abdominal pain upper	0/20 (0%)	0	1/21 (4.8%)	1
Diarrhoea	0/20 (0%)	0	5/21 (23.8%)	5
Dyspepsia	1/20 (5%)	1	5/21 (23.8%)	6
Eructation	0/20 (0%)	0	1/21 (4.8%)	1
Flatulence	0/20 (0%)	0	2/21 (9.5%)	2
Gastrooesophageal reflux disease	0/20 (0%)	0	1/21 (4.8%)	1
Nausea	4/20 (20%)	4	9/21 (42.9%)	19
Vomiting	1/20 (5%)	1	6/21 (28.6%)	18
General disorders
Complication associated with device	0/20 (0%)	0	1/21 (4.8%)	1
Injection site erythema	0/20 (0%)	0	1/21 (4.8%)	1
Injection site pruritus	0/20 (0%)	0	1/21 (4.8%)	1
Infections and infestations
Influenza	1/20 (5%)	1	0/21 (0%)	0
Nasopharyngitis	2/20 (10%)	2	3/21 (14.3%)	3
Otitis media	0/20 (0%)	0	1/21 (4.8%)	1
Pyelonephritis	1/20 (5%)	1	0/21 (0%)	0
Rhinitis	2/20 (10%)	2	1/21 (4.8%)	1
Urinary tract infection	1/20 (5%)	1	0/21 (0%)	0
Injury, poisoning and procedural complications
Face injury	0/20 (0%)	0	1/21 (4.8%)	1
Fall	0/20 (0%)	0	1/21 (4.8%)	1
Investigations
Alanine aminotransferase increased	1/20 (5%)	1	0/21 (0%)	0
Aspartate aminotransferase increased	1/20 (5%)	1	0/21 (0%)	0
Glomerular filtration rate decreased	0/20 (0%)	0	1/21 (4.8%)	1
Metabolism and nutrition disorders
Decreased appetite	0/20 (0%)	0	3/21 (14.3%)	3
Hypoglycaemia	1/20 (5%)	1	3/21 (14.3%)	8
Hypoglycaemia unawareness	0/20 (0%)	0	1/21 (4.8%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/20 (5%)	1	0/21 (0%)	0
Nervous system disorders
Carotid artery stenosis	1/20 (5%)	1	0/21 (0%)	0
Dizziness	1/20 (5%)	1	2/21 (9.5%)	2
Headache	2/20 (10%)	3	2/21 (9.5%)	3
Psychiatric disorders
Nervousness	1/20 (5%)	1	0/21 (0%)	0
Respiratory, thoracic and mediastinal disorders
Sleep apnoea syndrome	0/20 (0%)	0	1/21 (4.8%)	1
Skin and subcutaneous tissue disorders
Hyperhidrosis	0/20 (0%)	0	1/21 (4.8%)	1
Night sweats	1/20 (5%)	1	0/21 (0%)	0
Skin fissures	0/20 (0%)	0	1/21 (4.8%)	1
Skin swelling	0/20 (0%)	0	1/21 (4.8%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

MedImmune has 60 days to review results communications prior to public release and may delete information that compromises on going studies or is considered proprietary. This restriction is not intended to compromise the objective scientific integrity of the manuscript, it being understood that results shall be published regardless of outcome.