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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.

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Official Title

A Phase 1, combined Single Ascending Dose (SAD)  and Multiple-ascending Dose (MAD) study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of MEDI4166 in Subjects with Type 2 Diabetes Mellitus (T2D).

A Phase 1, Single- and Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of MEDI4166 in Subjects with Type 2 Diabetes

This study is a first time in human (FTIH), Phase 1, randomized, double-blind study to evaluate the safety, tolerability, PK, and PD of MEDI4166 administered as both single and multiple ascending doses to subjects with T2D.

NCT ID

Therapeutic Area

Research Site

A Phase 1, Combined Single- and Multiple-ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) of MEDI4166 in Subjects with Type 2 Diabetes Mellitus (T2D)

Treatment emergent adverse events (TEAEs) and serious adverse events (TESAEs)

12 lead electrocardiogram including RR, PR, QRS, QT and QTc intervals

Vital signs (systolic and diastolic blood pressure, pulse rate, temperature, and respiratory rate)

Clinical laboratory assessments (serum chemistry, hematology, urinalysis)

Part B: Change in glucose AUC measured up to 240 minutes after mixed meal tolerance test (MMTT) from baseline to Day 36

Part B: Change in LDL-C from baseline to Day 36

Age Continuous

Sex: Female, Male

Race (NIH/OMB)

Ethnicity (NIH/OMB)

Intent-to-treat (ITT): ITT population included all participants who were randomized and received any study drug.

TEAEs

TESAEs

An Adverse Event (AE) is any unfavourable and unintended sign, symptoms, or diseases temporally associated with use of study drug, whether or not considered related to study drug. SAE is any AE that resulted in death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, life-threatening, a congenital anomaly/birth defect, or an important medical event. TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 43 days.

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

Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs) or Treatment-emergent Serious Adverse Events (TESAEs)

Normochromic normocytic anaemia

Hypoglycaemia

Any clinically significant change in laboratory evaluations were recorded as AEs. The following parameters were analyzed for laboratory evaluations: haematology, serum chemistry, and urinalysis. Number of participants with TEAEs related to laboratory evaluations were reported.

Part A: Number of Participants With Abnormal Laboratory Parameter Reported as TEAEs

TEAEs related vital signs

TEAEs related to ECG

Vital sign parameters included blood pressure, heart rate, respiratory rate, and body temperature. TEAEs related to vital signs in participants were reported. ECG parameters included heart rate, RR, PR, QRS, QT intervals, and QTcF (corrected QT interval per Fridericia's formula) intervals from the primary lead of the digital 12-lead ECG. Number of participants with TEAEs related to ECG were reported.

Part A: Number of Participants With Vital Signs and Electrocardiogram (ECG) Abnormalities Reported as TEAEs

Change at Day 36

Glucose control was measured by the area under the glucose concentration versus time curve (glucose AUC) following an MMTT. MMTT involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes and timed serial blood samples were obtained for measurement of glucose metabolism through 4 hours after consumption of the standardized meal (with no additional food intake during this time). The MMTT was used to measure the effect of MEDI4166 on glucose lowering following a standard liquid meal.

Modified intent-to-treat (MITT):  MITT population included all participants who were randomized and received any study drug and were participated in at least 1 mixed MMTT.

Part B: Mean Change From Baseline in Glucose AUC Measured up to 4 hours (h) (AUC 0-4 h) After Mixed Meal Tolerance Test (MMTT) to Day 36

The LDL-c was measured following an overnight (at least 8 hours) fast as part of a fasting lipid panel taken.

Part B: Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline to Day 36

Change at Day 15

Glucose control was measured by the area under the glucose concentration versus time curve (glucose AUC) following an MMTT. The MMTT involved consumption of a standardized meal (nutritional supplement containing the components of fat, carbohydrate and protein, which make up a standard MMT) within 5 minutes and timed serial blood samples were obtained for measurement of glucose metabolism through 4 hours after consumption of the standardized meal (with no additional food intake during this time). The MMTT was used to measure the effect of MEDI4166 on glucose lowering following a standard liquid meal.

Pharmacodynamics (PD) population: PD population included all participants who participated in at least 1 MMTT (ie, gave at least 1 post MMTT PD blood sample).

Part A: Mean Change From Baseline in Glucose AUC Measured up to 4 hours (h) (AUC 0-4 h) After Mixed Meal Tolerance Test (MMTT) to Day 15

Low-density lipoprotein cholesterol levels were measured following an overnight (at least 8 hours) fast as part of a fasting lipid panel taken.

Part A: Change From Baseline in LDL-C at Day 15

The maximum observed serum drug concentration (Cmax) of MEDI4166 was determined directly from the concentration-time data.

Pharmacokinetic population included all participants who received at least 1 dose of study drug and had at least one PK sample taken that was above the lower limit of quantitation for this parameter.

Part A: Maximum Observed Serum Concentration (Cmax) of MEDI4166

The time to reach maximum serum concentration of MEDI4166 was determined directly from the concentration-time data as the time of occurrence of Cmax.

Part A: Time to Reach Maximum Observed Serum Concentration (Tmax) of MEDI4166

The apparent terminal elimination half-life (t1/2) of MEDI4166 was determined over the sampling period.

Part A: Terminal Elimination Half Life (t1/2) of MEDI4166

The area under the serum drug concentration versus time curve from zero to the time of the last quantifiable concentration (Clast) is reported.

Part A: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC [0-last]) of MEDI4166

Area under the serum concentration-time curve from doing extrapolated to infinity (AUC 0-infinity) was reported.

Part A: Area Under the Concentration-Time Curve From Zero to Infinity (AUC [0-infinity]) of MEDI4166

The PK parameter of apparent volume of distribution (Vz/F) was estimated based on the concentration-time data of MEDI4166.

Part A: Apparent Volume of Distribution of MEDI4166

The apparent clearance of MEDI4166 was calculated as follows: Dose/area under the plasma drug concentration-time curve extrapolated to infinity (AUC 0-infinity).

Part A: Apparent Clearance (CL/F) of MEDI4166

Baseline (Predose on Day 1)

Day 15

Day 29

Day 43

ADA incidence rate is defined as the treatment emergent ADA, which is sum of the treatment induced and treatment boosted.

Part A: Number of Participants Positive for Anti-Drug Antibodies to MEDI4166

An Adverse Event (AE) is any unfavourable and unintended sign, symptoms, or diseases temporally associated with use of study drug, whether or not considered related to study drug. SAE is any AE that resulted in death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, life-threatening, a congenital anomaly/birth defect, or an important medical event. TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 71 days.

Part B: Number of Participants With Treatment-emergent Adverse Events (TEAEs) or Treatment-emergent Serious Adverse Events (SAEs)

Anaemia

Hyperglycaemia

Hypokalaemia

Nephrolithiasis

Urinary casts present

Part B: Number of Participants With Abnormal Laboratory Parameter Reported as TEAEs

AV block

Sinus tachycardia

Tachycardia

TEAEs related to vital signs

Part B: Number of Participants With Vital Signs and Electrocardiogram (ECG) Abnormalities Reported as TEAEs

Fructosamine levels were studied to assess the longer-term glucose control and glucose variability.

Part B: Change From Baseline in Fructosamine Levels to Day 36

The Cmax of MEDI4166 was determined from the concentration-time data.

Part B: Maximum Observed Serum Concentration (Cmax) of MEDI4166

The time to reach maximum serum drug concentration of MEDI4166 was determined from the concentration-time data.

Part B: Time to Reach Maximum Observed Serum Concentration (Tmax) of MEDI4166

The area under the serum drug concentration versus time curve from zero to the end of the dosing interval tau (AUC 0-tau).

Part B: Area Under the Concentration-Time Curve From Time Zero to the End of Dosing Interval (AUC [0-tau]) of MEDI4166

Area under the serum concentration-time curve from dosing extrapolated to infinity (AUC0-inf) was calculated.

Part B: Area Under the Concentration-Time Curve From Zero to Infinity (AUC [0-infinity]) of MEDI4166

Part B: Terminal Elimination Half Life (t1/2) of MEDI4166

The PK parameter apparent volume of distribution at steady state (Vss/F) was estimated based on the concentration-time data of MEDI4166.

Part B: Apparent Volume of Distribution at Steady State (Vss/F) of MEDI4166

The apparent oral clearance at steady state MEDI4166 is presented below.

Part B: Apparent Clearance at Steady State (CLss/F) of MEDI4166

The observed accumulation ratio (R0) was calculated as R0 is equal to area under the serum concentration-time curve from time zero to the end of the dosing interval tau (AUC [0-tau]) Day 1/AUC (0-tau) Day 29.

Part B: Accumulation Ratio of MEDI4166

Baseline (predose on Day 1)

Day 71

Part B: Number of Participants Positive for Anti-Drug Antibodies to MEDI4166

Overall Study

Of the 498 participants, 395 participants were considered as screen failures. A total of 40 participants were randomized into Part A and 63 participants were randomized into Part B.

Meena Jain, MB, BChir, PhD

Part A: Pharmacokinetics of MEDI4166, maximum plasma concentration (Cmax)

Part A: Pharmacokinetics of MEDI4166, area under the curve concentration (AUC)

Part A: Proportion of subjects with ADA to MEDI4166

Part B: Pharmacokinetics of MEDI4166, maximum plasma concentration (Cmax)

Part B: Pharmacokinetics of MEDI4166, area under the curve concentration (AUC)

Part B: Change from baseline in fructosamine levels

Part B: Proportion of subjects with ADA to MEDI4166

Part A: Pharmacokinetics of MEDI4166, time to maximum observed plasma drug concentration (Tmax)

Part A: Change from baseline in glucose AUC up to 240 minutes

Part B: Pharmacokinetics of MEDI4166, time to maximum observed plasma drug concentration (Tmax)

Arms	Assigned Interventions
Experimental: MEDI-4166 MEDI-4166 administered subcutaneously	Biological/Vaccine: MEDI-4166 MEDI-4166 administered subcutaneously
Placebo Comparator: Placebo Placebo administered subcutaneously	Biological/Vaccine: Placebo Placebo administered subcutaneously

A Phase 1, Single- and Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of MEDI4166 in Subjects with Type 2 Diabetes

Official Title

Medical condition

Phase

Healthy volunteers

Study drug

Sex

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Study design

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Sponsors

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