Study Evaluating Safety, Tolerability, And Action Of OAP-189 In Subjects With Type 2 Diabetes On Metformin

A RANDOMIZED, PARALLEL-GROUP, OPEN-LABEL, PLACEBO CONTROLLED STUDY OF THE EFFECT OF OAP-189 ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF METFORMIN IN DIABETIC SUBJECTS.

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00970593

Acronym

3283K1-1008-US

Enrollment

Registered

2009-09-02

Start date

2009-09-02

Completion date

2011-07-25

Last updated

2020-11-02

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Diabetes Mellitus

Brief summary

This is a study to evaluate the safety, tolerability, and activity of OAP-189 in subjects with type 2 diabetes who are taking metformin for their diabetes.

Interventions

DRUGOAP-189

Group 1: OAP-189 BID (0.2 mg BID) x 7 days Group 2: OAP-189 (0.4 mg BID) x 7 days Group 3: OAP-189 QD (0.9 mg x 7 days followed by 1.2 mg x 7 days; MR formulation) Group 4: OAP-189 QD (1.2 mg x 7 days followed by 1.6 mg x 7 days; MR formulation) Group 5: OAP-189 QD (1.2 mg x 7 days followed by 1.6 mg x 7 days; different MR formulation) Group 6: OAP-189 QD (1.2 mg x 7 days followed by 1.6 mg x 7 days; different MR formulation)

DRUGplacebo comparator

Group 1 & 2: PBO x 7 days BID Group 3: PBO QD x 14 days Group 4: PBO QD x 14 days Group 5: PBO QD x 14 days Group 6: PBO QD x 14 days

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Inclusion criteria

* Subjects must have been diagnosed with type 2 diabetes, with HbA1c level \>=7.0% and \<=11.0% and a fasting glucose level \<=280 mg/dL. * Men or women of nonchildbearing potential (WONCBP), aged 18 to 65 years inclusive on study day 1. * Body mass index in the range of 27 to 40kg/m² (inclusive) and body weight \>=50 kg. * Subjects must be otherwise generally healthy, but may be enrolled with a stable chronic illness, if it is well controlled and does not interfere with the primary objective of the study. * Subjects must currently be treated for diabetes with metformin alone at a total daily dose of \>=1gm (administered QD or BID) and that dose must have been stable for at least 4 weeks before study day 1. * Nonsmoker.

Exclusion criteria

* Any significant disease with the exception of diabetes mellitus. * Any surgical or medical condition that may interfere with the absorption, distribution, metabolism, or excretion of the investigational product. * Acute disease state (eg, nausea, vomiting, fever, or diarrhea) within 7 days before study day 1. * Any clinically important problems in physical examination results, vitals sign measurements, ECGs, or clinical laboratory test results. * Positive serologic findings for human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen (HBsAg), and/or hepatitis C virus (HCV) antibodies. * Positive findings of urine drug screen * Use of any investigational or non-permitted prescription drug within 30 days before investigational product administration.

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline in Predose Fasting Glucose Levels at Day 15	Baseline, Day 15	Fasting glucose levels were determined before administration of OAP-189 using a glucometer.
Number of Participants With Clinically Significant Fasting Glucose Level Abnormalities	Baseline up to 17 days after last dose of study drug (Day 31)	Criteria: Blood glucose levels \>15 milligram per deciliter (mg/dL) above ULN or \>15 mg/dL below LLN.
Number of Participants With Hypoglycaemia	Baseline up to 17 days after last dose of study drug (Day 31)	Hypoglycaemia is a condition characterized by abnormally low blood glucose (blood sugar) levels, usually \<=50 mg/dL.
Number of Participants With Drug-Induced Liver Injury	Baseline up to 17 days after last dose of study drug (Day 31)	Criteria for drug induced liver injury: Levels of aspartate transaminase (AST) or alanine transaminase (ALT) should be \>= 3 times ULN concurrent with a total bilirubin of \>=2 times ULN with no evidence of hemolysis and an alkaline phosphatase should be \<=2 times ULN.
Change From Baseline in Predose Fasting Glucose Levels at Day 8	Baseline, Day 8	Fasting glucose levels were determined before administration of OAP-189 using a glucometer.
Number of Participants With Clinically Significant Physical Examination Abnormalities	Baseline up to 17 days after last dose of study drug (Day 31)	Physical examination included examination of skin, head, eyes, ears, nose, throat (HEENT), heart, lungs, abdomen, extremities, neurological function, back and lymph nodes. Clinically significant physical examination abnormalities were considered as adverse events based on investigator's discretion.
Number of Participants With Clinically Significant Vital Signs Abnormalities	Baseline up to 17 days after last dose of study drug (Day 31)	Criteria for clinically significant vital sign abnormalities: sitting systolic blood pressure (SBP) of (greater than equal to) \>=160 millimeter of mercury (mmHg), (less than equal to) \<=90 mmHg, \>=20 mmHg increase and decrease from baseline; sitting diastolic blood pressure (DBP) of \>=100 mmHg, \<=50 mmHg, \>=15 mmHg increase and decrease from baseline; heart rate of \>=120 beats per minute (bpm), \<=45 bpm, (greater than) \>15 bpm increase and decrease from baseline, orthostatic SBP: decrease of \>=20 mm Hg from sitting value, orthostatic DBP: decrease of \>=20 mm Hg from sitting value, orthostatic heart rate: increase of \>=30 bpm from sitting value, oral temperature of (less than) \<35 or \>38.3 degree celsius, respiratory rate of \<10 or \>25 breaths per minute, weight: maximum increase or decrease of \>=7 percent (%) from baseline.
Number of Participants With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities	Baseline up to 17 days after last dose of study drug (Day 31)	Criteria for clinically significant ECG abnormalities: PR interval \>=220 millisecond (msec) or a change of \>=20 msec from baseline values, QRS interval \>=120 msec, QTc interval \>450 msec (in males) and \>470 msec (in females).
Number of Participants With Clinically Significant Laboratory Abnormalities	Baseline up to 17 days after last dose of study drug (Day 31)	Hematocrit, haemoglobin: decrease of \>=0.05 L/L and \>=20 g/L from baseline respectively, WBC count:\<3\10\^9 /L, neutrophils: \<1.5\10\^9 /L, platelet count: \<100\10\^9 /L, eosinophil: \<0.5\10\^9 /L; prothrombin time, partial thromboplastin time \>1.5\upper limit of normal (ULN); sodium:\>5 mmol/L above ULN or below lower limit of normal(LLN), potassium \>0.5 mmol/L above ULN or below LLN, creatinine \>1.36\ULN, blood urea nitrogen \>1.5\ULN, glucose (fasting) \>0.83 mmol/L above ULN or below LLN, glucose (non-fasting) \>5 mmol/L above ULN or \>0.56 below LLN, calcium, magnesium: Change of \>=0.25 and \>=0.21 mmol/L from baseline respectively, phosphorus \>0.162 mmol/L above ULN or below LLN, total protein, albumin, uric acid: change of \>=20g/L, \>=10 g/L, \>0.119 mmol/L from baseline respectively, creatinine kinase \>3\ULN, total cholesterol \>7.77 mmol/L, triglycerides \>3.39 mmol/L: AST, ALT, total bilirubin \>2\ULN, alkaline phosphatase \>1.5\ULN, alpha-glumatyl transferase, lactate dehydrogenase \>3\*ULN.
Number of Participants With Injection Site Reactions	Baseline up to 17 days after last dose of study drug (Day 31)	Injection site reactions included irritation, erythema, pain, hematoma, inflammation.

Other

Measure	Time frame	Description
Plasma Concentration Versus Time Summary of Metformin Following Multiple Dose of OAP-189	Pre-dose (2 hours before dosing), 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 24 hours post-dose on Day 7	Concentration versus time summary was calculated by setting concentration values below the lower limit of quantification (LLOQ =2 nanogram per millliter) to zero. Summary statistics were not to be presented if number of observations above lower limit of quantification (NALQ) =0.
Plasma Concentration Versus Time Summary of Single Dose of OAP-189	Pre-dose (2 hours before dosing), 2, 4, 6 hours post-dose on Day 7; Pre-dose (2 hours before dosing), 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 24, 48, 72 hours post-dose on Day 14	Concentration versus time summary was calculated by setting concentration values below the lower limit of quantification (LLOQ = 0.500 nanogram per millliter) to zero. Summary statistics were not to be presented if number of observations above lower limit of quantification (NALQ) =0.
Plasma Concentration Versus Time Summary of Multiple Dose of OAP-189	Pre-dose (2 hours before dosing), 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 24 hours post-dose on Day 7	Concentration versus time summary was calculated by setting concentration values below the lower limit of quantification (LLOQ =0.500 nanogram per millliter) to zero. Summary statistics were not to be presented if number of observations above lower limit of quantification (NALQ) =0.
Plasma Concentration Versus Time Summary of Metformin Following Single Dose of OAP-189	Pre-dose (2 hours before dosing), 1, 2, 3, 4, 6 hours post-dose on Day 14	Concentration versus time summary was calculated by setting concentration values below the lower limit of quantification (LLOQ =2 nanogram per millliter) to zero. Summary statistics were not to be presented if number of observations above lower limit of quantification (NALQ) =0.

Countries

United States

Participant flow

Pre-assignment details

All participants received the background metformin immediate release tablets, during the 4 weeks run-in period. Compliant participants were then randomized to study treatments for a maximum period of 31 days.

Participants by arm

Arm	Count
OAP-189 0.2 mg IR Participants received OAP-189 0.2 milligram (mg), immediate release (IR) infusion subcutaneously twice daily from Day 1 to Day 7 along with background metformin 850 mg immediate release tablets or as per standard clinical practice (based on the dose prior to randomization).	11
OAP-189 0.4 mg IR Participants received OAP-189 0.4 mg, IR infusion subcutaneously twice daily from Day 1 to Day 7 along with background metformin 850 mg immediate release tablets or as per standard clinical practice (based on the dose prior to randomization).	15
OAP-189 MR (0.05:1 Z/P Ratio) 0.9 mg Followed by 1.2 mg Participants received OAP-189 0.9 mg, modified release (MR) infusion (with 0.05:1 zinc to peptide \[Z/P\] ratio) subcutaneously once daily from Day 1 to Day 7 followed by OAP-189 1.2 mg, MR infusion subcutaneously once daily from Day 8 to Day 14 along with background metformin 850 mg immediate release tablets or as per standard clinical practice (based on the dose prior to randomization).	13
OAP-189 MR (0.1:1 Z/P Ratio) 1.2 mg Followed by 1.6 mg Participants received OAP-189 1.2 mg, MR infusion (with 0.1:1 Z/P ratio) subcutaneously once daily from Day 1 to Day 7 followed by OAP-189 1.6 mg, MR infusion subcutaneously once daily from Day 8 to Day 14 along with background metformin 850 mg immediate release tablets or as per standard clinical practice (based on the dose prior to randomization).	12
OAP-189 MR (0.25:1 Z/P Ratio) 1.2 mg Followed by 1.6 mg Participants received OAP-189 1.2 mg, MR infusion (with 0.25:1 Z/P ratio) subcutaneously once daily from Day 1 to Day 7 followed by OAP-189 1.6 mg, MR infusion subcutaneously once daily from Day 8 to Day 14 along with background metformin 850 mg immediate release tablets or as per standard clinical practice (based on the dose prior to randomization).	20
Placebo IR Participants received placebo matched to OAP-189, IR infusion subcutaneously twice daily from Day 1 to Day 7 along with background metformin 850 mg immediate release tablets or as per standard clinical practice (based on the dose prior to randomization).	5
Placebo MR Participants received placebo matched to OAP-189, MR infusion subcutaneously once daily from Day 1 to Day 14 along with background metformin 850 mg immediate release tablets or as per standard clinical practice (based on the dose prior to randomization).	16
Total	92

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG006
Overall Study	Adverse Event	1	1	0	0
Overall Study	Discontinuation of study by sponsor	0	0	5	2
Overall Study	Withdrawal by Subject	0	0	1	0

Baseline characteristics

Characteristic	OAP-189 0.2 mg IR	OAP-189 0.4 mg IR	OAP-189 MR (0.05:1 Z/P Ratio) 0.9 mg Followed by 1.2 mg	OAP-189 MR (0.1:1 Z/P Ratio) 1.2 mg Followed by 1.6 mg	OAP-189 MR (0.25:1 Z/P Ratio) 1.2 mg Followed by 1.6 mg	Placebo IR	Placebo MR	Total
Age, Continuous	55.00 years STANDARD_DEVIATION 8.65	53.60 years STANDARD_DEVIATION 6.33	52.69 years STANDARD_DEVIATION 3.12	54.92 years STANDARD_DEVIATION 6.69	51.50 years STANDARD_DEVIATION 9.64	53.80 years STANDARD_DEVIATION 9.34	54.75 years STANDARD_DEVIATION 6.83	53.57 years STANDARD_DEVIATION 7.33
Sex: Female, Male Female	3 Participants	4 Participants	3 Participants	4 Participants	4 Participants	2 Participants	6 Participants	26 Participants
Sex: Female, Male Male	8 Participants	11 Participants	10 Participants	8 Participants	16 Participants	3 Participants	10 Participants	66 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	6 / 11	11 / 15	13 / 13	10 / 12	16 / 20	1 / 5	11 / 16
serious Total, serious adverse events	0 / 11	0 / 15	0 / 13	0 / 12	0 / 20	0 / 5	0 / 16

Outcome results

Primary

Change From Baseline in Predose Fasting Glucose Levels at Day 15

Fasting glucose levels were determined before administration of OAP-189 using a glucometer.

Time frame: Baseline, Day 15

Population: Safety population included all randomly assigned participants who received at least 1 dose of study medication. Here, 'N' signifies those participants who were evaluable for this measure. This outcome measure was not to be analyzed in participants of OAP-189 0.2, 0.4 mg IR and Placebo IR as pre-specified in protocol.

Arm	Measure	Value (MEAN)	Dispersion
OAP-189 0.2 mg IR	Change From Baseline in Predose Fasting Glucose Levels at Day 15	-2.62 millimole per liter	Standard Deviation 0.998
OAP-189 0.4 mg IR	Change From Baseline in Predose Fasting Glucose Levels at Day 15	-3.87 millimole per liter	Standard Deviation 1.783
OAP-189 MR (0.05:1 Z/P Ratio) 0.9 mg Followed by 1.2 mg	Change From Baseline in Predose Fasting Glucose Levels at Day 15	-3.49 millimole per liter	Standard Deviation 1.643
OAP-189 MR (0.1:1 Z/P Ratio) 1.2 mg Followed by 1.6 mg	Change From Baseline in Predose Fasting Glucose Levels at Day 15	-0.33 millimole per liter	Standard Deviation 1.273

Comparison: The Mixed model used fixed effects of treatment, study day and treatment by study day interaction.95% CI: [-3.52, -1.22]

Comparison: The Mixed model used fixed effects of treatment, study day and treatment by study day interaction.95% CI: [-4.16, -2.2]

Comparison: The Mixed model used fixed effects of treatment, study day and treatment by study day interaction.95% CI: [-4.01, -2.28]

Primary

Change From Baseline in Predose Fasting Glucose Levels at Day 8

Fasting glucose levels were determined before administration of OAP-189 using a glucometer.

Time frame: Baseline, Day 8

Population: Safety population included all randomly assigned participants who received at least 1 dose of study medication. Here, 'n' signifies those participants who were evaluable at specified time points. This outcome measure was not to be analyzed in participants of OAP-189 0.2, 0.4 mg IR and Placebo IR as pre-specified in the protocol.

Arm	Measure	Group	Value (MEAN)	Dispersion
OAP-189 0.2 mg IR	Change From Baseline in Predose Fasting Glucose Levels at Day 8	Baseline	10.02 millimole per liter	Standard Deviation 2.373
OAP-189 0.2 mg IR	Change From Baseline in Predose Fasting Glucose Levels at Day 8	Change at Day 8	-1.37 millimole per liter	Standard Deviation 2.222
OAP-189 0.4 mg IR	Change From Baseline in Predose Fasting Glucose Levels at Day 8	Change at Day 8	-2.75 millimole per liter	Standard Deviation 1.663
OAP-189 0.4 mg IR	Change From Baseline in Predose Fasting Glucose Levels at Day 8	Baseline	10.06 millimole per liter	Standard Deviation 2.583
OAP-189 MR (0.05:1 Z/P Ratio) 0.9 mg Followed by 1.2 mg	Change From Baseline in Predose Fasting Glucose Levels at Day 8	Baseline	9.27 millimole per liter	Standard Deviation 2.148
OAP-189 MR (0.05:1 Z/P Ratio) 0.9 mg Followed by 1.2 mg	Change From Baseline in Predose Fasting Glucose Levels at Day 8	Change at Day 8	-2.47 millimole per liter	Standard Deviation 1.4
OAP-189 MR (0.1:1 Z/P Ratio) 1.2 mg Followed by 1.6 mg	Change From Baseline in Predose Fasting Glucose Levels at Day 8	Baseline	9.01 millimole per liter	Standard Deviation 1.769
OAP-189 MR (0.1:1 Z/P Ratio) 1.2 mg Followed by 1.6 mg	Change From Baseline in Predose Fasting Glucose Levels at Day 8	Change at Day 8	-0.25 millimole per liter	Standard Deviation 1.166

Comparison: The Mixed model used fixed effects of treatment, study day and treatment by study day interaction.95% CI: [-1.79, 0.29]

Comparison: The Mixed model used fixed effects of treatment, study day and treatment by study day interaction.95% CI: [-2.98, -0.83]

Comparison: The Mixed model used fixed effects of treatment, study day and treatment by study day interaction.95% CI: [-3.06, -1.24]

Primary

Number of Participants With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities

Criteria for clinically significant ECG abnormalities: PR interval \>=220 millisecond (msec) or a change of \>=20 msec from baseline values, QRS interval \>=120 msec, QTc interval \>450 msec (in males) and \>470 msec (in females).