Effect of Copanlisib on Metformin Pharmacokinetics and Pharmacodynamics

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03655301
• Collaborator: (none)
• Enrollment: 13
• Location: 1
• Arm: 1
• Actual Duration (Months): 5.1
• Patients Per Site Per Month: 2.6

Study Details

Study Description

Brief Summary

The purpose of this study is to learn about a drug-drug interaction. When two medications are taken together at the same time, one medication may change the activity of the other medication in the body - this is called a drug-drug interaction. This study is looking at the effect the Bayer study drug, copanlisib, has on metformin, a commonly used medication to treat diabetes. During the study, blood and urine samples will be collected and analyzed to learn about pharmacokinetics (how copanlisib changes metformin levels in the body) and pharmacodynamics (the effect metformin has on the body when taken together with copanlisib) when someone takes both copanlisib and metformin together.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: Copanlisib (Aliqopa, BAY80-6946); Drug: Metformin	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Non-randomized, Phase I Study to Evaluate the Effect of Copanlisib (a Single Intravenous Dose of 60 mg) on the Pharmacokinetics (PK) and Pharmacodynamics (PD) of Metformin (MATE2-K Substrate) in Healthy Volunteers
• Actual Study Start Date: Sep 11, 2018
• Actual Primary Completion Date: Nov 12, 2018
• Actual Study Completion Date: Feb 12, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Copanlisib (Aliqopa, BAY80-6946) All subjects will receive a single dose of metformin 1000 mg on Days 1 and 8 in a fasting state. Subjects will also receive a single i.v. dose of 60 mg copanlisib on Day 8 as part of the combination with metformin.

Drug: Copanlisib (Aliqopa, BAY80-6946); The copanlisib dose for this study is the standard dose recently approved and also used in Phase 1, 2 and 3 studies across the copanlisib development program: 60 mg i.v. infusion administered intermittently on Days 1, 8 and 15 of a 28-day cycle. In this study subjects will receive a single i.v. dose of 60 mg copanlisib on day 8.; Drug: Metformin; Single dose of 1000 mg is administered orally.

Outcome Measures

Primary Outcome Measures

1. Maximum Drug Concentration of Metformin in Plasma After Single Dose Administration (Cmax) [Pre-dose and up to 24 hours after drug administration on Day 1 and Day 8]

   Maximum observed drug concentration of metformin in plasma after single dose administration without copanlisib (Day 1) and in combination with copanlisib (Day 8) were measured.

2. Area Under the Plasma Concentration Versus Time Curve From Zero to 24 Hours of Metformin After Single Dose Administration (AUC[0-24]) [Pre-dose and up to 24 hours after drug administration on Day 1 and Day 8]

   Area under the concentration versus time curve from zero to 24 hours of metformin after single dose administration without copanlisib (Day 1) and in combination with copanlisib (Day 8) were measured.

3. Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity of Metformin After Single Dose Administration (AUC) [Pre-dose and extrapolated up to infinity after drug administration on Day 1 and Day 8]

   Area under the concentration verus time curve from zero to infinity of metformin after single dose without copanlisib (Day 1) and in combination with copanlisib (Day 8) were measured.

Secondary Outcome Measures

1. Number of Participants With Treatment-Emergent Adverse Events [From start of study medication until 30 days after end of treatment with study medication.]

   An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Treatment-emergent adverse events (TEAEs) were defined as adverse events that started or worsened after the start of study drug administration up to 30 days after last administration of the study medication.

2. Number of Participants With Treatment-Emergent Adverse Events by Severity [From start of study medication until 30 days after end of treatment with study medication.]

   An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Treatment-emergent adverse events (TEAEs) were defined as adverse events that started or worsened after the start of study drug administration up to 30 days after last administration of the study medication. TEAEs per severity were reported.

3. Plasma Lactate Levels [Up to 24 hours after study drug administration on Day 1 and Day 8]

   Lactate levels were analyzed in plasma samples collected during metformin alone or in combination with copanlisib. Plasma lactate levels were summarized by treatment conditions (Day 1 and Day 8).

4. Maximum Change From Baseline in Plasma Lactate Levels [From pre-dose up to 24 hours after study drug administration on Day 1 and Day 8]

   Lactate levels were analyzed in plasma samples collected during metformin alone or in combination with copanlisib. Maximum change from baseline on Day 1 and Day 8 was summarized.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy male or female subjects - as determined by the investigator or medically qualified designee based on medical evaluations, including medical history, physical examination, laboratory tests and cardiac monitoring

• Aged 18 to 45 years at the first screening visit

• Body Mass Index (BMI) of 18.0 - 34 kg / m*2 , with body weight ≥ 50 kg

• Creatinine clearance ≥ 90 mL/min using the Modification of Diet in Renal Disease

• Adequate end organ and bone marrow function

Exclusion Criteria:

• Existing relevant diseases of vital organs (e.g. liver diseases, heart diseases), central nervous system (for example seizures) or other organs (e.g. diabetes mellitus)

• Incompletely cured pre-existing diseases for which it can be assumed that the absorption, distribution, metabolism, elimination and effects of the study drugs will not be normal

• Relevant respiratory insufficiency / disorder

• Administration of strong CYP3A4 inhibitors or inducers within 2 weeks prior to dosing

• Known history of hypersensitivity (or known allergic reaction) to copanlisib, metformin, related compounds, or any components of the formulation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pharmaceutical Product Development (PPD), LLC	Austin	Texas	United States	78744

Sponsors and Collaborators

• Bayer

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - May 15, 2018
• Statistical Analysis Plan - Dec 14, 2018

More Information

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT03655301
• Other Study ID Numbers: 19951
• First Posted: Aug 31, 2018
• Last Update Posted: Jan 28, 2020
• Last Verified: Jan 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Metformin

Study Results

Participant Flow

Recruitment Details	The study was conducted at one study center in the US, between 11-Sep-2018 (first participant first visit) and 12-Nov-2018 (last participant last visit).
Pre-assignment Detail	A total of 50 participants signed the informed consent form, of them 37 participants were screen failures. The remaining 13 participants received the study treatment.

Arm/Group Title	Copanlisib (Aliqopa, BAY80-6946) + Metformin
Arm/Group Description	Participants received 2 oral doses of metformin, 1 dose (1000 milligram [mg]) on Day 1 and 1 dose (1000 mg) on Day 8, and a single dose of copanlisib (60 mg, 1 h infusion) on Day 8. A wash-out period of 7 days was maintained between the 2 doses of metformin.
Period Title: Overall Study
STARTED	13
COMPLETED	13
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Copanlisib (Aliqopa, BAY80-6946) + Metformin
Arm/Group Description	Participants received 2 oral doses of metformin, 1 dose (1000 milligram [mg]) on Day 1 and 1 dose (1000 mg) on Day 8, and a single dose of copanlisib (60 mg, 1 h infusion) on Day 8. A wash-out period of 7 days was maintained between the 2 doses of metformin.
Overall Participants	13
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	28.4 (6.9)
Sex: Female, Male (Count of Participants)
Female	6 46.2%
Male	7 53.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 61.5%
Not Hispanic or Latino	5 38.5%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	6 46.2%
White	7 53.8%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Maximum Drug Concentration of Metformin in Plasma After Single Dose Administration (Cmax)
Description	Maximum observed drug concentration of metformin in plasma after single dose administration without copanlisib (Day 1) and in combination with copanlisib (Day 8) were measured.
Time Frame	Pre-dose and up to 24 hours after drug administration on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PKS): included all participants with a valid PK profile for metformin.

Arm/Group Title	Copanlisib (Aliqopa, BAY80-6946) + Metformin
Arm/Group Description	Participants received 2 oral doses of metformin, 1 dose (1000 milligram [mg]) on Day 1 and 1 dose (1000 mg) on Day 8, and a single dose of copanlisib (60 mg, 1 h infusion) on Day 8. A wash-out period of 7 days was maintained between the 2 doses of metformin.
Measure Participants	13
Day 1	1550 (16.4)
Day 8	1460 (27.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Copanlisib (Aliqopa, BAY80-6946) + Metformin
	Comments	Day 8 (with copanlisib) to Day 1 (without copanlisib) ratio of Cmax
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least squares mean
	Estimated Value	0.9405
	Confidence Interval	(2-Sided) 90%; 0.8093 to 1.0931
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Area Under the Plasma Concentration Versus Time Curve From Zero to 24 Hours of Metformin After Single Dose Administration (AUC[0-24])
Description	Area under the concentration versus time curve from zero to 24 hours of metformin after single dose administration without copanlisib (Day 1) and in combination with copanlisib (Day 8) were measured.
Time Frame	Pre-dose and up to 24 hours after drug administration on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PKS): included all participants with a valid PK profile for metformin.

Arm/Group Title	Copanlisib (Aliqopa, BAY80-6946) + Metformin
Arm/Group Description	Participants received 2 oral doses of metformin, 1 dose (1000 milligram [mg]) on Day 1 and 1 dose (1000 mg) on Day 8, and a single dose of copanlisib (60 mg, 1 h infusion) on Day 8. A wash-out period of 7 days was maintained between the 2 doses of metformin.
Measure Participants	13
Day 1	7710 (17.6)
Day 8	8640 (20.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Copanlisib (Aliqopa, BAY80-6946) + Metformin
	Comments	Day 8 (with copanlisib) to Day 1 (without copanlisib) ratio of AUC(0-24)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least squares mean
	Estimated Value	1.1205
	Confidence Interval	(2-Sided) 90%; 1.0000 to 1.2555
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity of Metformin After Single Dose Administration (AUC)
Description	Area under the concentration verus time curve from zero to infinity of metformin after single dose without copanlisib (Day 1) and in combination with copanlisib (Day 8) were measured.
Time Frame	Pre-dose and extrapolated up to infinity after drug administration on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PKS) with valid data for this evaluation.

Arm/Group Title	Copanlisib (Aliqopa, BAY80-6946) + Metformin
Arm/Group Description	Participants received 2 oral doses of metformin, 1 dose (1000 milligram [mg]) on Day 1 and 1 dose (1000 mg) on Day 8, and a single dose of copanlisib (60 mg, 1 h infusion) on Day 8. A wash-out period of 7 days was maintained between the 2 doses of metformin.
Measure Participants	12
Day 1	8000 (16.9)
Day 8	8900 (21.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Copanlisib (Aliqopa, BAY80-6946) + Metformin
	Comments	Day 8 (with copanlisib) to Day 1 (without copanlisib) ratio of AUC
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least squares mean
	Estimated Value	1.1147
	Confidence Interval	(2-Sided) 90%; 0.9772 to 1.2714
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events
Description	An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Treatment-emergent adverse events (TEAEs) were defined as adverse events that started or worsened after the start of study drug administration up to 30 days after last administration of the study medication.
Time Frame	From start of study medication until 30 days after end of treatment with study medication.

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): included all participants who received at least one dose of the study medication.

Arm/Group Title	Copanlisib (Aliqopa, BAY80-6946) + Metformin
Arm/Group Description	Participants received 2 oral doses of metformin, 1 dose (1000 milligram [mg]) on Day 1 and 1 dose (1000 mg) on Day 8, and a single dose of copanlisib (60 mg, 1 h infusion) on Day 8. A wash-out period of 7 days was maintained between the 2 doses of metformin.
Measure Participants	13
Day 1	5 38.5%
Day 8	9 69.2%
Total	11 84.6%

5. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events by Severity
Description	An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Treatment-emergent adverse events (TEAEs) were defined as adverse events that started or worsened after the start of study drug administration up to 30 days after last administration of the study medication. TEAEs per severity were reported.
Time Frame	From start of study medication until 30 days after end of treatment with study medication.

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): included all participants who received at least one dose of the study medication.

Arm/Group Title	Copanlisib (Aliqopa, BAY80-6946) + Metformin
Arm/Group Description	Participants received 2 oral doses of metformin, 1 dose (1000 milligram [mg]) on Day 1 and 1 dose (1000 mg) on Day 8, and a single dose of copanlisib (60 mg, 1 h infusion) on Day 8. A wash-out period of 7 days was maintained between the 2 doses of metformin.
Measure Participants	13
Mild	5 38.5%
Moderate	0 0%
No AEs	8 61.5%
Mild	7 53.8%
Moderate	2 15.4%
No AEs	4 30.8%
Mild	9 69.2%
Moderate	2 15.4%
No AEs	2 15.4%

6. Secondary Outcome

Title	Plasma Lactate Levels
Description	Lactate levels were analyzed in plasma samples collected during metformin alone or in combination with copanlisib. Plasma lactate levels were summarized by treatment conditions (Day 1 and Day 8).
Time Frame	Up to 24 hours after study drug administration on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): included all participants who received at least one dose of the study medication.

Arm/Group Title	Copanlisib (Aliqopa, BAY80-6946) + Metformin
Arm/Group Description	Participants received 2 oral doses of metformin, 1 dose (1000 milligram [mg]) on Day 1 and 1 dose (1000 mg) on Day 8, and a single dose of copanlisib (60 mg, 1 h infusion) on Day 8. A wash-out period of 7 days was maintained between the 2 doses of metformin.
Measure Participants	13
Day 1 (0h)	0.78
Day 1 (0.5h)	0.74
Day 1 (1h)	0.83
Day 1 (2h)	0.74
Day 1 (4h)	1.01
Day 1 (6h)	0.75
Day 1 (8h)	0.80
Day 1 (12h)	1.04
Day 1 (24h)	0.89
Day 8 (0h)	0.78
Day 8 (0.5h)	0.85
Day 8 (1h)	0.90
Day 8 (2h)	0.92
Day 8 (4h)	1.22
Day 8 (6h)	1.08
Day 8 (8h)	0.75
Day 8 (12h)	0.91
Day 8 (24h)	0.68

7. Secondary Outcome

Title	Maximum Change From Baseline in Plasma Lactate Levels
Description	Lactate levels were analyzed in plasma samples collected during metformin alone or in combination with copanlisib. Maximum change from baseline on Day 1 and Day 8 was summarized.
Time Frame	From pre-dose up to 24 hours after study drug administration on Day 1 and Day 8

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAF): included all participants who received at least one dose of the study medication.

Arm/Group Title	Copanlisib (Aliqopa, BAY80-6946) + Metformin
Arm/Group Description	Participants received 2 oral doses of metformin, 1 dose (1000 milligram [mg]) on Day 1 and 1 dose (1000 mg) on Day 8, and a single dose of copanlisib (60 mg, 1 h infusion) on Day 8. A wash-out period of 7 days was maintained between the 2 doses of metformin.
Measure Participants	13
Day 1 (0.5h)	-0.04
Day 1 (1h)	0.05
Day 1 (2h)	-0.04
Day 1 (4h)	0.23
Day 1 (6h)	-0.03
Day 1 (8h)	0.02
Day 1 (12h)	0.26
Day 1 (24h)	0.12
Day 8 (0h)	0.01
Day 8 (0.5h)	0.07
Day 8 (1h)	0.12
Day 8 (2h)	0.14
Day 8 (4h)	0.44
Day 8 (6h)	0.31
Day 8 (8h)	-0.02
Day 8 (12h)	0.13
Day 8 (24h)	-0.10

Adverse Events

Time Frame	From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
Adverse Event Reporting Description	The study has only 1 arm with all subjects having received 2 doses on D1 (metformin alone) and D8 (metformin+ copanlisib).The study is not designed to compare the safety following 2 doses.
Arm/Group Title	Copanlisib (Aliqopa, BAY80-6946) + Metformin
Arm/Group Description	Participants received 2 oral doses of metformin, 1 dose (1000 milligram [mg]) on Day 1 and 1 dose (1000 mg) on Day 8, and a single dose of copanlisib (60 mg, 1 h infusion) on Day 8. A wash-out period of 7 days was maintained between the 2 doses of metformin.
All Cause Mortality
	Copanlisib (Aliqopa, BAY80-6946) + Metformin
	Affected / at Risk (%)	# Events
Total	0/13 (0%)
Serious Adverse Events
	Copanlisib (Aliqopa, BAY80-6946) + Metformin
	Affected / at Risk (%)	# Events
Total	0/13 (0%)
Other (Not Including Serious) Adverse Events
	Copanlisib (Aliqopa, BAY80-6946) + Metformin
	Affected / at Risk (%)	# Events
Total	11/13 (84.6%)
Ear and labyrinth disorders
Ear pain	1/13 (7.7%)	1
Gastrointestinal disorders
Abdominal distension	3/13 (23.1%)	3
Abdominal pain	2/13 (15.4%)	2
Diarrhoea	5/13 (38.5%)	6
Dry mouth	2/13 (15.4%)	2
Nausea	5/13 (38.5%)	5
Vomiting	2/13 (15.4%)	2
General disorders
Fatigue	2/13 (15.4%)	2
Injury, poisoning and procedural complications
Contusion	1/13 (7.7%)	1
Infusion related reaction	1/13 (7.7%)	1
Metabolism and nutrition disorders
Hyperglycaemia	1/13 (7.7%)	1
Nervous system disorders
Dizziness	1/13 (7.7%)	1
Headache	1/13 (7.7%)	1
Paraesthesia	3/13 (23.1%)	3
Psychiatric disorders
Anxiety	1/13 (7.7%)	1
Renal and urinary disorders
Dysuria	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Paranasal sinus discomfort	2/13 (15.4%)	2
Skin and subcutaneous tissue disorders
Skin irritation	1/13 (7.7%)	1
Vascular disorders
Hot flush	1/13 (7.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.