Trial Outcomes & Findings for Effect of Copanlisib on Metformin Pharmacokinetics and Pharmacodynamics (NCT NCT03655301)
NCT ID: NCT03655301
Last Updated: 2020-01-28
Results Overview
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.
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
13 participants
Primary outcome timeframe
Pre-dose and up to 24 hours after drug administration on Day 1 and Day 8
Results posted on
2020-01-28
Participant Flow
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).
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.
Participant milestones
| Measure |
Copanlisib (Aliqopa, BAY80-6946) + Metformin
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.
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|---|---|
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Overall Study
STARTED
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13
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Overall Study
COMPLETED
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13
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Overall Study
NOT COMPLETED
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0
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Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
SAF
Baseline characteristics by cohort
| Measure |
Copanlisib (Aliqopa, BAY80-6946) + Metformin
n=13 Participants
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.
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Age, Continuous
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28.4 Years
STANDARD_DEVIATION 6.9 • n=5 Participants • SAF
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Sex: Female, Male
Female
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6 Participants
n=5 Participants • SAF
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Sex: Female, Male
Male
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7 Participants
n=5 Participants • SAF
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Ethnicity (NIH/OMB)
Hispanic or Latino
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8 Participants
n=5 Participants • SAF
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Ethnicity (NIH/OMB)
Not Hispanic or Latino
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5 Participants
n=5 Participants • SAF
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Ethnicity (NIH/OMB)
Unknown or Not Reported
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0 Participants
n=5 Participants • SAF
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Race (NIH/OMB)
American Indian or Alaska Native
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0 Participants
n=5 Participants • SAF
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Race (NIH/OMB)
Asian
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0 Participants
n=5 Participants • SAF
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Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
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0 Participants
n=5 Participants • SAF
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Race (NIH/OMB)
Black or African American
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6 Participants
n=5 Participants • SAF
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Race (NIH/OMB)
White
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7 Participants
n=5 Participants • SAF
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Race (NIH/OMB)
More than one race
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0 Participants
n=5 Participants • SAF
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Race (NIH/OMB)
Unknown or Not Reported
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0 Participants
n=5 Participants • SAF
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PRIMARY outcome
Timeframe: Pre-dose and up to 24 hours after drug administration on Day 1 and Day 8Population: Pharmacokinetic Analysis Set (PKS): included all participants with a valid PK profile for metformin.
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.
Outcome measures
| Measure |
Copanlisib (Aliqopa, BAY80-6946) + Metformin
n=13 Participants
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.
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Maximum Drug Concentration of Metformin in Plasma After Single Dose Administration (Cmax)
Day 1
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1550 microgram per liter (mcg/L)
Geometric Coefficient of Variation 16.4
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Maximum Drug Concentration of Metformin in Plasma After Single Dose Administration (Cmax)
Day 8
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1460 microgram per liter (mcg/L)
Geometric Coefficient of Variation 27.6
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PRIMARY outcome
Timeframe: Pre-dose and up to 24 hours after drug administration on Day 1 and Day 8Population: Pharmacokinetic Analysis Set (PKS): included all participants with a valid PK profile for metformin.
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.
Outcome measures
| Measure |
Copanlisib (Aliqopa, BAY80-6946) + Metformin
n=13 Participants
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.
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|---|---|
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Area Under the Plasma Concentration Versus Time Curve From Zero to 24 Hours of Metformin After Single Dose Administration (AUC[0-24])
Day 1
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7710 microgram*hour per liter (mcg*h/L)
Geometric Coefficient of Variation 17.6
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Area Under the Plasma Concentration Versus Time Curve From Zero to 24 Hours of Metformin After Single Dose Administration (AUC[0-24])
Day 8
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8640 microgram*hour per liter (mcg*h/L)
Geometric Coefficient of Variation 20.8
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PRIMARY outcome
Timeframe: Pre-dose and extrapolated up to infinity after drug administration on Day 1 and Day 8Population: Pharmacokinetic Analysis Set (PKS) with valid data for this evaluation.
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.
Outcome measures
| Measure |
Copanlisib (Aliqopa, BAY80-6946) + Metformin
n=12 Participants
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.
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|---|---|
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Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity of Metformin After Single Dose Administration (AUC)
Day 1
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8000 microgram*hour per liter (mcg*h/L)
Geometric Coefficient of Variation 16.9
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Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity of Metformin After Single Dose Administration (AUC)
Day 8
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8900 microgram*hour per liter (mcg*h/L)
Geometric Coefficient of Variation 21.2
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SECONDARY outcome
Timeframe: From start of study medication until 30 days after end of treatment with study medication.Population: Safety Analysis Set (SAF): included all participants who received at least one dose of the 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.
Outcome measures
| Measure |
Copanlisib (Aliqopa, BAY80-6946) + Metformin
n=13 Participants
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.
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Number of Participants With Treatment-Emergent Adverse Events
Day 1
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5 Participants
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Number of Participants With Treatment-Emergent Adverse Events
Day 8
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9 Participants
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Number of Participants With Treatment-Emergent Adverse Events
Total
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11 Participants
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SECONDARY outcome
Timeframe: From start of study medication until 30 days after end of treatment with study medication.Population: Safety Analysis Set (SAF): included all participants who received at least one dose of the 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.
Outcome measures
| Measure |
Copanlisib (Aliqopa, BAY80-6946) + Metformin
n=13 Participants
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.
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Number of Participants With Treatment-Emergent Adverse Events by Severity
Day 1 · Mild
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5 Participants
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Number of Participants With Treatment-Emergent Adverse Events by Severity
Day 1 · Moderate
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0 Participants
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Number of Participants With Treatment-Emergent Adverse Events by Severity
Day 1 · No AEs
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8 Participants
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Number of Participants With Treatment-Emergent Adverse Events by Severity
Day 8 · Mild
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7 Participants
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Number of Participants With Treatment-Emergent Adverse Events by Severity
Day 8 · Moderate
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2 Participants
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Number of Participants With Treatment-Emergent Adverse Events by Severity
Day 8 · No AEs
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4 Participants
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Number of Participants With Treatment-Emergent Adverse Events by Severity
Total · Mild
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9 Participants
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Number of Participants With Treatment-Emergent Adverse Events by Severity
Total · Moderate
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2 Participants
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Number of Participants With Treatment-Emergent Adverse Events by Severity
Total · No AEs
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2 Participants
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SECONDARY outcome
Timeframe: Up to 24 hours after study drug administration on Day 1 and Day 8Population: Safety Analysis Set (SAF): included all participants who received at least one dose of the study medication.
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).
Outcome measures
| Measure |
Copanlisib (Aliqopa, BAY80-6946) + Metformin
n=13 Participants
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.
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Plasma Lactate Levels
Day 8 (4h)
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1.22 mmol/L
Interval 0.7 to 2.2
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Plasma Lactate Levels
Day 1 (0.5h)
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0.74 mmol/L
Interval 0.4 to 1.0
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Plasma Lactate Levels
Day 1 (1h)
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0.83 mmol/L
Interval 0.5 to 1.6
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Plasma Lactate Levels
Day 1 (2h)
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0.74 mmol/L
Interval 0.5 to 1.0
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Plasma Lactate Levels
Day 1 (4h)
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1.01 mmol/L
Interval 0.6 to 1.7
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Plasma Lactate Levels
Day 1 (6h)
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0.75 mmol/L
Interval 0.6 to 1.0
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Plasma Lactate Levels
Day 1 (8h)
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0.80 mmol/L
Interval 0.6 to 1.1
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Plasma Lactate Levels
Day 1 (12h)
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1.04 mmol/L
Interval 0.7 to 2.4
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Plasma Lactate Levels
Day 1 (24h)
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0.89 mmol/L
Interval 0.5 to 1.8
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Plasma Lactate Levels
Day 8 (0h)
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0.78 mmol/L
Interval 0.6 to 1.2
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Plasma Lactate Levels
Day 8 (0.5h)
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0.85 mmol/L
Interval 0.5 to 1.4
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Plasma Lactate Levels
Day 8 (1h)
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0.90 mmol/L
Interval 0.6 to 1.4
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Plasma Lactate Levels
Day 8 (2h)
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0.92 mmol/L
Interval 0.5 to 1.3
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Plasma Lactate Levels
Day 8 (6h)
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1.08 mmol/L
Interval 0.8 to 1.7
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Plasma Lactate Levels
Day 8 (8h)
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0.75 mmol/L
Interval 0.6 to 1.1
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Plasma Lactate Levels
Day 8 (12h)
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0.91 mmol/L
Interval 0.6 to 1.5
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Plasma Lactate Levels
Day 8 (24h)
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0.68 mmol/L
Interval 0.4 to 1.0
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Plasma Lactate Levels
Day 1 (0h)
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0.78 mmol/L
Interval 0.5 to 1.1
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SECONDARY outcome
Timeframe: From pre-dose up to 24 hours after study drug administration on Day 1 and Day 8Population: Safety Analysis Set (SAF): included all participants who received at least one dose of the study medication.
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.
Outcome measures
| Measure |
Copanlisib (Aliqopa, BAY80-6946) + Metformin
n=13 Participants
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.
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|---|---|
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Maximum Change From Baseline in Plasma Lactate Levels
Day 1 (0.5h)
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-0.04 mmol/L
Interval -0.4 to 0.3
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Maximum Change From Baseline in Plasma Lactate Levels
Day 1 (1h)
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0.05 mmol/L
Interval -0.4 to 0.7
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Maximum Change From Baseline in Plasma Lactate Levels
Day 1 (2h)
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-0.04 mmol/L
Interval -0.4 to 0.3
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Maximum Change From Baseline in Plasma Lactate Levels
Day 1 (4h)
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0.23 mmol/L
Interval -0.3 to 0.7
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Maximum Change From Baseline in Plasma Lactate Levels
Day 1 (6h)
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-0.03 mmol/L
Interval -0.5 to 0.5
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Maximum Change From Baseline in Plasma Lactate Levels
Day 1 (8h)
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0.02 mmol/L
Interval -0.5 to 0.2
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Maximum Change From Baseline in Plasma Lactate Levels
Day 1 (12h)
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0.26 mmol/L
Interval -0.1 to 1.6
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Maximum Change From Baseline in Plasma Lactate Levels
Day 1 (24h)
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0.12 mmol/L
Interval -0.3 to 1.3
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Maximum Change From Baseline in Plasma Lactate Levels
Day 8 (0h)
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0.01 mmol/L
Interval -0.4 to 0.2
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Maximum Change From Baseline in Plasma Lactate Levels
Day 8 (0.5h)
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0.07 mmol/L
Interval -0.3 to 0.5
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Maximum Change From Baseline in Plasma Lactate Levels
Day 8 (1h)
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0.12 mmol/L
Interval -0.3 to 0.6
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Maximum Change From Baseline in Plasma Lactate Levels
Day 8 (2h)
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0.14 mmol/L
Interval -0.4 to 0.4
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Maximum Change From Baseline in Plasma Lactate Levels
Day 8 (4h)
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0.44 mmol/L
Interval -0.3 to 1.2
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Maximum Change From Baseline in Plasma Lactate Levels
Day 8 (6h)
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0.31 mmol/L
Interval -0.2 to 0.7
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Maximum Change From Baseline in Plasma Lactate Levels
Day 8 (8h)
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-0.02 mmol/L
Interval -0.4 to 0.1
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Maximum Change From Baseline in Plasma Lactate Levels
Day 8 (12h)
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0.13 mmol/L
Interval -0.1 to 0.5
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Maximum Change From Baseline in Plasma Lactate Levels
Day 8 (24h)
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-0.10 mmol/L
Interval -0.5 to 0.1
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Adverse Events
Copanlisib (Aliqopa, BAY80-6946) + Metformin
Serious events: 0 serious events
Other events: 11 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Copanlisib (Aliqopa, BAY80-6946) + Metformin
n=13 participants at risk
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.
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Gastrointestinal disorders
Abdominal pain
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15.4%
2/13 • Number of events 2 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
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Gastrointestinal disorders
Diarrhoea
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38.5%
5/13 • Number of events 6 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
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Gastrointestinal disorders
Dry mouth
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15.4%
2/13 • Number of events 2 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
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Gastrointestinal disorders
Nausea
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38.5%
5/13 • Number of events 5 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
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Gastrointestinal disorders
Vomiting
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15.4%
2/13 • Number of events 2 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
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General disorders
Fatigue
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15.4%
2/13 • Number of events 2 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
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Injury, poisoning and procedural complications
Contusion
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7.7%
1/13 • Number of events 1 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
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Injury, poisoning and procedural complications
Infusion related reaction
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7.7%
1/13 • Number of events 1 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
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Metabolism and nutrition disorders
Hyperglycaemia
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7.7%
1/13 • Number of events 1 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
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Nervous system disorders
Dizziness
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7.7%
1/13 • Number of events 1 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
|
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Nervous system disorders
Headache
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7.7%
1/13 • Number of events 1 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
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Nervous system disorders
Paraesthesia
|
23.1%
3/13 • Number of events 3 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
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Psychiatric disorders
Anxiety
|
7.7%
1/13 • Number of events 1 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
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Renal and urinary disorders
Dysuria
|
7.7%
1/13 • Number of events 1 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
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Respiratory, thoracic and mediastinal disorders
Paranasal sinus discomfort
|
15.4%
2/13 • Number of events 2 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
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Skin and subcutaneous tissue disorders
Skin irritation
|
7.7%
1/13 • Number of events 1 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
|
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Vascular disorders
Hot flush
|
7.7%
1/13 • Number of events 1 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
|
|
Ear and labyrinth disorders
Ear pain
|
7.7%
1/13 • Number of events 1 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
|
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Gastrointestinal disorders
Abdominal distension
|
23.1%
3/13 • Number of events 3 • From start of study medication until 30 days after end of treatment with study medication, up to 38 days.
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.
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Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place