Clinical trial NCT03655301
Conditions: Healthy Volunteers
Sponsor: Bayer
Start date: 2018-09-11; Completion date: 2019-02-12
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Detailed description:

Arms: arm 1: 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.
Interventions: intervention 1: Copanlisib (Aliqopa, BAY80-6946) intervention 2: Metformin
Intervention descriptions: intervention 1: 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. intervention 2: Single dose of 1000 mg is administered orally.

Protocol documents:
Prot_000.pdf: 
 
Document Type: 
Study Protocol 
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 
NCT Number: 
NCT03655301 
Document Date: 
15 May 2018 
 


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1.
Title page
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
Effect of copanlisib on metformin PK and PD
Test drug:
Copanlisib / BAY 80-6946
Study purpose:
To evaluate the effect of copanlisib on the PK and PD of 
metformin
Clinical study phase:
1
Date:
15 May 2018
Registration:
Not applicable
Version no.:
1.0
Sponsor’s study no.:
19951
Sponsor:
Bayer HealthCare Pharmaceuticals Inc., 100 Bayer 
Boulevard, P.O. Box 915, Whippany NJ 07981-0915, USA
Sponsor’s medical expert:
Bayer AG
Drug Discovery, Pharmaceuticals
Clinical PD ONC I
Building P300 
13342 Berlin, Germany
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document - whether in part or in full - to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (, TM) may not be 
displayed. Hence, the appearance of product names without these symbols does not imply 
that these names are not protected.
PPD
PPD
PPD


PPD
PPD


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Signature of principal investigator
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
Affiliation:
Date:
Signature:
Signed copies of this signature page are stored in the sponsor’s study file and in the respective 
center’s investigator site file.
In the protocol document, this page may remain unsigned.


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2.
Synopsis
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
Short title
Effect of Copanlisib on metformin PK and PD
Clinical study phase
Phase 1
Study objectives
The primary objective of this study is to:

Evaluate the effect of the co-administration of copanlisib on 
the PK of metformin
The secondary objectives of this study are to:

Assess the safety of copanlisib when administered to healthy 
subjects in combination with metformin

Evaluate the PD effect of copanlisib on metformin in terms of 
plasma lactate levels
Exploratory objectives of this study are to:

Assess additional copanlisib and metformin PK parameters

Assess additional PD parameters
Test drug
BAY 80-6946 (Copanlisib)
Name of active ingredient
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-
dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-
carboxamidedihydrochloride (IUPAC)
Dose
60 mg
Route of administration
Intravenous (i.v.)
Duration of treatment
Single dose on Day 8
Interaction drug
Metformin
Name of active ingredient
Metformin hydrochloride
Dose
1000 mg tablet
Route of administration
Oral
Duration of treatment
Single dose on Day 1
Single dose on Day 8
Indication
Not applicable
Diagnosis and main criteria for 
inclusion /exclusion
Healthy subjects, aged 18 to 45 years, with body mass index of 18.0 to 
34.0 kg/m2, body weight ≥50 kg, creatinine clearance ≥ 90 mL/min using 
the Modification of Diet in Renal Disease (MDRD formula), and adequate 
end organ function.
Study design
This study is a phase 1, non-randomized, single-center, open-label study to 
investigate the effect of copanlisib, a MATE2-K inhibitor, on the PK and 
PD of metformin (a MATE2-K substrate) in healthy subjects.


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Methodology
Pharmacokinetics
Type of control
Uncontrolled
Number of subjects
15 subjects, to have at least 12 subjects valid for PK
Primary variables
Primary variables:

PK parameters: Cmax, AUC(0-24) and AUC for metformin on 
Day 1 and Day 8
Time point/frame of 
measurement for primary 
variable(s)
Serial blood samples for the determination of metformin PK parameters will 
be collected on Day 1 and Day 8 – pre dose and up to 24 h after drug 
administration
Plan for statistical analysis
To investigate the primary objective of this study regarding the effect of 
copanlisib on metformin, an exploratory analysis of variance (ANOVA) 
with terms of treatment condition and subject will be performed on the 
natural logarithmic transformation of PK parameters (AUC, AUC(0-24) and 
Cmax) of metformin. The estimate and 90% confidence interval of the Day 8 
(with copanlisib) to Day 1 (without copanlisib) ratio of Cmax, AUC(0-24) 
and AUC for metformin are derived by inverse transformation of the 
estimates and the 90% confidence interval of the least squares mean 
differences that are obtained from the model above.


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Table of contents
1.
Title page............................................................................................................................ 1
Signature of the sponsor’s medically responsible person..................................................... 2
Signature of principal investigator......................................................................................... 3
2.
Synopsis.............................................................................................................................. 4
Table of tables........................................................................................................................... 8
Table of figures......................................................................................................................... 8
List of abbreviations................................................................................................................. 9
Definitions of terms ................................................................................................................ 12
3.
Introduction..................................................................................................................... 13
3.1
Background.................................................................................................................... 13
3.2
Rationale of the study .................................................................................................... 15
3.3
Benefit-risk assessment.................................................................................................. 15
4.
Study objectives............................................................................................................... 17
5.
Study design..................................................................................................................... 17
6.
Study population ............................................................................................................. 20
6.1
Inclusion criteria ............................................................................................................ 20
6.2
Exclusion criteria ........................................................................................................... 21
6.3
Justification of selection criteria.................................................................................... 23
6.4
Withdrawal of subjects from study................................................................................ 23
6.4.1
Withdrawal ................................................................................................................. 23
6.4.2
Replacement ............................................................................................................... 24
6.5
Subject identification ..................................................................................................... 24
7.
Treatments....................................................................................................................... 25
7.1
Treatments to be administered....................................................................................... 25
7.2
Identity of study treatment............................................................................................. 25
7.3
Treatment assignment.................................................................................................... 25
7.4
Dosage and administration............................................................................................. 26
7.5
Blinding ......................................................................................................................... 26
7.6
Drug logistics and accountability................................................................................... 26
7.7
Treatment compliance.................................................................................................... 26
8.
Non-study therapy........................................................................................................... 27
8.1
Prior and concomitant therapy....................................................................................... 27
8.2
Post-study therapy.......................................................................................................... 27
9.
Procedures and variables ............................................................................................... 27
9.1
Tabular schedule of evaluations .................................................................................... 27
9.2
Visit description............................................................................................................. 27
9.2.1
Screening .................................................................................................................... 27
9.2.2
Pre-dose (Study Day -1) ............................................................................................. 29
9.2.3
Randomization............................................................................................................ 29


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9.2.4
Treatment Period ........................................................................................................ 29
9.2.5
End of treatment visit ................................................................................................. 32
9.2.6
Follow-up ................................................................................................................... 32
9.2.7
Special conditions during the study............................................................................ 32
9.3
Population characteristics .............................................................................................. 33
9.3.1
Demographic .............................................................................................................. 33
9.3.2
Medical history........................................................................................................... 34
9.3.3
Other baseline characteristics..................................................................................... 34
9.4
Efficacy.......................................................................................................................... 34
9.5
Pharmacokinetics / pharmacodynamics......................................................................... 34
9.5.1
Pharmacokinetics........................................................................................................ 34
9.5.2
Pharmacodynamics..................................................................................................... 36
9.6
Safety ............................................................................................................................. 37
9.6.1
Adverse events............................................................................................................ 37
9.6.2
Pregnancies................................................................................................................. 45
9.6.3
Further safety.............................................................................................................. 45
9.7
Other procedures and variables...................................................................................... 46
9.8
Appropriateness of procedures / measurements ............................................................ 46
10. Statistical methods and determination of sample size ................................................. 47
10.1
General considerations................................................................................................... 47
10.2
Analysis sets .................................................................................................................. 47
10.3
Variables and planned statistical analyses..................................................................... 47
10.4
Determination of sample size......................................................................................... 48
10.5
Planned interim analyses ............................................................................................... 49
11. Data handling and quality assurance............................................................................ 49
11.1
Data recording................................................................................................................ 49
11.2
Monitoring ..................................................................................................................... 50
11.3
Data processing.............................................................................................................. 51
11.4
Missing data................................................................................................................... 51
11.5
Audit and inspection ...................................................................................................... 51
11.6
Archiving ....................................................................................................................... 51
12. Premature termination of the study .............................................................................. 52
13. Ethical and legal aspects................................................................................................. 53
13.1
Investigator(s) and other study personnel...................................................................... 53
13.2
Funding and financial disclosure ................................................................................... 53
13.3
Ethical and legal conduct of the study........................................................................... 54
13.4
Subject information and consent.................................................................................... 54
13.5
Publication policy and use of data ................................................................................. 55
13.6
Compensation for health damage of subjects / insurance.............................................. 56
13.7
Confidentiality ............................................................................................................... 56
14. Reference list.................................................................................................................... 56
15. Protocol amendments...................................................................................................... 57
16. Appendices....................................................................................................................... 58
16.1
Study flow chart............................................................................................................. 58
16.2
Laboratory analyses ....................................................................................................... 60


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16.3
Concomitant medication NOT permitted (or to be taken with caution) during 
screening and treatment phase of the study ................................................................... 62
16.4
Estimation of glomerular filtration rate (eGFR) using modification of diet in renal 
disease............................................................................................................................ 63
Table of tables
Table 3–1: Most common AEs (all Grade ≥2%) in copanlisib monotherapy studies in cancer 
patients after a single dose of copanlisib............................................................... 16
Table 5–1: Objectives and related variables............................................................................ 19
Table 7–1: Treatments to be administered ............................................................................... 25
Table 9–1: Restrictions during the study.................................................................................. 33
Table 9–2: PK sampling and dosing time points for metformin and copanlisib in plasma ..... 35
Table 9–3: Urine sample collection for metformin PK evaluation on Days 1 and 8 ............... 36
Table 9–4: Pharmacodynamic assessment and rationale ......................................................... 37
Table 9–5: Pharmacodynamic sampling .................................................................................. 37
Table 9–6: Management of transient post-infusion glucose increases..................................... 44
Table 10–1: 90% Confidence interval for metformin with N=12............................................ 49
Table 16–1: Study flow chart................................................................................................... 58
Table 16–2:
Schedule of evaluations: In-house treatment period......................................... 59
Table 16–3: Parameters of laboratory analyses........................................................................ 61
Table of figures
Figure 3-1: Key major known transporters involved in the absorption and urinary excretion of 
metformin.............................................................................................................. 15
Figure 5-1: Flow chart of study design .................................................................................... 18


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List of abbreviations
AE
adverse event
AE,ur(0-24)
amount excreted into urine from 0 to 24 h
%AE,ur(0-24)
Percentage of drug excreted in the urine between 0 and 24 hours
AE,ur(t1-t2)
amount excreted into urine from t1 to t2, where t1 and t2 are the start and 
the stop times of the urine collection interval
%AE,ur(t1-t2)
Percentage of drug excreted in the urine between t1 and t2, where t1 and t2 
are the start and the stop times of the urine collection interval
AKT
protein kinase B
ALT
alanine aminotransferase (also: glutamate pyruvate transaminase, GPT)
ANOVA
analysis of variance
anti-HIV 1+2
human immunodeficiency virus 1 and 2 antibody
AP
alkaline phosphatase
AST
aspartate aminotransferase (also: glutamic-oxaloacetic transaminase, GOT)
AUC
area under the concentration vs. time curve from zero to infinity after single 
dose
AUC(0-24)
AUC from time 0 to 24 hours
BCRP
breast cancer resistance protein
BMI
body mass index: weight [kg] / (height [m])²
BP
blood pressure
C24h
concentration at 24 hours
C6h
concentration at 6 hours
CI
confidence interval
CL/F
total body clearance of drug calculated after extravascular administration 
(e.g. apparent oral clearance)
CLR
renal body clearance of drug
Cmax
maximum observed drug concentration in measured matrix after single 
dose administration
CRF
case report form
CRO
contract research organization


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CTCAE
common terminology criteria for AEs
CV
coefficient of variation
CYP
cytochrome P450
DDI
drug-drug interaction
dL
deciliter
ECG
electrocardiogram
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EOT
End of Treatment
EudraCT
EU data repository for clinical trials
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma glutamyl transpeptidase (or gamma-glutamyl transferase)
GMP
Good Manufacturing Practice
GSK3
glycogen synthase kinase 3
HbA1c
glycated hemoglobin
HBsAg
Hepatitis B surface antigen
HCV-Ab
hepatitis C virus antibodies
HDL
high-density lipoprotein
HIV
human immunodeficiency virus
IB
investigator’s brochure
IC50
50% inhibition
ICH
International Conference on Harmonization
INR
international normalized ratio
i.e.
id est (that is)
IEC
independent ethics committee
IR
insulin receptor
IRB
institutional review board


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IUD
intrauterine device
IUPAC
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-
dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-
carboxamidedihydrochloride
IUS
intrauterine hormone-releasing system
i.v.
intravenous
kg
kilogram
L
liter
LDL
low-density lipoprotein
LLOQ
lower limit of quantitation
LSLV
last subject last visit
MATE
multidrug and toxin extrusion transporter
MDRD
Modification of Diet in Renal Disease
MedDRA
medical dictionary for regulatory activities
mmHg
millimeter of mercury
mTOR
mammalian target of rapamycin
n
number
OAT
organic anion transporter
OATP
organic anion-transporting polypeptide
OCT
organic cation transporter
OTC
over-the-counter
pAKT
phosphorylated protein kinase B (phospho-AKT)
PD
pharmacodynamic(s)
P-gp
permeability glycoprotein
PK
pharmacokinetic(s)
PI3K
phosphatidylinositol 3-kinase
PR
PR interval in ECG
PT
preferred term
QA
Quality Assurance
QC
quality control


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QRS
QRS duration in ECG
QT
QT interval in ECG
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected according to Bazett’s formula
RR
RR interval in ECG
RTK
receptor tyrosine kinase
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment emergent AE
t1/2
half-life associated with the terminal slope
tmax
time to reach Cmax
ULN
upper limit of norm (upper limit of normal laboratory values)
US(A)
United States (of America)
VZ/F
apparent volume of distribution during terminal phase after extravascular 
administration
Definitions of terms
BAY no.
BAY number is the main identifier for compounds within the Bayer 
Pharmaceuticals Organization
RAVE
validated electronic data capture system


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3.
Introduction
3.1
Background
Copanlisib characteristics
Further details can be found in the latest available version of the investigator’s brochure (IB), 
which contains comprehensive information on the study drug.
Copanlisib (BAY 80-6946) was approved via accelerated approval in the US on 14 SEP 2017,
as a monotherapy treatment in adult patients with relapsed follicular lymphoma who have 
received 2 prior systemic therapies. 
Copanlisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity 
predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. 
Copanlisib inhibits the catalytic activity of the class I PI3K-α, -β, -γ, and -δ isoforms with 
biochemical concentrations required for 50% inhibition (IC50) of 0.5, 3.7, 6.4, and 0.7 nM, 
respectively.  Copanlisib is being further developed for the treatment of advanced and 
refractory malignancies either as a single agent or in combination with other investigational 
agents. Copanlisib is the active ingredient (free base) of BAY 84-1236, the dihydrochloride 
salt, which for clinical use is formulated as an intravenous (i.v.) drug product solution.
The recommended approved dose of copanlisib is 60 mg administered as a 1- hour i.v.
infusion on Days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule (three 
weeks on and one week off).
Safety and efficacy
As of 21 JUN 2017, approximately 772 patients with advanced cancer have been treated with 
copanlisib as single agent or in combination with other anticancer drugs in Phase 1, 2 and 3 
studies. Copanlisib has also been studied in healthy volunteers. A mass balance study was
conducted in healthy subjects (Study 16353): 6 healthy male subjects were treated with a 
single i.v. administration of 12 mg [14C]copanlisib.  An additional ongoing Phase 1 study 
(18041) is being conducted in non-cancer subjects to assess the effect of hepatic and renal 
impairment on the pharmacokinetics (PK) of a single 12 mg dose of copanlisib in comparison 
to healthy subjects.
Based on the recent accelerated approval of copanlisib, the common adverse reactions based 
on the pooled safety analysis in more than 20% of patients were: hyperglycemia, diarrhea, 
fatigue, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, and 
thrombocytopenia. The most common grade 3-4 adverse reactions include hyperglycemia, 
leukopenia, hypertension, neutropenia, and lower respiratory tract infections. Serious 
non-infectious pneumonitis occurred in 6% of patients.
Clinical efficacy has been demonstrated based on results in 104 patients with relapsed 
follicular lymphoma enrolled in an open-label, single-arm, multi-center, Phase 2 study
(Study 16349) in which patients received 0.8 mg/kg or 60 mg of copanlisib by i.v. infusion on 
Days 1, 8, and 15 of a 28-day treatment cycle. The objective response rate was 59% with 
estimated median response duration of 12.2 months. The complete response rate was 14.4% 
and partial response rate was 44.2%.


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Copanlisib clinical pharmacology summary
Copanlisib plasma exposure (Cmax and AUC) increased in a dose-proportional manner over an 
absolute dose range of 5 to 93 mg (0.08 to 1.55 times the approved recommended dose of 
60 mg) with a terminal elimination half-life of 39.1 hours. There is no time-dependency and 
no accumulation in the PK of copanlisib with the weekly intermittent dosing schedule.
Copanlisib is eliminated predominantly via feces (64% of the administrative radioactive dose 
mean recovery with 30% unchanged copanlisib) compared to urine (22% mean recovery with 
15% unchanged copanlisib); 41% of the dose was excreted as oxidative metabolites. The 
minor M-1 metabolite accounts only for 5% of total radioactivity AUC with pharmacological 
activity comparable to copanlisib. Population PK analyses showed that age (20 to 90 years), 
gender, race, smoking status, body weight (41 to 130 kg), mild hepatic impairment, and mild 
to moderate renal impairment had no clinically significant effect on the PK of copanlisib. 
Based on the preliminary categorical analyses and the central tendency, copanlisib does not 
prolong the QT/QTc interval.
Copanlisib metabolism is predominantly mediated by cytochrome P450 (CYP) 3A4 (>90%) 
and to a minor extent by CYP1A1 (<10%). Concomitant use of copanlisib with strong 
CYP3A inducers may decrease copanlisib AUC and Cmax values, and should be avoided. 
Concomitant use of copanlisib with strong CYP3A inhibitors increases copanlisib AUC, and a 
dosage reduction to 45 mg is advised if patients require strong CYP3A inhibitors. Copanlisib 
has low potential for DDI as perpetrator to influence the PK of other drugs by inhibition or 
induction of metabolizing enzymes (CYPs, uridine 5'-diphospho-glucuronosyltransferase 
[UGT]) and transport proteins. Copanlisib is an inhibitor of multidrug and toxin extrusion 
transporter (MATE) MATE2-K transporter at the clinical relevant concentrations. Copanlisib 
is a weak substrate of permeability glycoprotein (P-gp), and breast cancer resistance protein 
(BCRP), and not a substrate for the efflux transporters MATE1 and MATE2-K or the uptake 
transporters organic cation transporter (OCT), organic anion transporter (OAT) and organic 
anion-transporting polypeptide (OATP).
Metformin (probe drug-substrate)
Metformin, a commonly used oral glucose-lowering drug for type II diabetes mellitus, is not 
metabolized in the liver. Metformin is widely used as a substrate drug for OCT1, OCT2 and 
OCT3 mediated transport, and for human MATE1 and MATE2-K mediated transport, for 
evaluating the effect of an inhibitor drug on OCT and MATE2-K transporters activities in 
vivo (Figure 3-1) (1).  Following a single oral dose, peak metformin concentrations are 
achieved at 1 to 2 hours with a half-life of about 5 hours. Metformin is excreted into urine 
(~90% within 12 hours), secreted by renal tubules with a population mean for renal clearance 
(CLR) ~ 450 mL/min. The extent of plasma protein binding of metformin is minimal. Dosage 
range is between 1 to 3 g/day (given up to 3 times a day).


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Figure 3-1: Key major known transporters involved in the absorption and urinary 
excretion of metformin
MATE=multidrug and toxin extrusion transporter; OCT=organic cation transporter
Graham et al, 2011 (2)
3.2
Rationale of the study
In vitro, copanlisib showed a concentration-dependent inhibition of the renal transporter 
MATE2-K using metformin as a probe substrate, with Cmaxcopanlisib /IC50 = 1.0 µM/0.089 µM
~ 11; which is greater than the recommended cut-off (Cmax/IC50 ≥ 0.1) for conducting a 
clinical drug-drug interaction (DDI) study according to the Food and Drug Administration
(FDA) DDI draft guidance. Furthermore, metformin, a MATE2-K substrate, is sometimes 
used as a concomitant medicine in clinical studies to control high blood sugar (transient 
hyperglycemia) observed with copanlisib. This is a known target effect due to the inhibition 
of the PI3K–α isoform pathway by copanlisib. Metformin is eliminated unchanged by renal 
mechanisms, and while the liver is important for the pharmacologic activity of metformin, 
biliary excretion of metformin is negligible (2). The co-administration of metformin and 
copanlisib might reduce the CLR of metformin, may increase the metformin concentration in 
the kidney, and potentially lead to increased plasma concentrations. Therefore, this study will 
be conducted to evaluate the effects of copanlisib as a perpetrator using the full recommended 
approved dose of 60 mg on the PK and pharmacodynamics (PD) of metformin (victim drug) 
in order to provide guidance for drug labeling recommendations when copanlisib is 
concomitantly administrated with sensitive MATE2-K substrate.
3.3
Benefit-risk assessment
Copanlisib full dose of 60 mg has not been used previously in healthy volunteers. In the 
context of this study, a full dose is required to truly assess the effect of copanlisib as a strong 
inhibitor of MATE2-K according to the FDA DDI guidance, 2017. A 12 mg dose will not be 
appropriate to fully characterize the clinical DDI effect due to copanlisib acting as a 
perpetrator of MATE2-K. No serious adverse events (SAEs) or adverse events (AEs) of 
severity >Grade 3 were reported from Study 16353 (mass balance study in healthy subjects 
using a copanlisib dose of 12 mg (3)). Preliminary safety data in the ongoing Study 18041 
(copanlisib single dose of 12 mg) in 3 renal and 1 hepatic impaired subjects showed no AEs
(clinical or laboratory) to date.


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The data from monotherapy studies include a total of 286 cancer patients who experienced 
AEs following the first dose of 60 mg or 0.8 mg/kg (equivalent to approximately 60 mg 
absolute dose), but before the second dose on Day 8. The most common (all Grade ≥2%) AEs
are identified in Table 3–1.
Table 3–1:
Most common AEs (all Grade ≥2%) in copanlisib monotherapy 
studies in cancer patients after a single dose of copanlisib
Preferred term (PT)
CTCAE Grade 3
(N=286)
CTCAE Grade 4
(N=286)
CTCAE All Grades
(N=286)
Hyperglycaemia
20.3%
0.7%
45.80%
Hypertension
14.7%
0
24.48%
Nausea
0.7%
0
12.94%
Diarrhoea
0.7%
0
9.09%
Vomiting
0.3%
0
3.50%
Constipation
0
0
3.15%
Pyrexia
1.0%
0
2.80%
Fatigue
0
0
2.45%
Chills
0
0
2.10%
Headache
0
0
2.10%
CTCAE = common terminology criteria for AEs
Copanlisib has not been associated with severe hypersensitivity reactions and no 
contraindications for copanlisib were identified from pooled safety data. The treatment 
emergent AEs (TEAEs) following first dose of copanlisib included transient and 
asymptomatic hyperglycemia and hypertension; in addition to gastrointestinal and general 
disorder events. There is no evidence to suggest the safety profile would be associated with 
more severe known toxicities or new safety issues in healthy volunteers compared to the 
patient population studied in the clinical trials. Considering safety data from the completed 
healthy volunteer study and manageable AEs, with absence of severe hypersensitivity related 
events associated with the first dose of copanlisib in monotherapy, a single dose of 60 mg 
copanlisib is considered safe for the proposed study and would not expose subjects to severe 
or unmanageable toxicities.
The monitoring and treatment of AEs will ensure that subjects will not be exposed to undue 
risk and the inclusion and exclusion criteria will ensure that subjects who might be 
predisposed to higher risk of drug-related TEAEs are excluded.
The toxicologic and safety-pharmacologic investigations identified the need for monitoring 
cardiovascular, hepatic, renal and metabolic functions during early studies in humans. 
Copanlisib is non-genotoxic in vitro and in vivo. Practically, this will be addressed in this 
study through physical examinations including check of vital signs, electrocardiograms 
(ECGs), monitoring of clinical chemistry laboratory, and in particular, close monitoring of 
glucose and blood pressure following the infusion.
Because changes in the reproductive system and adverse effects on development, including 
embryo-lethality and teratogenicity, cannot be excluded, women of childbearing potential and 
men must agree to use highly effective contraception from signing of the informed consent 
form until at least 3 months after copanlisib dosing. The investigator or a designated 
associate is requested to advise the subject how to achieve highly effective contraception.


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Metformin has a very broad therapeutic range with a low risk of overlapping toxicities. For 
full details on metformin, please refer to the current prescribing information / Summary of 
Product Characteristics (SmPC).
Study subjects are not expected to gain any direct benefit from the study, since they will have 
no malignancies susceptible to respond to copanlisib. However, the benefit of this trial will 
be the generation of further information on the effects of copanlisib on metformin with
regards to PK and PD. These data will provide guidance for drug labeling recommendations 
when copanlisib is concomitantly administrated with sensitive MATE2-K substrate, if needed. 
This is required as a post marketing requirement after the accelerated approval of copanlisib 
on 14 SEP 2017.
4.
Study objectives
The primary objective of this study is to

Evaluate the effect of the co-administration of copanlisib on the PK of metformin
The secondary objectives of this study are to

Assess the safety of copanlisib when administered to healthy subjects in 
combination with metformin

Evaluate the PD effect of copanlisib on metformin in terms of plasma lactate levels
Exploratory objectives of this study are to

Assess additional copanlisib and metformin PK parameters

Assess additional PD parameters
5.
Study design
Design overview
This study is a phase 1, non-randomized, single-center, open-label study to investigate the 
effect of copanlisib, a MATE2-K inhibitor, on the PK and PD of metformin in healthy 
subjects.
A total of approximately 15 subjects between the ages of 18 to 45 years will be enrolled, to 
achieve 12 evaluable subjects. 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 (Figure 5-1). After the first 
dose of metformin, there will be a 7-day wash-out before the second dose of metformin with 
copanlisib on Day 8, to assess the effect of copanlisib as a perpetrator on metformin (victim 
drug). Dosing of both drugs will be done at the site. Subjects will need to fast overnight 
before metformin administration on Days 1 and 8. They will continue fasting until 3 hours 
after metformin dosing and will then be given a low-carbohydrate meal (eggs, cheese and/or 
plain yogurt, vegetables, meat). On Day 8, metformin will be given just before the start of the 
copanlisib infusion.  No i.v. glucose preparations should be administered on the days of 
copanlisib i.v. infusion due to the known transient glucose elevation after copanlisib
administration related to the PI3K pathway.


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Following each metformin dose, subjects will be asked to drink 8 oz (~237 mL) of water 
every 2 hours during waking hours to maintain urine flow and pH.
Blood samples will be collected pre- and post-dose, and urine samples will be collected up to 
24 hours for metformin; blood samples will be collected up to 24 hours for copanlisib. 
Additional blood samples will be collected up to 24 hours after each dose of metformin for 
the PD evaluations.
Subjects will stay in-house at the study site from approximately 12 hours before until 
24 hours after each dose.
An end of treatment (EOT) visit will be conducted 7 to 14 days after copanlisib dosing.
Follow-up will be conducted 30 to 35 days after copanlisib dosing. This follow-up will be 
conducted by telephone, unless an in-house visit is clinically indicated.
Figure 5-1: Flow chart of study design
Screening
(within 
28 days of 
first dose)
Day 1
Day 8
Day 15-22
Day 38-43
Metformin 
1000 mg oral
Days 2-7
Washout
Metformin 
1000 mg oral
+
Copanlisib 
60 mg i.v. 1 hour 
infusion
EOT visit
(7-14 days 
after 
copanlisib 
dosing)
Follow-up 
phone call / 
visit
(30-35 days 
after 
copanlisib 
dosing)
Intensive
PK and PD 
sampling for
metformin
Intensive
PK and PD 
sampling for 
both drugs
EOT = End of treatment visit
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. The standard dose will be 
used to maximize the potential for a clinical impact of MATE2-K inhibition by copanlisib. 
The metformin dose is 1000 mg. The marketed drugs used in this study will be administered 
at doses according to their approved label.
The variables related to each study objective are shown in Table 5–1.


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Table 5–1:
Objectives and related variables
Objective
Variable
Section
Primary

To evaluate the effect of the 
co-administration of copanlisib 
on the PK of metformin

PK parameters: Cmax, AUC(0-24) 
and AUC for metformin on Day 1 
and Day 8
See Section 9.5.1
Secondary

To assess the safety of 
copanlisib when administered 
to healthy subjects in 
combination with metformin

To evaluate the PD effect of 
copanlisib on metformin in 
terms of plasma lactate levels

Frequency/severity of treatment 
emergent AEs
PD parameters: plasma lactate 
levels and maximum change from 
baseline on Day 1 and Day 8
See Section 9.6
See Section 9.5.2
Exploratory

To assess additional copanlisib 
and metformin PK parameters

Metformin:
Day 1 and Day 8:
%AE,ur, AE,ur, %AE,ur(t1-t2), 
AE,ur(t1-t2) where t1 and t2 are the 
start and the stop times of the urine 
collection interval
tmax, VZ/F, CL/F and t1/2; and CLR 
(calculated as CLR = 
AE,ur(0-24)/AUC(0-24))

Copanlisib:
Day 8:
Cmax, tmax, C6h, C24h and AUC(0-
24)
See Section 9.5.1

To assess additional PD 
parameters

Glucose, insulin and C-peptide on 
Day 1 and Day 8
See Section 9.5.2
Justification of the design
For study objectives please see Section 4 and Table 5–1 above.
This study will investigate the effect of copanlisib, a MATE2-K inhibitor, on the PK and PD 
of metformin (substrate drug of MATE2-K) in healthy subjects.
The PK measurements are the primary focus of the study, therefore a non-randomized, open-
label, single group design was considered adequate. Blinding procedures are not required in 
this study as the PK parameters will not be affected by either the subjects or the 
investigator(s).
The rationale for the use of metformin is provided in Section 3.2. The metformin dose of 
1000 mg is in the range of approved clinical dose of metformin and similar to previous DDI 
studies with metformin as a victim drug (4). The rationale for the choice of copanlisib dose is 
provided in Section 3.3. The choice of regimen/schedule of administration is in accordance 
with the respective approved label for copanlisib and metformin.
It was chosen to conduct this study in healthy subjects because copanlisib is considered to be 
non-genotoxic in vitro and in vivo, and safe for the proposed study. Futhermore, previous 


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studies have already been conducted with copanlisib in healthy subjects; see Section 3.3 for 
further details. See also Section 6.3 for the justification of selection criteria.
The rationale for the choice of PD parameters is provided in Section 9.5.2.
For handling of missing data see Section 11.4.
End of study
As for this study, important data may be collected after last subject last visit (LSLV), the end 
of the study as a whole will be the date when the clean database is available.
Primary completion
The primary completion event for this study is LSLV.
6.
Study population
6.1
Inclusion criteria
Subjects must fulfill all of the following criteria before being included in the treatment period:
1. Written informed consent obtained, dated and signed prior to any screening 
procedures.
2. Healthy male or female subject – as determined by the investigator or medically 
qualified designee based on medical evaluations, including medical history, physical 
examination, laboratory tests and cardiac monitoring.
3. Age: 18 to 45 years at the first screening visit.
4. Women of childbearing potential and men must agree to use highly effective
contraception from signing of the informed consent form until at least 3 months after 
dosing. The investigator or a designated associate is requested to advise the subject
how to achieve highly effective contraception. Highly effective (failure rate of less 
than 1% per year) contraception methods include: combined (estrogen and 
progesterone containing: oral, intravaginal, transdermal) and progesterone-only (oral, 
injectable, implantable) hormonal contraception; intrauterine device (IUD); 
intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; or 
vasectomized partner (provided that partner is the sole sexual partner and has received 
medical assessment of the surgical success). Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception. In addition, the use of condoms for subjects or 
their partners is required unless the woman is postmenopausal or permanently 
sterilized (hysterectomy, bilateral oophorectomy).
Male subjects must abstain from fathering a child.
5. Women must have a negative pregnancy test (in blood or urine) within 7 days prior to 
the dose of study drug or be surgically or biologically sterile or postmenopausal.
Postmenopausal women are defined as:

Age ≤45 years with 6 months of spontaneous amenorrhea and follicle stimulating 
hormone level within postmenopausal range (>40 mI U/mL) or

Permanently sterilized women (hysterectomy, bilateral oophorectomy).


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6. Body mass index (BMI) of 18.0-34.0 kg/m2, with body weight 50 kg
7. Subject must be willing to comply with dietary, fluid, and activity restrictions during 
the treatment period (including abstaining from alcohol use) (see Sections 9.2.7.1 and
9.2.7.2).
8. Subject must have venous access sufficient to allow blood sampling as required by the 
protocol.
9. Subject must be willing to undergo multiple blood draws as required by the protocol.
10. Ability to understand and follow study-related instructions.
11. Creatinine clearance ≥ 90 mL/min using the Modification of Diet in Renal Disease 
(MDRD formula; see Section 16.4).
12. Adequate end organ and bone marrow function as defined by:

Total bilirubin in the normal range

International normalized ratio (INR) lower or equal to 1.5 x upper limit of normal 
(≤1.5 ULN)

Alkaline phosphatase (AP) ≤1.5 ULN, Alanine aminotransferase (ALT)
≤1.5 ULN, aspartate aminotransferase (AST) ≤1.5 ULN

Neutrophils ≥ 1500/μL, platelets ≥ 100,000/μL
13. Vital signs within the following ranges:

Systolic blood pressure (BP) ≥90 mmHg and ≤150 mmHg

Diastolic BP ≥50 mmHg and ≤90 mmHg

Pulse rate 45 to 100 bpm
6.2
Exclusion criteria
Subjects are to be excluded from the study if they display any of the following criteria:
Medical and surgical history
1. 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).
2. 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.
3. Febrile illness within 1 week before the first study drug administration.
4. A positive Hepatitis B surface antigen (HBsAg), Hepatitis C or human 
immunodeficiency virus (HIV) test result.
5. A medical history of risk factors for Torsades de pointes (e.g. family history of Long 
QT Syndrome) or other arrhythmias.
6. Known severe allergies, allergies requiring therapy with corticosteroids, non-allergic 
drug reactions, or (multiple) drug allergies (excluding untreated asymptomatic 
seasonal allergies such as non-severe hay fever during the time of study conduct).
7. Known history of hypersensitivity (or known allergic reaction) to copanlisib,
metformin, related compounds, or any components of the formulation.


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8. Relevant renal disorders like recurrent glomerulonephritis, renal injury, and renal 
insufficiency.  However, a history of a single episode of uncomplicated nephrolithiasis 
will not prevent participation.
9. Relevant respiratory insufficiency / disorder (lung conditions that cause difficulty 
breathing).
10. Subjects with sleep apnoea syndrome (frequent interruption of breathing during sleep).
11. Subjects with active pathological bleeding, with evidence or history of bleeding 
diathesis.
12. Previous or concurrent cancer except for curatively treated cervical cancer in situ and 
curatively treated non-melanoma skin cancer.
13. Subjects with any type of psychiatric disorder, especially any mood disorders 
including medical history with suicidal ideation and/or suicide attempts, which may 
disable the subject to consent.
Medication, drug use and special behavioral patterns
14. Subjects with known drug abuse within 1 month prior to dosing or evidence of such 
abuse as indicated by the laboratory assays conducted during the screening or baseline 
evaluations.
15. Alcohol consumption above the equivalent of 20 g alcohol average per day.
16. Donation or loss of 400 mL or more of blood within 4 weeks prior to dosing.
17. Administration of strong CYP3A4 inhibitors or inducers within 2 weeks prior to 
dosing (see Appendix 16.3).
18. Use of immunosuppressive drugs.
19. Administration of medications that prolong the QT interval within 2 weeks prior to 
dosing (A list of agents that prolong the QT interval can be found at 
http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm. However, 
this list may not be comprehensive).
20. Use of any prescription drug or over-the-counter (OTC) medication within 2 weeks or 
5-half-lives of the prescription medication prior to dosing with copanlisib (whichever 
is longer), except for acetaminophen or ibuprofen within 7 days before dosing.
21. Use of supplements or herbal remedies within 2 weeks prior to dosing with the 
exception of vitamins.
22. Use of investigational drugs (i.e. participation in any clinical investigation) within 
30 days prior to dosing or longer if required by local regulation, or within 10-half-
lives of the investigational agent taken (whichever is longer).
23. Intake of foods or beverages containing grapefruit, pomelo or Seville oranges within
1 week before the study drug administration. The juices and products containing these 
fruits must also be avoided.
24. Regular use of therapeutic or recreational drugs, e.g. carnitin products, anabolics, high 
dose vitamins.


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Other exclusion criteria
25. Inability to understand the protocol requirements, instructions and study related 
restrictions, the nature, scope, and possible consequences of the study.
26. Unlikelihood to comply with the protocol requirements, instructions and study related 
restrictions; e.g. uncooperative attitude, inability to return for follow-up visits, and 
improbability of completing the study.
27. Subject is the Investigator or any Sub-Investigator, research assistant, pharmacist, 
study coordinator, other staff or relative thereof directly involved in the conduct of the 
study.
28. Subject is in custody by order of an authority or a court of law.
29. Previous assignment to treatment during this study.
6.3
Justification of selection criteria
The selection criteria are chosen to ensure that subjects with specific risks for administration 
of the study drugs and/ or subjects with conditions which may have an impact on the aims of 
the study are excluded.
Justification of gender selection: Male and female subjects will be included providing they 
meet all the criteria for inclusion and do not fulfill any of those for exclusion. No sex-specific 
effects of treatment are anticipated.
6.4
Withdrawal of subjects from study
6.4.1
Withdrawal
Withdrawal criteria
Subjects must be withdrawn from the study if any of the following occurs:

At their own request or at the request of their legally acceptable representative. At 
any time during the study and without giving reasons, a subject may decline to 
participate further.  The subject will not suffer any disadvantage as a result.
Subjects may be withdrawn from the study if any of the following occurs:

If, in the investigator’s opinion, continuation of the study would be harmful to the 
subject’s well-being

At the specific request of the sponsor and in liaison with the investigator (e.g. 
obvious non-compliance, safety concerns).

Violation of in-/exclusion criteria: if the subject develops conditions which would 
have prevented his/her entry into the study according to the in-/exclusion criteria, 
he/she must be withdrawn immediately if safety is concerned; in other cases, the 
investigator will decide, after consultation with the sponsor, whether there is a 
conflict with the study objectives.
Depending on the time point of withdrawal, a withdrawn subject is referred to as either 
“screening failure” or “dropout” as specified below:


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Screening failure
A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before the time point used for the definition of “dropout” (see below) is regarded a 
“screening failure”.  
Re-starting the defined set of screening procedures to enable the “screening failure” subject’s 
participation at a later time point is not allowed – with the following exceptions:

The subject had successfully passed the screening procedures, but could not start 
subsequent treatment on schedule.

Initial screening occurred too early to complete the required washout period after 
prior therapy.

The in-/exclusion criteria preventing the subject’s initial attempt to participate 
have been changed (via protocol amendment).
Thus, participation of an initial “screening failure” subject at a later time point even if he/she 
meets all selection criteria upon re-screening is not acceptable.
In any case, the investigator has to ensure that the repeated screening procedures do not 
expose the subject to an unjustifiable health risk.  Also, for re-screening, the subject has to 
re-sign the informed consent form, even if it was not changed after the subject’s previous 
screening.
Dropout
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has already been administered at least one dose of study medication.
General procedures
In all cases, the reason for withdrawal must be recorded in the case report form (CRF) and in 
the subject’s medical records.
The subject may object to the generation and processing of post-withdrawal data as specified 
in Section 13.4.
Any subject removed from the trial will remain under medical supervision until discharge or 
transfer is medically acceptable. If the subject has received study drug, an EOT visit is to be 
performed.
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12 (Premature termination of the study).
6.4.2
Replacement
Subjects who drop out or do not receive all doses of study drugs will be replaced to obtain a 
minimum of 12 subjects valid for PK of metformin.
6.5
Subject identification
At the beginning of screening, every subject is given a subject number (9-digit number 
consisting of: Digits 1 to 5 = Unique center number, Digits 6 to 9 = Current subject number)
within the center.


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7.
Treatments
7.1
Treatments to be administered
All subjects will receive 2 oral doses of metformin, 1 dose (1000 mg) on Day 1 and 1 dose
(1000 mg) on Day 8, and a single i.v. dose of copanlisib (60 mg, 1 h infusion) on Day 8.
The treatments to be administered during the study are displayed in Table 7–1.
Table 7–1: Treatments to be administered
Treatment
Route of 
administration
Dose, formulation
Frequency and time of 
administration
Number of 
subjects treated
Metformin
Oral
1000 mg, tablet 
Single dose on Day 1
12-15
Metformin 
Oral
1000 mg, tablet
Single dose on Day 8
12-15
Copanlisib
i.v.
60 mg, 1 h infusion
Single dose on Day 8
12-15
7.2
Identity of study treatment
Copanlisib
Copanlisib is supplied as a lyophilized preparation in a 6 mL glass injection vial. The total 
amount of BAY 80-6946 per vial is 60 mg. The solution for i.v. infusion is obtained after 
reconstitution of the lyophilisate with 0.9% sodium chloride solution.
Please refer to the Pharmacy Manual for detailed instructions for the reconstitution of the 
lyophilisate and for further dilution of the reconstituted solution.
Please refer to IB for copanlisib for more details regarding drug properties and formulation.
Metformin
Metformin will be sourced centrally or locally depending on the local law and requirements.  
The source of the metformin will be documented in the sponsor’s study file.  For full details 
on metformin, please refer to the current prescribing information / SmPC.
Study drug supply
All centrally supplied study drugs will be labeled according to the requirements of local law
and legislation.  Label text will be approved according to the sponsor’s agreed procedures, 
and a copy of the labels will be made available to the study site upon request.
For all centrally supplied study drugs, a system of numbering in accordance with all 
requirements of Good Manufacturing Practice (GMP) will be used, ensuring that each dose of 
study drug can be traced back to the respective bulk batch of the ingredients.  Lists linking all 
numbering levels will be maintained by the sponsor’s clinical supplies Quality Assurance
(QA) group. 
A complete record of batch numbers and expiry dates of all study treatment as well as the 
labels will be maintained in the sponsor’s study file.
7.3
Treatment assignment
All subjects will receive the same treatments in this open-label, non-randomized study.
Please refer to Section 6.5 for subject identification.


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7.4
Dosage and administration
All subjects will receive 2 doses of metformin, 1 dose (1000 mg tablet) on Day 1 and 1 dose
(1000 mg tablet) on Day 8, and a single dose of copanlisib (60 mg infusion) on Day 8.
Copanlisib is administered in a normal saline solution i.v. over 1 hour; refer to Section 7.2 for 
further details.
Regarding the selection of copanlisib and metformin dose in the study, refer to Section 3.3.
Regarding doses, route / mode of administration, and formulations, refer to Section 7.1.
Subjects will need to fast overnight before metformin administration on Days 1 and 8. They 
will continue fasting until 3 hours after metformin dosing and will then be given a low-
carbohydrate meal (eggs, cheese and/or plain yogurt, vegetables, meat).  On Day 8, metformin 
will be given just before the start of the copanlisib infusion.
7.5
Blinding
This study will be performed in a non-blinded design, as the primary objective of this trial is 
the investigation of PK and because the PK results will neither be affected by the subjects nor 
by the investigator(s).
7.6
Drug logistics and accountability
All study drugs will be stored at the investigational site in accordance with GCP and GMP 
requirements and the instructions given by the clinical supplies department of the sponsor (or 
its affiliate/contract research organization [CRO]), and will be inaccessible to unauthorized 
personnel.  Special storage conditions and a complete record of batch numbers and expiry 
dates can be found in the sponsor’s study file; the site-relevant elements of this information 
will be available in the investigator site file.  On the day of receipt, the responsible site 
personnel will confirm receipt of study drug in writing.  The personnel will use the study drug 
only within the framework of this clinical study and in accordance with this protocol.  
Receipt, distribution, return and destruction (if any) of the study drug must be properly 
documented according to the sponsor’s agreed and specified procedures.
Written instructions on medication destruction will be made available to affected parties as 
applicable.
If performing drug accountability implies a potential risk of contamination, a safety process/ 
guidance for handling returned drug will be provided.
7.7
Treatment compliance
The administration of the study drugs will be done by a member of the investigator’s team. 
This person will ascertain and document that the subject receives the treatment as planned.
Further information about the subject’s treatment compliance can be derived from drug 
concentration measurements in plasma.


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8.
Non-study therapy
8.1
Prior and concomitant therapy
All prior medication used within 4 weeks before the screening visit will be documented 
(medication history).
Refer to Section 6.2 for medication representing exclusion criteria.
Copanlisib is primarily metabolized by CYP3A4. Concomitant use of CYP3A4 inhibitors 
and inducers (see list in Appendix 16.3) is therefore not permitted from 2 weeks before the 
administration of study drug until 24 hours after dosing on Day 8 (after the last PK blood 
sample has been collected) in this study.
Use of medication for concomitant therapy is not planned. Especially the use of medication 
that may have an impact on the study objectives is not permitted. This comprises any 
medication (including herbal remedies or food supplements), which could affect the PK 
and/or PD of the study drugs. The subjects will be instructed to report any concomitant 
medication used to the investigator. All concomitant medication will be documented.  In 
particular, this documentation will be expanded by the exact time of day for any concomitant 
medication used during the in-house phase.
8.2
Post-study therapy
After the end of this study, further treatment is not necessary since only healthy subjects will 
be included in the study.
9.
Procedures and variables
9.1
Tabular schedule of evaluations
See flow charts in Section 16.1.
Regarding protocol deviations, the processes and responsibilities defined by the sponsor will 
be followed. Respective details (e.g. identification and classification of protocol deviations) 
are described separately.
9.2
Visit description
The following measures/actions will be performed at the time points given in the flow charts 
in Section 16.1. Details on the parameters measured for safety laboratory examinations are 
provided in Section 16.2.
If not stated otherwise, the measures/actions listed in the following Sections 9.2.1 to 9.2.7 will 
be performed by or under the supervision of an investigator.
9.2.1
Screening
Due to the fact that not all subjects may fulfill the inclusion/exclusion criteria, a higher 
number of subjects than needed to be valid for the evaluation of the study will be asked to 
participate in the screening examinations.
A subject information session will be held. If the (first) screening procedures already start on 
the same day (same date) as the subject signs the informed consent form, the time of the 
subject’s signature must be recorded in the source documents.


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Note: No screening procedures may be performed unless written informed consent has 
been obtained.
After obtaining the subject’s signature on the consent form, the below listed screening 
procedures will be performed and the respective results will be assessed within approximately 
28 days prior to the first study drug administration:

Allocation of subject number (see Section 6.5)

Demographic data

Weight, height, BMI

Questioning for special behavior (e.g. smoking history, alcohol consumption, 
dietary habits incl. consumption of food supplements)

Medical and surgical history

Participation in previous clinical studies

Current and previous medication (relevant medication history up to 28 days prior
to first study drug administration) and concomitant medication

Physical examination (general)

Vital signs: blood pressure, pulse rate and temperature, after resting for at least 
10 min in supine position

12-lead ECG after resting for at least 10 min in a supine position

Adverse events before start of treatment (e.g. signs / symptoms of the subject; 
results of physical examination)

Blood and urine samples for the safety laboratory examinations described in 
Section 16.2

Glycated hemoglobin (HbA1c)

Virology (described in Section 16.2)

Urine drug screen (see Section 16.2 for details)

Alcohol breath test

Pregnancy test (blood or urine), if applicable.
Based on the information obtained from the above assessments, i.e. once all results (including 
laboratory data) are available, the subject’s eligibility will be decided upon:

Eligibility check
No subject may be included unless adherence to all selection criteria as given in Sections 6.1
and 6.2 is established.
In case of abnormal results caused by intercurrent diseases, short-term treatable conditions or 
other temporary health disorders (e.g. acute infection, iron deficiency, blood pressure outside 
defined range), the investigator may decide to repeat the respective screening parameter(s). 
As a rule, up to 2 repetitions are acceptable.  In any case, the investigator must ensure that the 
repeated screening procedures do not expose the subject to an unjustifiable health risk.


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9.2.2
Pre-dose (Study Day -1)
The subjects will arrive at the study site in the evening of Study Day -1, the day before study
drug administration. The following measures/actions will be carried out: 

Open questioning for and documentation of AEs and update on previous 
medication

Alcohol breath test

Physical examination

Vital signs: blood pressure (to be measured in the same arm throughout the study), 
pulse rate and temperature, after resting for at least 10 min in supine position

Start overnight fasting for at least 10 hours before administration of the study 
medication (drinking of water allowed)

Pregnancy test (blood or urine), if applicable, if screening pregnancy test was not 
within the previous 7 days.
9.2.3
Randomization
Randomization is not applicable.
9.2.4
Treatment Period
If 2 or more measures/ actions coincide at one time point, they should be performed according 
to the preferred sequence: ECG – blood pressure/ pulse rate – blood sampling for PK at 
defined time point(s) – blood sampling for safety – urine sample. In the event that results of 
the plasma glucose testing are not available, capillary glucose measurements may be used to 
manage the safety of the subject. Any of the standardized meals will be served after the 
measures/actions for a given time point are completed.
9.2.4.1
Study Day 1
The following measures/actions will be performed before dosing:

Fasting to be continued (drinking of water allowed)

Open questioning for and documentation of AEs and update on concomitant 
medication

12-lead ECG after resting for at least 10 min in a supine position

Vital signs: blood pressure, pulse rate and temperature, after resting for at least
10 min in supine position

Blood and urine samples for the safety laboratory examinations described in 
Section 16.2. These may be done on Day -1 if necessary, to ensure that the results 
are available prior to dosing.

Fasting glucose pre-dose

Final check of inclusion and exclusion criteria

Blood sample for metformin PK (baseline sample)

Blood samples for PD evaluation (plasma lactate, glucose, insulin and c-peptide;
baseline samples)

Urine sample for metformin PK (baseline sample)


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Subjects will receive study treatment in the morning as follows:

Single dose of metformin (1000 mg tablet)
The following measures/actions will be performed after dosing at the time points given in the 
schedule in Table 16–2:

Subjects will be asked to drink 8 oz (~237 mL) of water every 2 hours during 
waking hours to maintain urine flow and pH

Fasting to be continued until 3 hours after metformin dosing

Open questioning for and documentation of AEs and update on concomitant 
medication

12-lead ECG after resting for at least 10 min in a supine position

Vital signs: blood pressure, pulse rate and temperature, after resting for at least 
10 min in supine position

Blood samples for metformin PK

Blood samples for PD evaluation (plasma lactate, glucose, insulin and c-peptide)

Urine sample collections for metformin PK

Blood and urine samples for the safety laboratory examinations described in 
Section 16.2.
After completion of the Day 1 measures/actions (relative time Day 1, up to 24 hours), the 
subjects will be discharged from the study site in the morning of Day 2, provided there are no 
medical objections. They will return in the evening of Day 7.
9.2.4.2
Study Day 7
The subjects will arrive at the investigational site in the evening before study drug 
administration. The following measures/actions will be carried out: 

Open questioning for and documentation of AEs and update on concomitant 
medication

Alcohol breath test

Physical examination

Vital signs: blood pressure, pulse rate and temperature, after resting for at least 
10 min in supine position

Start overnight fasting for at least 10 hours before administration of the study 
medication (drinking of water allowed)
9.2.4.3
Study Day 8
The following measures/actions will be performed before dosing:

Fasting to be continued (drinking of water allowed)

Open questioning for and documentation of AEs and update on concomitant 
medication

12-lead ECG after resting for at least 10 min in a supine position

Vital signs: blood pressure, pulse rate and temperature, after resting for at least 
10 min in supine position.


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Blood pressure will be measured prior to the administration of the copanlisib, until 
2 consecutive values are <150/90 mmHg with at least a 15 min interval between 
measurements. Up to 4 measurements may be taken before drug administration.
If the blood pressure is not <150/90 mmHg, copanlisib cannot be administered.

Blood and urine samples for the safety laboratory examinations described in 
Section 16.2. These may be done on Day 7 if necessary, to ensure that the results 
are available prior to dosing.

Fasting plasma glucose. Copanlisib infusion can only be administered if fasting 
glucose is ≤125mg/dL

Blood sample for metformin PK (baseline sample)

Blood sample for copanlisib PK (baseline sample)

Blood samples for PD evaluation (plasma lactate, glucose, insulin and c-peptide;
baseline samples)

Urine sample for metformin PK (baseline sample)
Subjects will receive study treatment in the morning as follows:

Single dose of metformin (1000 mg tablet)

Intravenous infusion of copanlisib (60 mg, 1 hour infusion), immediately (within 
5-10 mins) after the metformin dose
The following measures/actions will be performed after dosing at the time points given in the 
schedule in Table 16–2:

Subjects will be asked to drink 8 oz (~237 mL) of water every 2 hours during 
waking hours to maintain urine flow and pH

Fasting to be continued until 3 hours after metformin dosing

Open questioning for and documentation of AEs and update on concomitant 
medication

12-lead ECG after resting for at least 10 min in a supine position

Vital signs: blood pressure, pulse rate and temperature, after resting for at least 
10 min in supine position

Blood samples for metformin PK

Blood samples for copanlisib PK

Blood samples for PD evaluation (plasma lactate, glucose, insulin and c-peptide)

Urine sample collections for metformin PK

Blood and urine samples for the safety laboratory examinations described in 
Section 16.2.
After completion of the Day 8 measures/actions (relative time Day 8, up to 24 hours), the 
subjects will be discharged from the study site on the morning of Day 9, provided there are no 
medical objections.


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9.2.5
End of treatment visit
The following measures/actions will be performed at the EOT visit, 7 to 14 days after 
administration of copanlisib:

Adverse events

Current and previous medication (medication history)

Physical examination

Vital signs: blood pressure, pulse rate, temperature

ECG

Plasma glucose

HbA1c

Blood and urine samples for the safety laboratory examinations described in 
Section 16.2
9.2.6
Follow-up
A follow-up assessment will be conducted by telephone, 30 to 35 days after last 
administration of the study medication. The following measures/actions will be performed:

Adverse events

Current and previous medication (medication history)
If clinically indicated (e.g. if the subject has any AEs), then a follow-up visit should be 
conducted in-house, and the following measures/actions performed:

Adverse events

Current and previous medication (medication history)

Physical examination

Vital signs: blood pressure, pulse rate, temperature

ECG

Blood sample for safety (clinical chemistry, hematology, coagulation)

Urine sample for safety (dipstick ± sediment)
9.2.7
Special conditions during the study
9.2.7.1
Restrictions
Restrictions to be observed by the subjects are displayed in Table 9–1.


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Table 9–1: Restrictions during the study
Restriction
Period of restriction
Concomitant medications
Please refer to Section 8.1
Smoking 
Not allowed during the in-house phases of the study
Caffeine
Not permitted on PK sampling days
Alcohol
Not permitted from 48 hours prior to each study drug 
administration and during the in-house phases
Xanthine-containing beverages and food
Not permitted from 24 hours prior to each drug 
administration and during the in-house phases
Foods or beverages containing grapefruit, 
pomelo or Seville oranges. Juices and 
products containing these fruits must also be 
avoided.
Not permitted within 1 week before the study drug 
administration until EOT
Physical activity
Strenuous exercise is not allowed from 72 hours 
before admission to the study site until 96 hours after 
study drug administration
Donation of whole blood/components of blood
Donation of 400 mL or more of blood within 4 weeks 
prior to dosing and through EOT visit
9.2.7.2
Food and drink
Subjects must fast overnight before metformin administration on Days 1 and 8 (water is 
permitted). They must continue fasting until 3 hours after metformin dosing and will then be 
given a low-carbohydrate meal (eggs, cheese and/or plain yogurt, vegetables, meat).
Food and drink will be served after the study-related measures/actions of that time point have 
been performed.
9.2.7.3
Accomodation
Visit:
Approximate duration:
Overnight stays:
Screening
2 hours
Day 1
36-48 hours
2
Day 8
36-48 hours
2
EOT
1 hour
Follow-up
1 hour (if conducted in-house)
9.3
Population characteristics
9.3.1
Demographic
For demographic assessment, the following parameters will be recorded:
Year of birth/age, sex, race, body weight, height, and BMI.


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9.3.2
Medical history
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the investigator:

Start before signing of the informed consent 

Considered relevant for the subject’s study eligibility.
Detailed instructions on the differentiation between (i) medical history and (ii) AEs can be 
found in Section 9.6.1.1.
9.3.3
Other baseline characteristics
Information on smoking, diet, and alcohol consumption will be collected.
9.4
Efficacy
Not applicable.
9.5
Pharmacokinetics / pharmacodynamics
9.5.1
Pharmacokinetics
9.5.1.1
Drug measurements
Blood samples for PK analysis of metformin and copanlisib in plasma will be collected at the 
time points given in the schedule of assessments in Section 16.1 (Table 16–2) and in Table 9–
2 below.
Urine for PK analysis of metformin will be collected at the time points given in the schedule 
of assessments in Section 16.1 (Table 16–2) and in Table 9–3 below.
Regarding handling of the samples collected, refer to Section 16.2. The PK analyses will be 
performed using validated analytical methods. Quality control (QC) and calibration samples 
will be analyzed concurrently with study samples. The results of calibration samples and QC 
samples will be reported in the Bioanalytical Report which will be included in the Clinical 
Study Report for this study. Concentrations are calculated from the chromatographic raw data 
in accordance with current Bayer guidelines.
The PK calculations will be based on the actual sampling and dosing times. Therefore, it is of 
importance to have this data thoroughly documented in the CRF. Deviations from the 
specified time points will be documented and taken into account when calculating the PK 
parameters.
Whenever possible, all efforts should be made to adhere to the sampling schedule in the Table 
16–2. However, based on practical considerations, the following time range is provided: 
pre-dose samples should be collected within 30 min before drug administration; for planned 
time points ≤6 h post-dose (except for pre-dose samples), PK samples should be collected 
within ±15 min of the planned time; and for planned time points >6 h post-dose, PK samples 
should be collected within ±30 min.
Cumulated substantial deviations of sampling times and/or consecutive, missing PK samples 
may lead to an insufficient description of the concentration-time profile(s) of analyte(s), and 
thus affect the quality of the PK evaluation of the respective subject(s). In this case these 


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deviations should be classified as “important” and may lead as declared “validity findings” to 
the exclusion of the respective subject(s) from the PK analysis set.
Detailed information about the collection, processing, storage and shipment of the samples 
will be provided separately, e.g. sample handling sheets and/or laboratory manual.
Table 9–2: PK sampling and dosing time points for metformin and copanlisib in 
plasma
Day
Relative time 
after dose (h)
1000 mg Metformin oral
PK sampling 
for metformin
PK sampling 
for copanlisib
1
0a
x
xa
-
1
0.5
x
-
1
1
x
-
1
1.5
x
-
1
2
x
-
1
2.5
x
-
1
3
x
-
1
4
x
-
1
6
x
-
1
8
x
-
1
10
x
-
1
12
x
-
1
16
x
-
1
24
x
-
Day
Relative time 
after dose (h)
60 mg copanlisib i.v.
1 h infusion +
1000 mg metformin oral
PK sampling 
for metformin
PK sampling 
for copanlisib
8
0a
x
xa
xa
8
0.5
x
x
8
1
x
x
8
1.5
x
-
8
2
x
x
8
2.5
x
-
8
3
x
-
8
4
x
x
8
6
x
x
8
8
x
x
8
10
x
-
8
12
x
x
8
16
x
-
8
24
x
x
a = pre-dose before drug administration
- =no sample collection


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Table 9–3: Urine sample collection for metformin PK evaluation on Days 1 and 8
Study Day
Time windows
1
0-2 h
2-4 h
4-8 h
8-12 h
12-24 h
8
0-2 h
2-4 h
4-8 h
8-12 h
12-24 h
9.5.1.2
Pharmacokinetic evaluation
Non compartmental analysis (NCA)
The PK parameters will be calculated according to the Sponsor’s current guidelines and the 
version of the PK software WinNonlin used at the time of evaluation. Detailed information 
regarding the version will be given in the study report. Based on the concentration time data, 
the following PK parameters will be calculated:
Main parameters:
Metformin:
Day 1 and Day 8: Cmax, AUC(0-24) and AUC
Additional parameters
Metformin:
Day 1 and Day 8:
%AE,ur, AE,ur, %AE,ur(t1-t2), AE,ur(t1-t2) where t1 and t2 are the 
start and the stop times of the urine collection interval
tmax, VZ/F, CL/F, t1/2, and CLR (calculated as 
CLR = AE,ur(0-24)/AUC(0-24))
Copanlisib:
Day 8: Cmax, tmax, C6h, C24h and AUC(0-24)
Optional analysis
Simulations of plasma concentration versus time profiles might be performed utilizing 
compartmental evaluation methods to estimate systemic exposure following administration of 
other dosing regimens. This will be reported under separate cover, if applicable.
Pharmacokinetic data for copanlisib collected during the study may be analyzed using non-
linear mixed-effects models. Details of the model building process including model 
evaluation will be provided in a separate data analysis plan.
9.5.2
Pharmacodynamics
The change in PD markers will be analyzed in plasma samples collected during metformin 
alone or in combination with copanlisib. The list of PD parameters and the rationale for 
measurement for both metformin and copanlisib is provided in Table 9–4. Pharmacodynamic 
sampling time points are provided in Table 9–5.


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Table 9–4: Pharmacodynamic assessment and rationale
Pharmacodynamic 
measurements
Rationale
Plasma lactate levels on 
Days 1 and 8
Lactic acidosis is a rare, but serious and infrequent 
(0.03/1000 patient-years) complication of metformin therapy for 
diabetes mellitus, where plasma lactate levels exceed 5 mmol/L(5). 
Plasma lactate levels will be measured in this study as a PD variable
Glucose, insulin and c-peptide 
on Days 1 and 8
These glucose metabolism markers will be used as PD markers 
mediated by PI3K of copanlisib effects as shown below [PI3K 
signaling pathway in glucose metabolism]
GSK3 = Glycogen synthase kinase 3
IRs = insulin receptors
PD = pharmacodynamic
pAKT = phosphorylated protein kinase B (phospho-AKT)
PI3K = phosphatidylinositol 3-kinase
RTKs = receptor tyrosine kinases
Table 9–5: Pharmacodynamic sampling
Pharmacodynamic measurements
Sampling time point
Plasma lactate levels on Day 1 and 8
0 (pre-dose before drug administration), 30 min, 
and 1, 2, 4, 6, 8, 12 and 24 h
Glucose, insulin and c-peptide on Day 1 and 8
0 (pre-dose before drug administration) 30 min, 
and 1, 2, 4, 6, 8, 12 and 24 h
9.6
Safety
9.6.1
Adverse events
9.6.1.1
Definitions
Definition of adverse event (AE)
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject after providing written informed consent for participation in the 
study.  Therefore, an AE may or may not be temporally or causally associated with the use of 
a medicinal (investigational) product.


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A surgical procedure that was planned prior to the start of the study by any physician treating 
the subject should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE).
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal e.g. physical examination findings, symptoms, diseases, laboratory, ECG.

Conditions that started before signing of informed consent and for which no 
symptoms or treatment are present until signing of informed consent are recorded 
as medical history (e.g. seasonal allergy without acute complaints).

Conditions that started before signing of informed consent and for which 
symptoms or treatment are present after signing of informed consent, at unchanged 
intensity, are recorded as medical history (e.g. allergic pollinosis).

Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events.  This includes intercurrent illnesses.
Definition of serious adverse event (SAE)
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f):
a.
Results in death
b. Is life-threatening
The term ‘life-threatening’ in the definition refers to an event in which the subject was 
at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met:
- The admission results in a hospital stay of less than 12 hours
- The admission is pre-planned
(e.g. elective or scheduled surgery arranged prior to the start of the study; 
admission is part of the study procedures as described in Section 9.2)
- The admission is not associated with an AE 
(e.g. social hospitalization for purposes of respite care).
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
d. Results in persistent or significant disability / incapacity
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
e.
Is a congenital anomaly / birth defect
f.
Is another serious or important medical event as judged by the investigator


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9.6.1.2 Classifications for adverse event assessment
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.
9.6.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1.
9.6.1.2.2
Intensity
The intensity of an AE is classified according to the following categories:
-
Mild (A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living)
-
Moderate (A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the research participant)
-
Severe (A type of AE that requires intensive therapeutic intervention. The event
interrupts usual activities of daily living, or significantly affects clinical status. The event 
possesses a significant risk of harm to the research participant and hospitalization may be 
required).
9.6.1.2.3
Causal relationship
The assessment of the causal relationship between an AE and the administration of treatment 
is a decision to be made by the investigator, who is a qualified physician, based on all 
information available at the time of the completion of the CRF.
Causality should be assessed separately for each study treatment as detailed in the CRF.  If the 
investigator feels that the event cannot be firmly attributed to one of the study treatments 
(e.g. owing to a suspected underlying interaction), the same assessment will be documented 
for each study treatment.
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.
Possible answers are “yes” or “no”.
An assessment of “no” would include:
1. The existence of a highly likely alternative explanation, e.g. mechanical bleeding at 
surgical site.
or
2. Non-plausibility, e.g. the subject is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
developing a few days after the first drug administration.
An assessment of “yes” indicates that that the AE is reasonably associated with the use of the 
study treatment.


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Important factors to be considered in assessing the relationship of the AE to study treatment 
include:
- The temporal sequence from drug administration:  The event should occur after the drug 
is given.  The length of time from drug exposure to event should be evaluated in the 
clinical context of the event.
- Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge): Subject’s response after de-challenge or re-challenge should be 
considered in view of the usual clinical course of the event in question.
- Underlying, concomitant, intercurrent diseases:  
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the subject may have.
- Concomitant medication or treatment: 
The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them might have caused the event in question.
- Known response pattern for this class of drug: Clinical/preclinical
- Exposure to physical and/or mental stresses: The exposure to stress might induce adverse 
changes in the recipient and provide a logical and better explanation for the event
- The pharmacology and PK of the study treatment: 
The PK properties (absorption, distribution, metabolism and excretion) of the study 
treatment, coupled with the individual subject’s pharmacodynamics should be 
considered.
Causal relationship to protocol-required procedure(s)
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s).
Possible answers are “yes” or “no”.
9.6.1.2.4
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.
The study treatment action should be recorded separately for each study treatment as detailed 
in the CRF.
- Drug withdrawn
- Drug interrupted
- Not applicable
- Unknown
9.6.1.2.5
Other specific treatment(s) of adverse events
- None
- Remedial drug therapy
- Other


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9.6.1.2.6
Outcome
The outcome of the AE is to be documented as follows: 
- Recovered/resolved
- Recovering/resolving
- Recovered/resolved with sequelae
- Not recovered/not resolved
- Fatal
- Unknown
9.6.1.3
Assessments and documentation of adverse events
The investigator has to record on the respective CRF pages all AEs occurring in the period 
between the signing of the informed consent and the end of the follow-up phase (30 to 
35 days after last dose of study medication). AEs observed, mentioned upon open 
questioning by a member of the investigator’s team, or spontaneously reported by the subject 
will be documented. After the end of the follow-up phase, there is no requirement to actively 
collect AEs including deaths. In case of ongoing AEs after the last follow-up visit –
especially when related to treatment with the study medication – the respective AE will be 
followed until resolution, if possible.
The type of information that should be assessed and recorded by the investigator for each AE 
is listed in Section 9.6.1.2. The date and time of onset will be recorded.
“Death” should not be recorded as an AE on the AE page.  Instead, “death” is the outcome of 
underlying AE(s).
For all SAEs the sponsor has to carry out a separate assessment for expectedness, seriousness 
and causal relationship to study drug.
9.6.1.4
Reporting of serious adverse events
The definition of SAEs is given in Section 9.6.1.1.  Each SAE must be followed up until 
resolution or stabilization by submission of updated reports to the designated recipient.
Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs.  This information, including all relevant contact 
details, is summarized in the investigator site file.  This information will be updated as 
needed.
The investigator must report immediately (within 24 hours of the investigator’s awareness) all 
SAEs occurring during the observation period defined in Section 9.6.1.3 to the recipient 
detailed in the instructions for SAE reporting included in the Investigator File.  For this, an 
AE page in the CRF must be completed for each SAE.
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.
In each case of fatal or life-threatening reaction, the investigator must seek relevant follow-up 
information and must complete a follow-up report to be faxed to the sponsor as soon as 
possible but not later than 8 calendar days after the initial report is sent.


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For all SAEs, the investigator is required to document in full, the course of the SAE and any 
therapy given, including any relevant findings / records in the report.
Notification of the IECs / IRBs
Notification of the independent ethics committees (IECs) / institutional review boards (IRBs)
about all relevant events (e.g. SAEs, suspected unexpected serious adverse reactions 
[SUSARs]) will be performed by the sponsor and/or by the investigator according to all 
applicable regulations.
Notification of the authorities
The processing and reporting of all relevant events (e.g. SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (e.g. SUSARs)
according to all applicable regulations.
9.6.1.5 Expected adverse events
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.
Adverse events possibly related to the test drug, copanlisib
For this study, the applicable reference document is the most current version of the IB.
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB.  If relevant new safety information is identified, the information will 
be integrated into an update of the IB and distributed to all participating sites.
Adverse events possibly related to the interaction drug, metformin
For this study, the applicable reference document is the summary of product characteristics of 
metformin (6).
Very common side effects (1/10): gastrointestinal disorders such as nausea, vomiting, 
diarrhoea, abdominal pain and loss of appetite. These undesirable effects occur most 
frequently during initiation of therapy and resolve spontaneously in most cases.
Common side effects (>1/100 and <1/10): taste disturbance
Very rare side effects (<1/10,000): skin reactions such as erythema, pruritus, and urticaria; 
lactic acidosis.
Frequency not known: isolated reports of liver function tests abnormalities or hepatitis 
resolving upon metformin hydrochloride discontinuation.


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Expected conduct-related AEs
The frequent blood sampling (by single vein puncture and / or indwelling cannula) may be 
accompanied by mild pain, hematoma and in rare cases inflammation of the vessel wall or 
injury of a nerve. Awareness should be raised to the possibility of a vasovagal attack or 
syncope (marked by pallor, nausea, sweating, bradycardia, decrease in arterial blood pressure 
which, when below critical level, results in dizziness and /or loss of consciousness) during the 
sampling procedure.
The use of adhesive electrodes (ECG leads) and / or adhesive dressings may be accompanied 
by mild and transient reddening and / or itching of the skin.
9.6.1.6
Adverse events of special safety interest
Copanlisib is an investigational drug and current knowledge of the AEs associated with this 
compound is limited.  As with any new chemical entity, there is always potential for 
unexpected AEs, including hypersensitivity reactions. 
Based on data from prior and ongoing clinical studies with copanlisib, as soon as there is 
reasonable suspicion of the following AE, the investigator should immediately notify the 
sponsor as outlined in Section 9.6.1.4, regardless of whether the investigator assessed the AE 
as serious or non-serious:

Non-infectious pneumonitis.
9.6.1.7
Recommendations for the management of specific adverse events
9.6.1.7.1
Management of glucose increases that can occur with study treatment
Asymptomatic transient glucose increases
Mild to moderate asymptomatic increases of blood glucose may occur after study drug 
infusion, with larger increases potentially occurring post-prandial. Transient asymptomatic 
glucose increases that are ≤250 mg/dL do generally not require treatment with glucose-
lowering medication. Subjects with post-dose blood glucose >250 mg/dL should have 
repeated laboratory glucose measurements to verify if the values are persistent or decreasing. 
If the repeated glucose values are decreasing, glucose levels may be followed without 
glucose-lowering medication if the subject is asymptomatic and if hydration status is normal 
as clinically assessed.
In the event that results of the plasma glucose testing are not available, capillary glucose 
measurements may be used to manage the safety of the subject.
Symptomatic or persisting glucose increases
Hydration status: If the subject has symptomatic glucose increase of any grade, hydration 
status should be clinically assessed. If the clinical assessment is consistent with dehydration, 
fluids should be given as clinically appropriate (orally or i.v.).
Glucose-lowering medication: Subjects with post-dose blood glucose >250 mg/dL should 
have repeated laboratory glucose measurements to verify if values are persistent or 
decreasing. If a blood glucose level of >250 mg/dL persists upon confirmation by repeated 
laboratory analysis, and/or the subject is symptomatic, and/or the hydration status indicates 
the need for hydration, glucose-lowering medication should be administered: Rapid or short-
acting (regular) insulin may be given for blood glucose levels that are persisting at 
>250 mg/dL, or if the subject is symptomatic during the infusion day. “Sliding scale” short-


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acting or (regular) insulin coverage of blood glucose levels that are persisting at >250 mg/dL 
is recommended, with oral or i.v. hydration as clinically appropriate. Only the use of short-
acting (rapid-acting) insulin is recommended for treatment of glucose increases after the 
single dose copanlisib infusion in non-diabetic subjects. Meal timing is added to the glucose 
management log used by the investigator and to be continued as long as hyperglycemia 
induced by the copanlisib infusion persists.
Monitoring during the study
Subjects should be kept on ward as long as the post-dose glucose level is >250 mg/dL.
Table 9–6: Management of transient post-infusion glucose increases
Criteria
Recommendation
Suggested treatment
Asymptomatic glucose 
increases ≤ 250mg/dL
Does not generally require treatment 
with glucose lowering medication
None
Asymptomatic glucose 
increase > 250 mg/dL
-
Should have repeated laboratory 
glucose determination.
-
If the repeated glucose value is 
decreasing, the glucose may be 
followed without glucose lowering 
medication treatment if hydration 
status is normal as clinically 
assessed.
-
Consultation with endocrinologist 
is recommended
-
Hydration if appropriate
Symptomatic or persisting 
glucose increases 
> 250mg/dL
-
Hydration status should be 
clinically assessed.
-
If clinical assessment is consistent 
with dehydration, fluids should be 
given as clinically appropriate 
(orally or i.v.).
-
Laboratory test confirming 
increase should be repeated.
If the repeated glucose value is 
persistent and/or patient is 
symptomatic and/or the hydration 
status indicates the need for 
hydration, glucose lowering 
medication should be 
administered.
-
Prompt input from a diabetes 
specialist should be obtained.
-
Hydration if appropriate
-
Rapid/ short acting insulin 
may be given for glucose 
persisting at > 250 mg/dL, 
or if the patient is 
symptomatic during the 
infusion day.
-
Rapid/short acting insulin 
according to the institution 
sliding scale coverage of 
glucose persisting at 
> 250 mg/dL is 
recommended, with oral or 
i.v. hydration as clinically 
appropriate.
9.6.1.7.2
Treatment of arterial hypertension associated with copanlisib
The management of acute arterial hypertension following copanlisib will need to be 
individualized for each subject, but the experience in Phase I studies on copanlisib has 
suggested the benefit of dihydropyridine calcium channel blockers (i.e. amlodipine, 
felodipine). Topical nitrates, verapamil and diltiazem (nondihydropyridine calcium channel 
blockers) can be also considered. If arterial hypertension (≥160/100 mmHg) occurs during 


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copanlisib i.v. infusion, the copanlisib i.v. infusion should be interrupted or slowed down, 
administration of anti-hypertensive therapy initiated and copanlisib infusion may be resumed 
when BP has returned to <150/90 mmHg.
9.6.1.7.3
Treatment of vomiting and diarrhea
Adequate hydration through appropriate fluid maintenance is essential for the treatment of 
diarrhea or vomiting. Anti-diarrhea medications may be introduced if symptoms occur.
9.6.2
Pregnancies
A subject’s participation is to be terminated immediately if a pregnancy is supposed (i.e. in 
case her pregnancy test becomes positive).
The investigator must report to the sponsor any pregnancy occurring in a female study subject 
during her participation in this study.  The outcome of the pregnancy should be followed up 
carefully, and any outcome of the mother and the child at delivery should be reported.
The child’s health should be followed up until 1 year.
For a pregnancy in the partner of a male study subject, all efforts will be made to obtain 
similar information on course and outcome, subject to the partner’s consent.
For all reports, the forms provided are to be used.  The investigator should submit them within 
the same timelines as an SAE.  
9.6.3
Further safety
In the event of implausible results, the laboratory may measure additional parameters to 
assess the quality of the sample (e.g. clotted or hemolyzed) and to verify the results.  The 
results from such additional analyses may neither be included in the clinical database of this 
study nor evaluated further.  If the results are relevant, the investigator will be informed to 
determine follow-up activities outside of this protocol.
The following safety examinations will be performed at the time points specified in the study 
flowcharts in Section 16.1.
9.6.3.1
Body weight and height, BMI
Body weight will be measured by a member of the investigator’s team under the following 
conditions:

Subject in underwear and without shoes after having emptied his/her bladder

Electronic physician (column) scale with digital display, measurement units 0.1 kg
The subject’s height will be measured (without shoes) to calculate the BMI.
9.6.3.2
Physical examination
The physical examination (by means of inspection, palpation, auscultation) will be performed 
by a physician at the study site covering at least the organs of the cardiovascular, respiratory, 
and abdominal system. The physical examination also includes a basic neurological 
examination.
Abnormal physical examination findings are recorded either as medical history or as AEs (see 
Section 9.6.1.1).


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9.6.3.3
Blood pressure/pulse rate and temperature
Systolic and diastolic blood pressure and pulse rate will be measured by a member of the 
investigator’s team under the following conditions:

Position: Supine (small pillow under head allowed) for at least 10 min

Measuring site: cuff to be placed on the right/left upper arm (if possible, the same 
arm will be used for all measurements in one subject); cuff location will be 
documented

Method: oscillometric by automatic measurement device
Body temperature will be measured by a member of the investigator’s team using always the 
same method according to local practice. The measured values are to be recorded in the 
electronic CRF in degree Celsius (°C).
9.6.3.4
Electrocardiogram
A complete standard 12-lead ECG will be recorded by a member of the investigator’s team 
under the following conditions:

Position: supine (small pillow under head allowed) for at least 10 min

Device: computerized ECG device

Automatic calculation of the following parameters: RR interval, pulse rate, 
P-duration, PR (PQ) interval, QRS-duration, QT / QTcB / QTcF interval 
(uncorrected and corrected QT interval according to Bazett’s / Fridericia’s
formula); corrected QT intervals of different calculation will be provided during 
data evaluation process

Evaluation of ECG by a site physician providing an overall assessment (including 
clinical relevance)
QTcB and QTcF provided by the ECG device will be used only for local safety evaluation by 
the investigator. For data analysis by the sponsor, the frequency-corrected QT interval will be 
calculated according to both the formulae of Bazett (QTcB) and Fridericia (QTcF).
9.6.3.5
Laboratory examinations
Blood and urine samples will be collected by a member of the investigator’s team.  For time 
points and parameters see Section 16.1 and Section 16.2 in the appendix.
9.7
Other procedures and variables
Not applicable.
9.8
Appropriateness of procedures / measurements
All PK, PD and safety parameters, as well as the methods to measure them, are standard 
variables/ methods in clinical studies and/ or clinical practice. They are widely used and 
generally recognized as reliable, accurate and relevant.


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10.
Statistical methods and determination of sample size
10.1
General considerations
Statistical analysis will be performed using the software package SAS release 9.2 or higher 
(SAS Institute Inc., Cary, NC, USA).
All data will be listed and summary tables will be provided where appropriate. Quantitative 
data will be described by the following summary statistics: arithmetic mean, standard 
deviation, median, minimum and maximum. Whenever appropriate, summary statistics will 
be provided for the original data as well as for the change versus baseline. Graphical 
illustrations will be provided where appropriate. Frequency tables will be provided for 
qualitative data.
10.2
Analysis sets
Safety Analysis Set
All subjects who received at least one dose of the study medication will be included in the 
safety evaluation.
The PD data will also be analyzed using the Safety Analysis Set.
PK Analysis Sets
All subjects with a valid PK profile for metformin will be included in the PK set (PKS) for 
analyzing and evaluating the PK profile of metformin.
All subjects with a valid PK profile for metformin both alone and in combination with 
copanlisib will be included in the per-protocol set (PPS) for analyzing and evaluating the
effect of copanlisib on the PK profile of metformin.
10.3
Variables and planned statistical analyses
The primary and secondary variables are specified in Section 5.
Pharmacokinetic parameters are specified in Section 9.5.1.2.
Pharmacodynamic variables are specified in Section 9.5.2.
Safety variables are specified in Section 9.6

Demographic and other baseline characteristics
Summary statistics (arithmetic mean, standard deviation, median, minimum and maximum for 
quantitative variables) will be presented. Frequency tables for qualitative data will be 
provided. Medical history findings will be summarized using medical dictionary for 
regulatory activities (MedDRA) terms.

Safety examinations
Individual listings of AEs will be provided. The incidence of treatment-emergent AEs and
drug-related AEs, respectively, will be summarized using MedDRA terms. Listings of deaths, 
SAEs and AEs leading to discontinuation will be provided.
AEs are considered to be treatment-emergent if they start or worsen after first administration 
of study medication up to 30 days after end of treatment with study medication.


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Quantitative data (hematology, blood chemistry, vital signs, ECG) will be summarized.
These summary statistics will be presented for the original data as well as for the difference to 
baseline. Frequency tables will be provided for qualitative data. Laboratory data outside the 
reference range will be listed and flagged with ‘L’ for low and ‘H’ for high. Additional tables 
with all abnormal values will be presented.

Pharmacodynamic data
Plasma lactate levels, glucose, insulin and c-peptide will be summarized by treatment 
conditions (Day 1 and Day 8) for the original data as well as for the difference from baseline.  
Maximum change from baseline on Day 1 and Day 8 will also be summarized.

Pharmacokinetic data
The concentration–time data of all analytes will be tabulated by treatment condition. The 
following statistics will be calculated for each plasma sampling point: arithmetic mean,
standard deviation and coefficient of variation (CV), geometric mean, geometric standard
deviation (re-transformed standard deviation of the logarithms) and CV, minimum, median,
maximum value and the number of measurements. Means at any time will only be calculated
if at least 2/3 of the individual data were measured and were above the lower limit of
quantification (LLOQ). For the calculation of the mean value a data point below LLOQ will
be substituted by one half of this limit. In tables showing mean values, where values below
LLOQ are included in the calculation of mean values, these means will be marked.
Individual and geometric mean concentration versus time profiles of all analytes (by using the 
actual sampling times for individual plots and the planned sampling times for mean plots) will 
be plotted on both linear and semi-logarithmic axes. Optionally the amount (%) of metformin 
excreted into urine will be graphically illustrated by treatment condition for each sampling 
interval as well as for the whole sampling period (bar-charts for the individual data and for the 
arithmetic means including standard deviation).
Pharmacokinetic characteristics (except tmax) will be summarized by the statistics mentioned 
above. Tmax will be described utilizing minimum, maximum and median as well as frequency 
counts.
To investigate the primary objective of this study regarding the effect of copanlisib on 
metformin, an exploratory analysis of variance (ANOVA) with terms of treatment condition 
and subject will be performed on the natural logarithmic transformation of PK parameters 
(AUC, AUC(0-24) and Cmax) of metformin. The estimate and 90% confidence interval of the 
Day 8 (with copanlisib) to Day 1 (without copanlisib) ratio of Cmax, AUC(0-24) and AUC for 
metformin are derived by inverse transformation of the estimates and the 90% confidence 
interval of the least squares mean differences that are obtained from the model above.
10.4
Determination of sample size
No formal statistical sample size estimation has been performed for this clinical study. The 
planned sample size of a minimum of 12 evaluable subjects is based on empirical 
considerations and is considered sufficient for drug-drug interaction and in humans.
Using previously reported metformin PK data in healthy volunteers (7), the inter-subject 
standard deviation (SD) for log-transformed AUC and Cmax was estimated as 0.23 and 0.29 
respectively. To be on the conservative side for the current study, we assume the intra-subject 
SD of 0.23 for log-transformed AUC and AUC(0-24), and 0.29 for log-transformed Cmax. 


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With 12 evaluable subjects, 90% confidence intervals for the ratio “Day 8 (with copanlisib) / 
Day 1 (without copanlisib)” for metformin AUC and Cmax are provided in Table 10–1.
Table 10–1: 90% Confidence interval for metformin with N=12
90% CI for metformin
Observed Ratio
AUC (SD=0.23,
factor=1.184)
Cmax (SD=0.29, 
factor=1.237)
1
(0.845, 1.184)
(0.808, 1.237)
1.1
(0.929, 1.302)
(0.889, 1.361)
1.2
(1.014, 1.42)
(0.970, 1.484)
1.3
(1.098, 1.539)
(1.051, 1.608)
CI = confidence interval
10.5
Planned interim analyses
No interim analysis is planned.
11.
Data handling and quality assurance
11.1
Data recording
The data collection tool for this study will be a validated electronic data capture system called 
RAVE.  Subject data necessary for analysis and reporting will be entered/transmitted into a 
validated database or data system (SAS).
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet based electronic data capture (EDC) software system RAVE, 
which Bayer has licensed from Medidata Solutions Worldwide.  RAVE has been validated by 
Medidata Solutions Worldwide and Bayer for use in its clinical studies.  RAVE allows for the 
application of software logic to set-up data entry screens and data checks to ensure the 
completeness and accuracy of the data entered by the site personnel.  Bayer extensively 
applies the logic to ensure data are complete and reflect the clinical data requirements of the 
study.  Data queries resulting from the application of the software logic are resolved by the 
site personnel.  The data are stored at a secure host facility maintained by Medidata Solutions 
Worldwide and transferred to Bayer’s internal computer system via a secure Virtual Private 
Network.
All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software.  All internal Bayer and external investigator site personnel seeking 
access must go through a thorough RAVE training process before they are granted access to 
RAVE for use in Bayer's clinical studies.  Training records are maintained.
All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner.
The RAVE System contains a system-generated audit trail that captures any changes made to 
a data field, including who made the change, why the change was made and the date and time 
it was made.  This information is available both at the investigator’s site and at Bayer.  Data 
entries made in the RAVE EDC screens are supported by source documents maintained for all 
subjects enrolled in this study.


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Source documentation
The site must implement processes to ensure availability of all required source 
documentation.  A source document checklist (not part of this protocol) will be used at the 
site to identify the source data for key data points collected and the monitor will work with the 
site to complete this.
It is the expectation of the sponsor that all data entered into the CRF has source 
documentation available at the site.
Data recorded from screening failures
At minimum, the following data should be recorded in the CRF:

Demographic information (subject number; year of birth / age; sex; if applicable race / 
ethnicity)

Date of informed consent

Relevant inclusion/exclusion criteria

Reason for premature discontinuation

Date of last visit.
These data will be transferred to the respective database.
For screening failures with an SAE, the following data should be collected in the CRF in 
addition to the data specified above:

All information related to the SAE such as: 
- The SAE itself
- Concomitant medication
- Medical history
- Other information needed for SAE complementary page
11.2
Monitoring
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements.  When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items.
The sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate and complete.  
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes). 

Safety and rights of subjects are being protected

Study is conducted in accordance with the currently approved protocol 
(including study treatment being used in accordance with the protocol)

Any other study agreements, GCP, and all applicable regulatory requirements are 
met.


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The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.
11.3
Data processing
Data will be collected as described in Section 11.1.  Clinical data management will be 
performed in accordance with applicable sponsor’s/CRO’s standards and data cleaning 
procedures.  This is applicable for data recorded on CRF as well as for data from other 
sources (e.g. laboratory, ECG, adjudication committees).
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used.
Bioanalytical results for PK evaluation will electronically be transferred from the 
Bioanalytical Department to Data Management using a predefined uniform file format. Data 
Management will include these data in the corresponding SAS data repository. Data 
Management will create a transfer file containing the bioanalytical results, demographic data, 
dosing data, and actual dosing and sample collection times and will electronically send this 
file to Clinical Science. Clinical Science will calculate the PK parameters indicated in this 
protocol as described in Section 9.5.1.2. The finalized evaluation will electronically be 
transferred to Data Management where all data will be included in the corresponding SAS 
data repository. All electronic file transfer processes will follow validated procedures.
11.4
Missing data
The occurrence of missing values is expected to be very low in this 8-day study. The 
imputation of missing data is not planned. All available data will be used for statistical 
analysis. Further information will be provided in the SAP.
11.5
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there.  The 
investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible.  The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues.  Audits and inspections may occur at any time during or after 
completion of the study.
11.6
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution or private practice.  Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 


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alternative arrangements must be made to ensure the availability of the source documents for 
the required period.
The investigator/institution notifies the sponsor if the archival arrangements change 
(e.g. relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The contract with the investigator/institution will contain all regulations relevant for the study 
center.
12.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. treatment arms; dose steps; centers]) at any time, which may be due but not limited to the 
following reasons: 

If risk-benefit ratio becomes unacceptable owing to, for example,
o
Safety findings from this study (e.g. SAEs)
o
Results of any interim analysis
o
Results of parallel clinical studies
o
Results of parallel animal studies 
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity).

If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable 
time frame.
The investigator has the right to close his/her center at any time.
For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties.  Final 
decision on the closure must be in writing.

All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study 
center; head of study center) must be informed as applicable according to local 
law.

All study materials (except documentation that has to remain stored at site) must 
be returned to the sponsor.  The investigator will retain all other documents until 
notification is given by the sponsor for destruction.

In the event of a partial study closure, ongoing subjects, including those in post 
study follow-up, must be taken care of in an ethical manner.
Details for individual subject’s withdrawal can be found in Section 6.4.1.


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13.
Ethical and legal aspects
13.1
Investigator(s) and other study personnel
Sponsor’s Medical Expert
Name:
Title:
Address:
Bayer AG
Drug Discovery, Pharmaceuticals
Clinical PD ONC I
Building P300 
13342 Berlin, Germany
Phone:
Principal investigator for the Study
Name:
Title:
Address:
Phone:
Fax:
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate.  This list will be updated as needed; an 
abbreviated version with personnel relevant for the center will be available in the investigator 
site file.
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site.
The principal investigator must sign the protocol signature page and must receive all required 
external approvals (e.g. health authority, ethics committee, sponsor) before subject 
recruitment may start.  Likewise, all amendments to the protocol must be signed by the 
principal investigator and must have received all required external approvals before coming 
into effect at the center.
13.2
Funding and financial disclosure
Funding
This study will be funded by its sponsor.
Financial disclosure
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research subjects has to provide a financial disclosure 
PPD
PPD
PPD
PPD


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according to all applicable legal requirements.  All relevant documentation will be filed in the 
trial master file.
13.3
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
Good Clinical Practice (GCP) guidelines and the guiding principles detailed in the 
Declaration of Helsinki.  The study will also be carried out in keeping with applicable local 
law(s) and regulation(s).
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations.  When necessary, an extension, amendment or renewal of the IEC/IRB 
approval must be obtained and also forwarded to the sponsor.  The responsible unit (e.g. 
IEC/IRB, head of the study center/medical institution) must supply to the sponsor, upon 
request, a list of the IEC/IRB members involved in the vote and a statement to confirm that 
the IEC/IRB is organized and operates according to GCP and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.  
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties.  However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial subjects without prior IEC/IRB/sponsor approval/favorable opinion.  As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/sponsor.  Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.
13.4
Subject information and consent
All relevant information on the study will be summarized in an integrated subject information 
sheet and informed consent form provided by the sponsor or the study center.  A sample 
subject information and informed consent form is provided as a document separate to this 
protocol.
Based on this subject information sheet, the investigator or designee will explain all relevant 
aspects of the study to each subject, prior to his/her entry into the study (i.e. before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms).
The investigator will also mention that written approval of the IRB/IEC has been obtained.


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Each subject will be informed about the following aspects of premature withdrawal:
Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision.  
The subject’s consent covers end-of-study examinations as specified in the visit 
description described in Section 9.2 to be conducted after withdrawal of consent.
The subject’s data that have been collected until the time of withdrawal will be retained 
and statistically analyzed in accordance with the statistical analysis plan. 
Subject-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. image reading, analysis of biological specimen such as 
blood, urine or tissues); these data would also be retained and statistically analyzed in 
accordance with the statistical analysis plan.  The subject has the right to object to the 
generation and processing of this post-withdrawal data. The subject’s oral objection may 
be documented in the subject’s source data.
Each subject will have ample time and opportunity to ask questions.
Only if the subject voluntarily agrees to sign the informed consent form and has done so, may 
he/she enter the study.  Additionally, the investigator will personally sign and date the form.  
The subject will receive a copy of the signed and dated form.
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the subject’s note/file of the medical institution.
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject’s clinical record must clearly show that informed 
consent was obtained prior to these procedures.
The informed consent form and any other written information provided to subjects will be 
revised whenever important new information becomes available that may be relevant to the 
subject’s consent, or there is an amendment to the protocol that necessitates a change to the 
content of the subject information and/or the written informed consent form.  The investigator 
will inform the subject of changes in a timely manner and will ask the subject to confirm 
his/her participation in the study by signing the revised informed consent form.  Any revised 
written informed consent form and written information must receive the IEC/IRB’s approval / 
favorable opinion in advance of use.
13.5
Publication policy and use of data
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov.
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations.  The sponsor is interested in the publication of the 
results of every study it performs.
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study.  However, the investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 


Clinical Study Protocol
No.  BAY 80-6946 / 19951
15 May 2018
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Page: 56 of 63
publication manuscript before its submission.  To this end, the investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract.  
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript.
13.6
Compensation for health damage of subjects / insurance
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.
13.7
Confidentiality
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Subject names will not be supplied to the sponsor.  Only the subject number will be recorded 
in the CRF, and if the subject name appears on any other document (e.g. pathologist report), it 
must be obliterated before a copy of the document is supplied to the sponsor.  Study findings 
stored on a computer will be stored in accordance with local data protection laws.  As part of 
the informed consent process, the subjects will be informed in writing that representatives of 
the sponsor, IEC/IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws.
If the results of the study are published, the subject’s identity will remain confidential.
The investigator will maintain a list to enable subjects to be identified.
14.
Reference list
1.
Stage TB, Brøsen K, Christensen MM. A Comprehensive Review of Drug-Drug 
Interactions with Metformin. Clin Pharmacokinet. 2015 Aug;54(8):811-24
2.
Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, et al. Clinical 
pharmacokinetics of metformin. Clin Pharmacokinet. 2011 Feb;50(2):81-98
3.
Gerisch M, Schwarz T, Lang D, Rohde G, Reif S, Genvresse I, et al. Pharmacokinetics 
of intravenous pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor 
[14C]copanlisib (BAY 80-6946) in a mass balance study in healthy male volunteers. 
Cancer Chemother Pharmacol. 2017 Sep;80(3):535-44
4.
Johansson S, Read J, Oliver S, Steinberg M, Li Y, Lisbon E, et al. Pharmacokinetic 
Evaluations of the co-administrations of Vandetanib and Metformin, Digoxin, 
Midazolam, Omeprazole or Ranitidine. Clinical Pharmacokinet. 2014;53:837-47
5.
Howlett HC, Bailey CJ. A risk-benefit assessment of metformin in type 2 diabetes 
mellitus. Drug Saf. 1999 Jun;20(6):489-503
6.
Glucophage 500 mg film coated tablets (Summary of Product Characteristics). Merck. 
Updated 19-Jan-2017
7.
Shin D, Cho YM, Lee S, Lim KS, Kim JA, Ahn JY, et al. Pharmacokinetic and 
pharmacodynamic interaction between gemigliptin and metformin in healthy subjects. 
Clin Drug Investig. 2014 Jun;34(6):383-93


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15 May 2018
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15.
Protocol amendments
Not applicable.


Clinical Study Protocol
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16.
Appendices
16.1
Study flow chart
Table 16–1 provides a flow chart presenting the assessments conducted during the study; 
Table 16–2 presents the detailed time points for the assessments conducted on Days 1 and 8.
Table 16–1: Study flow chart
Visit 
Screening Day -1 Day 1
Day 7
Day 8
EOT
Day 15-22
Follow
-upa
Informed consent
X
Allocation of Screening Number
X
Demographic data collection
X
Height, weight, BMI
X
Smoking history, alcohol / diet
X
Medical and surgical history
X
Participation in previous clinical studies
X
Current and previous medication
(medication history)
X
X
X
X
X
X
X
Physical examination
X
X
X
X
(X)d
Vital signs: blood pressure, pulse rate, 
temperature
X
X
Xb
X
Xb
X
(X)d
ECG
X
Xb
Xb
X
(X)d
Virology (HIV, HBsAg, Anti HCV-Ab)
X
Urine drug screen
X
Alcohol breath test
X
X
X
Blood samples for safety (clinical 
chemistry, hematology, coagulation)
X
Xbc
Xbc
X
(X)d
HbA1c
X
X
Fasting plasma glucose
Xb
Xb
Urine sample for safety
(dipstick ± sediment)
X
Xbc
Xbc
X
(X)d
Check of inclusion / exclusion criteria
X
X
Metformin administration
X
X
Copanlisib administration
X
Blood samples for PK
Xb
Xb
Urine samples for PK
Xb
Xb
Plasma glucose
Xb
Xb
X
Plasma insulin
Xb
Xb
C-peptide
Xb
Xb
Plasma lactate levels
Xb
Xb
Pregnancy test (blood or urine)
X
Xe
Adverse events
X
X
X
X
X
X
X
a
The follow-up will be conducted by telephone unless an in-house visit is clinically indicated.
b
See Table 16–2 for individual timepoints.
c
Laboratory safety tests may be performed either the day before or on the day of dosing, with the exception of 
plasma glucose, which must be performed on the day of dosing.
d
These tests will be performed if the follow-up is conducted in-house.
e
Pregnancy test, if applicable, if screening pregnancy test was not within the previous 7 days.
BMI = body mass index; ECG = electrocardiogram; EOT = End of treatment; HbA1c = glycated hemoglobin;
HBsAg = Hepatitis B surface antigen; HCV-Ab = hepatitis C virus antibodies; HIV = human immunodeficiency 
virus; PK = pharmacokinetic


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Table 16–2:
Schedule of evaluations: In-house treatment period
Visit 
D-1, D7
Day 1 and Day 8
Relative time
   (day)
D00 and D07
(relative to metformin and
(hour)
Pre-
dose
00
00
00
01
01
02
02
03
04
06
08
10
12
16
24
copanlisib administration)
(minute)
00
10
30
00
30
00
30
00
00
00
00
00
00
00
00
Final eligibility check (Day 1 only)
X
Study drug administration metformin
X
Study drug administration copanlisib (Day 8 only)




Blood sample safety
Xa
X
Blood sample metformin PK
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood sample copanlisib PK (Day 8 only)
X
X
X
X
X
X
X
X
X
Urine sample metformin PK
X
[




][


][

][

][

]
Urine sample safety
Xa
X
Pregnancy test (blood or urine)
Xb
Plasma glucose
X
X
X
X
X
X
X
X
X
Plasma insulin
X
X
X
X
X
X
X
X
X
C-peptide
X
X
X
X
X
X
X
X
X
Plasma lactate levels
X
X
X
X
X
X
X
X
X
Physical examination
X
Blood pressure, pulse rate, temperature 
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
Alcohol breath test
X
Adverse events
X
















Concomitant medication
X
















Fastc
X









D = Day.
a
Laboratory safety tests may be performed either the day before or on the day of dosing, with the exception of plasma glucose, which must be performed on the day of 
dosing
b
Pregnancy test, if applicable, if screening pregnancy test was not within the previous 7 days.
c
Fasting should start at least 10 hours before administration of study medication (drinking of water allowed) and continue until 3 hours after metformin dosing.


Clinical Study Protocol
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Page: 60 of 63
16.2
Laboratory analyses
Detailed information about the collection, processing, storage and shipment of the samples 
will be provided separately e.g. sample handling sheets and/or laboratory manual.
The amount of blood planned to be drawn during the course of this study will be given in the 
Subject Information Sheet and Consent Form.
Table 16-2 provides information on the parameters to be analyzed and indicates the
laboratories to be used.
The safety analyses will be done by the local laboratory except for the urine drug screen and
alcohol breath test which will be performed at the investigational site. The laboratory test
results will be made promptly available to the investigator. Samples collected for non-safety
purposes may be stored under pre-defined conditions until final analysis.
The time of blood samplings are given in the trial flow chart (see Section 16.1).
Refer to Section 9.2.5.2 for alimentary restrictions imposed during the treatment period.
During the study, drug screening or alcohol testing may be carried out without announcement.
A listing including the total amount of blood withdrawn per subject will be stored in the study
files.
In the event of implausible results, the laboratory may measure additional parameters to 
assess the quality of the sample (e.g. clotted or hemolyzed) and to verify the results.  The 
results from such additional analyses may neither be included in the clinical database of this 
study nor evaluated further.  If the results are relevant, the investigator will be informed to 
determine follow-up activities outside of this protocol.


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15 May 2018
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Table 16–3: Parameters of laboratory analyses
Parameters (by category)
Sample destination
Hematology:
Local laboratory
Leukocytes (white blood cell count), erythrocytes, 
hemoglobin, hematocrit, mean corpuscular volume (MCV), 
mean corpuscular hemoglobin (MCH), reticulocytes 
(absolute), platelets, neutrophils, eosinophils, basophils, 
lymphocytes, monocytes
Other:
Glycated hemoglobin (HbA1c) (screening and EOT only)
Clotting status:
Local laboratory
Prothrombin time (sec), reagent-independent prothrombin 
ratio (INR, international normalized ratio), activated partial 
thromboplastin time
Serum chemistry:
Local laboratory
Creatinine, sodium, potassium, calcium, chloride, amylase, 
lipase, total protein, albumin,
creatine kinase, cholesterol (total, high-density lipoprotein 
[HDL]-/low density lipoprotein [LDL]-cholesterol), 
triglycerides, C-reactive protein
Liver function:
Local laboratory
Alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), gamma-glutamyl transferase (GGT), glutamate 
dehydrogenase, alkaline phosphatase, lactate 
dehydrogenase, total bilirubin
Virology:
Local laboratory
HBsAg, anti HCV-Ab, anti-HIV 1+2
Urinalysis – dip stick:
To be performed at study site
pH-value, urobilinogen, erythrocytes, hemoglobin, protein, 
ketone, bilirubin, nitrite, glucose
Urinalysis – sediment:
Local laboratory
Crystals
Urine drug screen:
To be performed at study site
Amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine, methadone, methamphetamine, 
opiates, tricyclic antidepressives, phencyclidin
Alcohol breath test
To be performed at study site
Pharmacokinetic analyses:
Analytical laboratory
Parameters are specified in Section 9.5.1
Pharmacodynamic analyses:
To be performed at study site
Plasma glucose, plasma insulin, C-peptide, plasma lactate 
levels; details are provided in Section 9.5.2


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16.3
Concomitant medication NOT permitted (or to be taken with caution) 
during screening and treatment phase of the study
CYP3A4 inhibitors and inducers are NOT permitted during this study.
Strong CYP3A4 inhibitors
Boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, voriconazole, atazanavir, tipranavir, troleoandomycin, 
elvitegravir, danoprevir, conivaptan, boceprevir, suboxone and 
cobicistat
Strong CYP3A4 inducers
Avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, 
rifabutin, rifampin (rifampicin), St. John's wort (hypericum perforatum) 
and enzalutamide
FDA. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. 
Available online: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIntera
ctionsLabeling/ucm093664.
FDA. Clinical Drug Interaction Studies — Study Design, Data Analysis, and Clinical 
Implications. Guidance for Industry. Draft Guidance (2017). Available from: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/uc
m292362.pdf


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16.4
Estimation of glomerular filtration rate (eGFR) using modification of
diet in renal disease
In accordance with established nephrology practice and guidelines, renal function at baseline 
will be assessed by means of the eGFR, calculated using the abbreviated MDRD Study 
equation.
This equation of 4 variables (serum creatinine level, age, sex, and ethnicity) is recommended 
by the National Kidney Foundation for use in individuals 18 years or older.  The formula is as 
follows:
GFR (mL/min/1.73 m2) = k × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African 
American),
where
k=175 if serum creatinine was measured by methods calibrated to an IDMS reference method.
For the purpose of the study, it is recommended to use the Bayer-verified calculator 
(preferred) or online MDRD GFR calculator at http://mdrd.com/

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
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 
NCT Number: 
NCT03655301 
Document Date: 
14 December 2018 
 


Statistical Analysis Plan
BAY 80-6946 / 19951
Page: 1 of 11:
Title page
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
Effect of copanlisib on metformin PK and PD
Bayer study drug
BAY 80-6946/Copanlisib
Study purpose:
To evaluate the effect of copanlisib on the PK and PD of metformin
Clinical study 
phase:
I
Date:
14 Dec 2018
Study No.:
19951
Version:
1.0
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.
Hence, the appearance of product names without these symbols does not imply that these names are not 
protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


Statistical Analysis Plan
BAY 80-6946 / 19951
Page: 2 of 11:
Table of Contents
Title page................................................................................................................................... 1
Table of Contents ..................................................................................................................... 2
Table of Figures........................................................................................................................ 2
Abbreviations............................................................................................................................ 3
1.
Introduction....................................................................................................................... 5
2.
Study Objectives................................................................................................................ 5
3.
Study Design ...................................................................................................................... 5
4.
General Statistical Considerations .................................................................................. 7
4.1
General Principles............................................................................................................ 7
4.2
Handling of Dropouts ...................................................................................................... 7
4.3
Handling of Missing Data................................................................................................ 7
4.4
Interim Analyses and Data Monitoring ........................................................................... 7
4.5
Data Rules........................................................................................................................ 7
4.6
Blind Review ................................................................................................................... 8
5.
Analysis Sets ...................................................................................................................... 8
5.1
Assignment of analysis sets ............................................................................................. 8
6.
Statistical Methodology .................................................................................................... 9
6.1
Population Characteristics ............................................................................................... 9
6.1.1
Demographic and other baseline characteristics .......................................................... 9
6.1.2
Disposition.................................................................................................................... 9
6.1.3
Medical history............................................................................................................. 9
6.1.4
Prior and concomitant medication................................................................................ 9
6.1.5
Other baseline characteristics....................................................................................... 9
6.2
Efficacy............................................................................................................................ 9
6.3
Pharmacokinetics/pharmacodynamics............................................................................. 9
6.3.1
Pharmacokinetic Data................................................................................................... 9
6.3.2
Pharmacodynamic Data.............................................................................................. 10
6.4
Safety ............................................................................................................................. 11
6.4.1
Adverse Events (AEs) ................................................................................................ 11
6.4.2
Safety examinations.................................................................................................... 11
7.
Document history and changes in the planned statistical analysis............................. 11
8.
References ........................................................................................................................ 11
Table of Figures
Figure 3—1:  Flow chart of study design............................................................................... 6


Statistical Analysis Plan
BAY 80-6946 / 19951
Page: 3 of 11:
Abbreviations
%AE,ur(t1-t2)
percentage of dose excreted into urine from t1 to t2
AUC(tlast-)
percentage of AUC from the last data point > LLOQ to infinity
AE,ur
Amount excreted into urine
%AE,ur
Percentage amount excreted into urine
AE,ur(0-24)
Amount excreted into urine from 0 to 24 hours
AE,ur(t1-t2)
Amount excreted into urine from t1 to t2
AE
adverse event
ANOVA
analysis of variance
AUC
area under the concentration vs. time curve from zero to infinity after single (first) dose
AUC(0-24)
AUC from time 0 to 24 hours
AUC(0-tlast)
AUC from time 0 to the last data point > LLOQ
AUC(0-tlast)u
AUC from time 0 to the last data point > LLOQ of unbound drug 
AUC(tlast-)
AUC from the last data point to infinity
BAY no.
BAY number is the main identifier for compounds within the Bayer Pharmaceuticals 
Organization
CL/F
total body clearance of drug calculated after extravascular administration (e.g. apparent 
oral clearance)
CLR
renal body clearance of drug
Cmax
maximum observed drug concentration in measured matrix after single dose 
administration
C6h
Concentration at 6 hours
C24h
Concentration at 24 hours
CV
coefficient of variation
ECG
electrocardiogram
EOT
End of treatment
i.v.
intravenous
kg
kilogram
LLN
Lower limit of norm (upper limit of normal laboratory values)


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 19951
Page: 4 of 11:
LLOQ
lower limit of quantitation
MATE
Multidrug and toxin extrusion transporter
MedDRA
medical dictionary for regulatory activities
mg
milligram
min
minute
mL
milliliter
NCA
Non compartmental analysis
PD
pharmacodynamics
PK
pharmacokinetics
PKS
pharmacokinetic analysis set
PPS
Per-protocol set
SAE
serious adverse event
SAF
safety analysis set
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
t1/2
half-life associated with the terminal slope
TEAE
treatment-emergent adverse event
tmax
time to reach Cmax (in case of two identical Cmax values, the first tmax will be used)
ULN
upper limit of norm (upper limit of normal laboratory values)
US(A)
United States (of America)
Vz/F
apparent volume of distribution during terminal phase after extravascular administration
WHO DD
World Health Organization Drug Dictionary


Statistical Analysis Plan
BAY 80-6946 / 19951
Page: 5 of 11:
1.
Introduction
Copanlisib (BAY 80-6946) was approved via accelerated approval in the US on 14 SEP 2017, 
as a monotherapy treatment in adult patients with relapsed follicular lymphoma who have 
received 2 prior systemic therapies. Copanlisib is being further developed for the treatment of 
advanced and refractory malignancies either as a single agent or in combination with other 
investigational agents. Copanlisib is the active ingredient (free base) of BAY 84-1236, the 
dihydrochloride salt, which for clinical use is formulated as an intravenous (i.v.) drug product 
solution. 
This study will investigate the effect of copanlisib, a multidrug and toxin extrusion transporter 
(MATE)2-K inhibitor, on the pharmacokinetics (PK) and pharmcodynamics (PD) of 
metformin (substrate drug of MATE2-K) in healthy subjects.
This document is based on the 

Clinical Study Protocol BAY 80-6946 / 19951, Version 1.0, 15 May 2018[1].
This Statistical Analysis Plan (SAP) describes the final analysis of this study. No statistical 
interim analysis will be performed.
2.
Study Objectives
The primary objective of this study is to 

Evaluate the effect of the co-administration of copanlisib on the PK of metformin 
The secondary objectives of this study are to

Assess the safety of copanlisib when administered to healthy subjects in combination 
with metformin

Evaluate the PD effect of copanlisib on metformin in terms of plasma lactate levels
Exploratory objectives of this study are to 

Assess additional copanlisib and metformin PK parameters 

Assess additional PD parameters
3.
Study Design
This study is a phase 1, non-randomized, single-center, open-label study to investigate the 
effect of copanlisib, a MATE2-K inhibitor, on the PK and PD of metformin in healthy 
subjects. 
A total of approximately 15 subjects between the ages of 18 to 45 years will be enrolled, to 
achieve 12 evaluable subjects. 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. After the first dose of 
metformin, there will be a 7-day wash-out before the second dose of metformin with 
copanlisib on Day 8, to assess the effect of copanlisib as a perpetrator on metformin. 
Blood samples will be collected pre- and post-dose, and urine samples will be collected up to 
24 hours for metformin; blood samples will be collected up to 24 hours for copanlisib. 
Additional blood samples will be collected up to 24 hours after each dose of metformin for 
the PD evaluations. 


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 19951
Page: 6 of 11:
Subject will stay in-house at the study site from approximately 12 hours before until 24 hours 
after each dose.
An end of treatment (EOT) visit will be conducted 7 to 14 days after copanlisib dosing. 
Follow-up will be conducted 30 to 35 days after copanlisib dosing.
Figure 3—1: Flow chart of study design
The variables related to each study objective are as below:
Primary variables
The primary variables of this study, to be determined for metformin are:

Cmax, AUC(0-24), and AUC on Day 1 and Day 8
Secondary variable
The secondary variables of this study are :

Frequency/severity of treatment emergent AEs

PD parameter plasma lactate levels and maximum change from baseline on Day 1 and 
Day 8


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 19951
Page: 7 of 11:
Exploratory variable
The exploratory variables of this study are:

Additional PK Parameters for Metformin on Day 1 and Day 8 – %AE,ur, AE,ur, 
%AE,ur(t1-t2),  AE,ur(t1-t2) where t1 and t2 are the start and the stop times of the urine 
collection interval. tmax, VZ/F, CL/F and t1/2; and CLR (calculated as CLR = AEur(0-
24)/AUC(0-24))

Additional PK Parameters for Copanlisib on Day 8 – Cmax, tmax, C6h, C24h and AUC(0-
24)

Additional PD Parameters – Glucose, Insulin and C-Peptide on Day 1 and Day 8
4.
General Statistical Considerations
4.1
General Principles
The statistical evaluation will be performed by using the software package SAS release 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA). 
All data will be listed and analyzed by descriptive statistical methods where appropriate. The 
number of measurements available, mean, standard deviation, minimum, median, and 
maximum will be presented for quantitative data. Whenever appropriate, summary statistics 
will be provided for the original data as well as for the change versus baseline. Graphical 
illustrations will be provided where appropriate. Frequency tables will be provided for 
qualitative data.
The analysis and reporting will be based on the Clinical Pharmacology Standards (CLIPS), 
version 2.0[2], and the Clinical Pharmacology Standard Listings_V1.0_final_09052018, 
version 1.0[3].
4.2
Handling of Dropouts
A subject who discontinues study participation prematurely for any reason is defined as a
“dropout” if the subject has already been administered at least one dose of study medication.
Subjects who drop out or do not receive all doses of study drugs will be replaced to obtain a
minimum of 12 subjects valid for PK of metformin.
4.3
Handling of Missing Data
Missing data will not be replaced. All available data will be used for statistical analysis.
All missing or partial data will be presented in the subject data listing as they are recorded.
4.4
Interim Analyses and Data Monitoring
No formal statistical interim analysis is planned.
4.5
Data Rules
Baseline is defined as the last observation prior to first administration of study medication (at 
Day -1/Day 1). 
In case of more than one measurement at screening, the last observation of those will be used 
for descriptive statistics tables as well as for frequency tables. 


Statistical Analysis Plan
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If multiple measurements for a planned time point except screening are available, the first 
value (i.e. of the planned measurement) will be used for the calculation of descriptive 
statistics.
Measurements at unplanned visits, except for screening, will be listed but not summarized by 
descriptive statistics.
For laboratory data, values incorporated as ‘< x’ into the database will be substituted by 1/2x, 
values incorporated as ‘> x’ will be substituted by ‘x’ itself for calculation of summary 
statistics.
4.6
Blind Review
The results of the final data assessment will be documented in the final list of important 
deviations, validity findings and assignment to analysis sets. Any relevant changes to the 
statistical analysis prompted by the results of the review of study data will be documented in 
an amendment to this SAP.
Relevant changes to the approved SAP requested after Database Release will be described in 
the Clinical Study Report.
5.
Analysis Sets
5.1
Assignment of analysis sets
Final decisions regarding the assignment of subjects to analysis sets will be made during the 
review of study data and documented in the final list of important deviations, validity findings 
and assignment to analysis sets (see Section 4.6).
Safety Analysis Set (SAF)
All subjects who received at least one dose of the study medication will be included in the 
safety evaluation.
Safety evaluation will be done on the SAF. The PD data will also be analyzed using the 
Safety Analysis Set.
Pharmacokinetic Analysis Set (PKS)
All subjects with a valid PK profile for metformin will be included in the PKS for analyzing 
and evaluating the PK profile of metformin.
Per-protocol set (PPS)
All subjects with a valid PK profile for metformin both alone and in combination with 
copanlisib will be included in the PPS for analyzing and evaluating the effect of copanlisib on 
the PK profile of metformin.
In case, the number of subjects are identical in the PKS compared to the PPS, then the 
analysis will be done only on the PPS.


Statistical Analysis Plan
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6.
Statistical Methodology
6.1
Population Characteristics
6.1.1
Demographic and other baseline characteristics
Demographic and other baseline characteristics will be performed on the SAF. 
Demographic data will be summarized using descriptive statistics (arithmetic mean, standard 
deviation, median, minimum and maximum for quantitative variables). Frequency tables for 
qualitative data will be provided. 
6.1.2
Disposition
Disposition at the end of screening will be summarized for all enrolled subjects. Disposition 
at the end of treatment and for follow-up will be summarized for all subjects assigned to 
treatment.
6.1.3
Medical history
Medical history findings will be summarized using the most recent effective version of 
Medical Dictionary for Regulatory Activities (MedDRA, version 21.0 or higher) terms. 
6.1.4
Prior and concomitant medication
The number of subjects that used prior medications (medications that began before the start of 
the study drug and are ongoing after administration of study drug) and/or concomitant 
medications (medications that began after the administration of study drug) will be analyzed 
separately by using frequency tables based on classified data. Concomitant and prior 
medication data will be classified according to the most recent effective WHO-DD version.
6.1.5
Other baseline characteristics
Data collected on smoking and alcohol consumption will be summarized and listed as 
appropriate.
6.2
Efficacy
Not applicable
6.3
Pharmacokinetics/pharmacodynamics
6.3.1
Pharmacokinetic Data
Non compartmental analysis (NCA)
The PK parameters will be calculated by the PK scientist/expert group and provided to the 
Statistical Analysis team for  further analysis. Based on the concentration time data, the 
following calculated PK parameters will be provided:
Main PK Parameters: Metformin:
Day 1 and Day 8 : Cmax, AUC(0-24) and AUC
Additional parameters: Metformin:
Day 1 and Day 8: 
%AE,ur, AE,ur, %AE,ur(t1-t2), AE,ur(t1-t2) where t1 and t2 are the start 
and the stop times of the urine collection interval 


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 19951
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tmax, VZ/F, CL/F, t1/2, and CLR (calculated as CLR = AE,ur(0-24)/AUC(0-
24))
Copanlisib:
Day 8 : Cmax, tmax, C6h, C24h and AUC(0-24)
The concentration–time data of all analytes will be tabulated by treatment condition. The 
following statistics will be calculated for each plasma sampling point: arithmetic mean, 
standard deviation and coefficient of variation (CV), geometric mean, geometric standard 
deviation (re-transformed standard deviation of the logarithms) and CV, minimum, median, 
maximum value and the number of measurements. Means at any time will only be calculated 
if at least 2/3 of the individual data were measured and were above the lower limit of 
quantification (LLOQ). For the calculation of the mean value a data point below LLOQ will 
be substituted by one half of this limit. In tables showing mean values, where values below 
LLOQ are included in the calculation of mean values, these means will be marked. 
Individual and geometric mean concentration versus time profiles of all analytes (by using the 
actual sampling times for individual plots and the planned sampling times for mean plots) will 
be plotted on both linear and semi-logarithmic axes. The amount (%) of metformin excreted 
into urine will be graphically illustrated by treatment condition for each sampling interval as 
well as for the whole sampling period (bar-charts for the individual data and for the arithmetic 
means including standard deviation). 
Pharmacokinetic characteristics (except tmax) will be summarized by the statistics mentioned 
above. tmax will be described utilizing minimum, maximum and median as well as frequency 
counts. 
To investigate the primary objective of this study regarding the effect of copanlisib on 
metformin, an exploratory analysis of variance (ANOVA) with terms of treatment condition 
and subject will be performed on the natural logarithmic transformation of PK parameters 
(AUC, AUC(0-24) and Cmax) of metformin. The estimate and 90% confidence interval of the 
Day 8 (with copanlisib) to Day 1 (without copanlisib) ratio of Cmax, AUC(0-24) and AUC for 
metformin are derived by inverse transformation of the estimates and the 90% confidence 
interval of the least squares mean differences that are obtained from the model above. This 
analysis will be performed on the PPS. 
A code, similar to one below, will be used for the above analysis:
proc glm data=tab.pk;
class Day Subject;
model l&var= Day Subject / solution;
lsmeans Day  /pdiff cl alpha=0.1;
run;
6.3.2
Pharmacodynamic Data
Plasma lactate levels, glucose, insulin and c-peptide will be summarized by treatment 
conditions (Day 1 and Day 8) for the original data as well as for the difference from baseline. 
Maximum change from baseline on Day 1 and Day 8 and change in PD data between Day 1 
and Day 8 will also be summarized.


Statistical Analysis Plan
Protocol No.: BAY 80-6946 / 19951
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6.4
Safety
6.4.1
Adverse Events (AEs)
Individual listings of AEs will be provided. The incidence of treatment-emergent AEs, worst 
severity per subject and drug-related AEs, respectively, will be summarized using MedDRA 
(version 21.0 or higher) terms, by treatment day and total. Listings of deaths, SAEs and AEs 
leading to discontinuation will be provided.
For presenting AEs by treatment day, following will be considered:
Day 1 : include all AEs starting/worsening post metformin administration on day 1 until pre-
dose of metformin administration on day 8.
Day 8 : include all AEs starting post metformin administration on day 8.
AEs are considered to be treatment-emergent if they start or worsen after first administration 
of study medication up to 30 days after end of treatment with study medication.
AE of special interest will be tabulated and listed separately.
6.4.2
Safety examinations
Quantitative data (hematology, blood chemistry, vital signs, ECG) will be summarized. These 
summary statistics will be presented for the original data as well as for the difference to 
baseline, by treatment day. Frequency tables will be provided for qualitative data. Laboratory 
data outside the reference range will be listed and flagged with ‘L’ for low and ‘H’ for high. 
Additional tables with all abnormal values will be presented. 
Graphical displays of individual data as well as mean values with standard deviation will be 
included.
7.
Document history and changes in the planned statistical analysis
Not applicable
8.
References
[1]
Clinical Study Protocol BAY BAY 80-6946 / 19951, Version 1.0, 15 May 2018
[2]
Clinical Pharmacology Standards (CLIPS), Version 2.0, Dated 09 May 2018
[3]
Clinical Pharmacology Standard Listings_V1.0_final_09052018, Version 1.0, 
Dated 09 May 2018