Clinical trial NCT03359590
Conditions: Pharmacological Action
Sponsor: Profil Institut für Stoffwechselforschung GmbH
Start date: 2018-03-21; Completion date: 2019-07-17
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Sitagliptin, through its effects on sensitizing alpha-cell sensitivity to glucose, can initiate counter-regulatory glucagon responses at higher glycemic thresholds, thus reducing the number of clinically apparent hypoglycemic episodes, and/or ameliorating the severity of hypoglycemic episodes in the case that they should occur. The endpoints have defined such that consequences of this hypothesis can be measured.

Detailed description:

Arms: arm 1: Sitagliptin 100 mg arm 2: Placebo comparator
Interventions: intervention 1: Sitagliptin 100 mg intervention 2: Placebo
Intervention descriptions: intervention 1: The treatment consists of sitagliptin tablets (100 mg/day) for up to 24 weeks. intervention 2: The treatment consists of placebo tablets for up to 24 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
1 of 74 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
Trial ID: DPP4-Hypo 
 
 
 
DPP-4 inhibition with sitagliptin and the risk for hypoglycaemia in 
the fasting state in subjects with type 2 diabetes treated to fasting 
plasma glucose targets with insulin glargine and metformin 
 
 
 
 
Principal Investigator:  
Dr. Christoph Kapitza 
 
Profil Institut für Stoffwechselforschung GmbH 
Authors and affiliation: 
Dr. Eric Zijlstra, Dr. Daniela Lamers 
 
Profil Institut für Stoffwechselforschung GmbH 
 
 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
2 of 74 
 
 
 
Agreement on the Protocol 
 
Principal Investigator: 
Dr. med. Christoph Kapitza, CEO 
Name & title (printed) 
Signature 
Date 
 
Sponsor Representative (Profil): 
Dr. med. Christoph Kapitza, CEO 
Name & title (printed) 
Signature 
Date 
 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
3 of 74 
 
 
Names and Addresses  
Sponsor/Principal Investigator:  
Dr. med. Christoph Kapitza 
Profil Institut für Stoffwechselforschung GmbH 
Hellersbergstr. 9 
D-41460 Neuss 
GERMANY 
Tel: 
+49 2131 4018 157 
Fax: 
+49 2131 4018 557 
Email: christoph.kapitza@profil.com 
 
Clinical Trial Centre:  
 
 
Profil Institut für Stoffwechselforschung GmbH 
Hellersbergstr. 9 
D-41460 Neuss 
GERMANY 
 
Scientific Consultants: 
Prof. Dr. Michael Nauck 
Ruhr-University Bochum, Division of Diabetology, 
Medical Department I, St. Josef-Hospital  
Gudrunstraße 56 
D-44791 Bochum 
GERMANY 
Tel: 
 +49-234-509 6332 
Fax: 
 +49-234-509 2714 
Email: michael.nauck@rub.de 
 
Prof. Dr. Juris Meier 
 
Ruhr-University Bochum, Division of Diabetology, 
Medical Department I, St. Josef-Hospital  
Gudrunstraße 56 
D-44791 Bochum 
GERMANY 
Tel: 
 +49-234-509 2471 / 2330 
Fax: 
 +49-234-509 2714 
Email: juris.meier@rub.de 
 
Medical Monitor:  
 
 
 
Dr. Tim Heise 
Profil Institut für Stoffwechselforschung GmbH 
Hellersbergstr. 9 
D-41460 Neuss 
GERMANY 
Tel: 
+49 2131 4018 411 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
4 of 74 
 
 
Fax: 
+49 2131 4018 511 
Email: Tim.Heise@profil.com 
 
Safety Laboratory: 
MLM Medical Labs GmbH  
Attn: Prof. Dr. Stephan Wnendt  
Dohrweg 63  
D-41066 Mönchengladbach  
Tel.:  +49 2161 4642 101 
Fax:  +49 2161 4642 190 
Email: SWnendt@mlm-labs.com 
 
PD Laboratory: 
Universitätsmedizin Greifswald, Institut für Klinische 
Chemie und Laboratoriumsmedizin 
 
Attn: Prof. Dr. med. Matthias Nauck 
Ferdinand-Sauerbruch-Straße 
17475 Greifswald 
Tel. +49 3834 86 5500 
Fax +49 3834 86 5502 
Email: matthias.nauck@uni-greifswald.de 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
5 of 74 
 
 
Table of Contents 
Names and Addresses ....................................................................................................................................... 3 
Table of Contents.............................................................................................................................................. 5 
List of Abbreviations ........................................................................................................................................ 8 
1 
Synopsis .................................................................................................................................................... 10 
2 
Schematic Trial Overview ...................................................................................................................... 14 
2.1 
Chronological Structure of the Trial ............................................................................................ 14 
2.2 
Trial Flow Chart ........................................................................................................................... 15 
2.3 
Assessment Schedules ................................................................................................................. 17 
3 
Introduction ............................................................................................................................................. 20 
3.1 
Background Information on Investigational Medicinal Product (IMP) Sitagliptin ..................... 20 
3.1.1 
Description ..................................................................................................................... 21 
3.1.2 
Non-clinical Findings ..................................................................................................... 22 
3.1.3 
Clinical Findings ............................................................................................................ 23 
3.2 
Rationale for the Trial .................................................................................................................. 23 
4 
Objectives and Endpoints ....................................................................................................................... 24 
4.1 
Objectives .................................................................................................................................... 24 
4.2 
Endpoints ..................................................................................................................................... 24 
5 
Trial Design .............................................................................................................................................. 26 
5.1 
Type of Trial ................................................................................................................................ 26 
5.2 
Randomisation ............................................................................................................................. 26 
5.3 
Blinding and Code Breaking Procedures ..................................................................................... 26 
5.4 
Treatment of Subjects .................................................................................................................. 27 
5.5 
Duration ....................................................................................................................................... 28 
5.6 
Stopping Rules ............................................................................................................................. 28 
5.7 
Rationale for the Trial Design and Treatment ............................................................................. 28 
6 
Trial Population ...................................................................................................................................... 30 
6.1 
Number of Subjects to be Studied ............................................................................................... 30 
6.2 
Inclusion Criteria ......................................................................................................................... 30 
6.3 
Exclusion Criteria ........................................................................................................................ 30 
6.4 
Inhouse visit Exclusion Criteria ................................................................................................... 32 
6.5 
Withdrawal Criteria ..................................................................................................................... 32 
6.6 
Subject Replacement .................................................................................................................... 33 
6.7 
Rationale for Trial Population ..................................................................................................... 33 
7 
Trial Materials ......................................................................................................................................... 35 
7.1 
Investigational Medicinal Products (IMPs) ................................................................................. 35 
7.2 
Packaging and Labelling of Investigational Medicinal Product (sitagliptin and placebo) .......... 36 
7.2.1 
Storage and Drug Accountability of Investigational Medicinal Product ........................ 36 
7.2.2 
Dispensing of Investigational Medicinal Product(s) ...................................................... 36 
7.3 
Retention Samples ....................................................................................................................... 36 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
6 of 74 
 
 
7.4 
Preparation and Application of IMP (sitagliptin and placebo) .................................................... 37 
8 
Visits and Assessments ............................................................................................................................ 38 
8.1 
Visit Procedures ........................................................................................................................... 38 
8.2 
Visit 0 – Informed Consent Visit ................................................................................................. 38 
8.3 
Visit 1 – Screening Visit .............................................................................................................. 38 
8.4 
Visit 2 – Randomisation Visit ...................................................................................................... 39 
8.4.1 
Insulin titration period .................................................................................................... 39 
8.5 
Visit 3 and 4 – Inhouse visits ....................................................................................................... 40 
8.5.1 
Washout and insulin titration period .............................................................................. 42 
8.6 
Assessment of Treatment Compliance ......................................................................................... 42 
8.7 
Assessments for Pharmacodynamics ........................................................................................... 42 
8.7.1 
Hypoglycaemic episodes ................................................................................................ 42 
8.7.2 
Plasma glucose, Insulin, C-peptide, glucagon and (other) counter-regulatory 
hormones ........................................................................................................................ 43 
8.7.3 
Continuous glucose monitoring (CGM) ......................................................................... 44 
8.8 
Assessments for Safety ................................................................................................................ 44 
8.8.1 
Clinical Assessments ...................................................................................................... 44 
8.8.2 
Laboratory Assessments ................................................................................................. 46 
8.9 
Other Assessments and Dietary Requirements ............................................................................ 48 
8.10 
Volume of Blood Sampled during Trial ...................................................................................... 49 
9 
Adverse Events ........................................................................................................................................ 51 
9.1 
Definitions ................................................................................................................................... 51 
9.2 
Collection, Recording and Reporting of Adverse Events ............................................................ 53 
9.3 
Follow-up of Adverse Events ...................................................................................................... 54 
9.4 
Hypoglycaemia ............................................................................................................................ 54 
9.5 
Pregnancy..................................................................................................................................... 55 
9.6 
Precautions ................................................................................................................................... 56 
10 Risk-Benefit Assessment ......................................................................................................................... 57 
11 Data Management ................................................................................................................................... 59 
11.1 
Case Report Forms (CRFs) .......................................................................................................... 59 
12 Monitoring Procedures ........................................................................................................................... 60 
13 Statistical Considerations ....................................................................................................................... 61 
13.1 
Sample Size Calculation .............................................................................................................. 61 
13.2 
Selection of Subjects for Analyses .............................................................................................. 61 
13.3 
Statistical Methods ....................................................................................................................... 62 
13.3.1 Analysis of the Primary Efficacy Endpoint(s) ................................................................ 63 
13.3.2 Analysis of the Secondary Efficacy Endpoints .............................................................. 63 
13.3.3 Safety Criteria ................................................................................................................. 64 
13.4 
Interim Analysis ........................................................................................................................... 64 
14 Independent Ethics Committee and Competent Authority ................................................................. 65 
14.1 
Independent Ethics Committee .................................................................................................... 65 
14.2 
Informed Consent Process for Subjects ....................................................................................... 65 
14.3 
Competent Authority ................................................................................................................... 66 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
7 of 74 
 
 
14.4 
Premature Termination of the Trial ............................................................................................. 67 
15 Administrative Matters........................................................................................................................... 68 
15.1 
Deviations from the Protocol ....................................................................................................... 68 
15.2 
Essential Documents .................................................................................................................... 68 
15.3 
Responsibilities ............................................................................................................................ 68 
15.4 
Reports and Publications ............................................................................................................. 69 
15.5 
Audits and Inspections ................................................................................................................. 69 
15.6 
Retention of Clinical Trial Documentation .................................................................................. 70 
Appendix 1: Insulin titration guideline ........................................................................................................ 71 
Appendix 2: Mixed high lipid meal examples .............................................................................................. 72 
16 References ................................................................................................................................................ 73 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
8 of 74 
 
 
List of Abbreviations  
AE 
 
Adverse event 
ALT/GPT 
Alanine aminotransferase 
AMG  
Arzneimittelgesetz 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
APTT  
Activated partial thromboplastin time 
AST/GOT 
Aspartate aminotransferase 
BMI 
 
Body mass index 
CGM  
Continuous glucose monitoring 
CK 
 
Creatine kinase 
CKMB 
Creatine kinase isoform MB  
CRF 
 
Case report form 
DPP 
 
Dipeptidyl peptidase 
ECG   
Electrocardiogram 
EMA  
European Medicine Agency 
EOT 
 
End of text 
EPAR  
European public assessment report 
EU 
 
European Union 
FAS 
 
Full analysis set  
FPG 
 
Fasting plasma glucose 
FSFV  
First subject first visit 
FSH 
 
Follicle stimulating hormone 
GCP  
Good clinical practice 
GIP 
 
Glucose-dependent insulinotropic peptide 
GLP-1  
Glucagon-like peptide 1 
HbA1C 
N-(1-deoxy)-fructosyl-haemoglobin 
HDL  
High-density lipoprotein 
HEENT 
Head, ears, eyes, nose, throat 
HIV 
 
Human immunodeficiency virus 
HR 
 
Heart rate 
ICH 
 
International conference on harmonisation 
ICMJE  
International Committee of Medical Journal Editors 
ID 
 
Identifier 
IEC 
 
Independent ethics committee 
IMP 
 
Investigational medicinal product 
INR 
 
International normalised ratio  
IRB 
 
Institutional review board 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
9 of 74 
 
 
IU 
 
International unit 
LDH  
Lactic dehydrogenase 
LDL 
 
Low-density lipoprotein  
LSLV  
Last subject last visit 
MCH  
Mean corpuscular haemoglobin  
MCHC 
Mean corpuscular haemoglobin concentration  
MCV  
Mean corpuscular volume  
MSD  
Merck Sharp & Dohme 
NIMP  
Non-investigational medicinal product 
OAD  
Oral antidiabetic drug 
OGT  
Oral glucose test 
PD 
 
Pharmacodynamic 
PG 
 
Plasma glucose 
PPP 
 
Per-Protocol Population  
SAE 
 
Serious adverse event 
SAP 
 
Statistical analysis plan 
SAS 
 
Statistical Analysis System 
SIV 
 
Site initiation visit 
SMPG  
Self monitoring of plasma glucose 
SmPC  
Summary of Product Characteristics  
SOP 
 
Standard operating procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions  
TIF 
 
Trial investigator file 
TZD 
 
Thiazolidinedione 
U 
 
Units 
β-HCG 
Beta-human chorionic gonadotropin 
γ-GT  
Gamma-glutamyltransferase 
 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
10 of 74 
 
 
1 Synopsis  
Name of Sponsor: 
Profil 
Trial ID: 
DPP4-Hypo 
Title of the trial: 
DPP-4 inhibition with sitagliptin and the risk for hypoglycaemia in the fasting state in subjects with type 2 diabetes 
treated to fasting plasma glucose targets with insulin glargine and metformin 
Trial design:  
Single center, randomised, double blind, two-way, placebo controlled, crossover design 
Clinical phase of development: 
Phase 2 
Trial centre: 
Profil Institut für Stoffwechselforschung GmbH, Hellersbergstraße 9, 41460 Neuss, Germany  
Principal Investigator:  
Dr. Christoph Kapitza, Profil Institut für Stoffwechselforschung GmbH, Hellersbergstraße 9, 41460 Neuss, Germany 
Planned trial start (First Subject First Visit): 
11/2017 
Planned trial end (Last Subject Last Visit): 
05/2019 
Trial population:  
Subjects with diabetes mellitus type 2, treated with basal insulin glargine and metformin 
Key Objectives: 
It is the purpose of the present trial to test the influence of DPP-4 inhibition (comparing sitagliptin 100 mg per day 
versus placebo in a cross-over design) on 
(a) the risk to develop hypoglycemia and on 
(b) hormonal responses and recovery from hypoglycemia in the case that they occur 
Hypothesis: 
Sitagliptin, through its effects on sensitizing -cell sensitivity to glucose, can initiate counter-regulatory glucagon 
responses at higher glycemic thresholds, thus reducing the number of clinically apparent hypoglycemic episodes, 
and/or ameliorating the severity of hypoglycemic episodes in the case that they should occur. The endpoints have 
defined such that consequences of this hypothesis can be measured. 
Key Endpoints:  
Primary Endpoint(s):  
 
The difference between sitagliptin and placebo treatment regarding the number of hypoglycaemic episodes 
characterized by a plasma glucose nadir of ≤ 70 mg/dl (i.e. in chemical hypoglycaemic episodes) occurring during 
the in-house period. 
Secondary Endpoints:  
 
The difference between sitagliptin and placebo treatment regarding the number of any (confirmed or not) 
symptomatic hypoglycaemic episodes or regarding asymptomatic hypoglycaemia occurring during the in-house 
period.  
 
The time spent at an interstitial (plasma-calibrated) glucose concentration ≤ 70 mg/dl as determined by CGM.  
 
The concentration of counter-regulatory hormones (first of all, glucagon) at times when plasma glucose is ≤ 70 
mg/dl, as well as 30 and 60 min later will be compared between sitagliptin and placebo treatment.  
 
The rise in glucose between the index time point and 30 and 60 min later (taking into account any compensatory 
oral carbohydrate administration). 
Exploratory Endpoints:  


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
11 of 74 
 
 
 
the above-mentioned parameters broken down to specific periods of the supervised fast: 
(a) 8 a.m. to 4 p.m. (8 hours following oral glucose, day 1) 
(b) 4 p.m. to 8 a.m. (fasting period of day 1) 
(c) 8 a.m. to 1 p.m. (5 hours following the lipid meal on day 2, release of incretin hormones expected) 
(d) 1 p.m. to 4 p.m. (period following exercise on day 2) 
(e) 4 p.m. to 8 a.m. (fasting period day 2) 
(f) 8 a.m. to 1 p.m. (oral glucose and exercise day 3). 
 
the time spent at an interstitial glucose concentration ≥ 180 mg/dl as determined by CGM (“hyperglycaemia”) 
 
the (relative) difference between sitagliptin and placebo treatment regarding the number of any self-reported 
hypoglycaemic episodes during the insulin titration period. 
 
Characterization of the insulin titration algorithm (e.g., number of subjects reaching titration goal, reduction in 
fasting plasma glucose, duration of titration, number of hypoglycaemic episodes, change in insulin daily dose). 
 
Comparison of venous and capillary blood glucose values (applicable for venous plasma glucose values < 90 
mg/dL as well as for all hypoglycemia-related measurements) 
Safety: 
 
AEs, excluding hypoglycaemic episodes 
 
Vital signs 
 
ECG 
 
Safety laboratory parameters 
Key inclusion and key exclusion criteria: 
Inclusion: 
 
Male or female subject with diabetes mellitus type 2.  
 
Age between 18 and 64 years, both inclusive.  
 
HbA1c <= 8.5%.  
 
Stable treatment with insulin glargine (any dose) and metformin (>= 1500 mg/day or at highest tolerated dose) for 
at least 3 months prior to inclusion into the trial with or without additional oral glucose-lowering agents (except 
thiazolidinediones). 
 
Considered generally healthy (apart from diabetes mellitus type 2 and associated conditions such as hypertension, 
hyperlipidaemia and hyperuricaemia) upon completion of medical history, physical examination, vital signs, ECG 
and analysis of laboratory safety variables, as judged by the Investigator. 
Exclusion: 
 
Known or suspected hypersensitivity to sitagliptin or related products. 
 
More than one episode of severe hypoglycaemia with seizure, coma or requiring medical assistance of another 
person during the past 6 months or hypoglycaemic unawareness as judged by the Investigator. 
 
Current or previous treatment (less than 3 months prior to screening) with insulin products other than insulin 
glargine and/or with GLP-1 receptor agonists and/or with thiazolidinediones.  
 
Unwillingness to wash-off any oral glucose-lowering agents other than metformin. 
Sample size: 
Twenty (20) subjects are planned to be randomized in the trial.  
IMPs:  
 
Sitagliptin 50 mg coated tablets (Januvia®, Merck Sharp & Dohme Ltd., UK) to be taken orally at a dose of 100 
mg/day 
 
Matching placebo tablets 
 
Insulin glargine (for in-house days) 
 
OGT solution 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
12 of 74 
 
 
Duration of treatment:  
The treatment consists of sitagliptin 100 mg/day or placebo taken together with a morning dose of metformin during 
two treatment periods. At the end of each treatment period a 54 hour inpatient period is performed. The duration of 
each treatment period is planned to be between 1 and 16 weeks. At the discretion of the investigator the treatment 
period may be increased up to a maximum of 24 weeks. 
 
Assessments:  
All subjects will undergo outpatient insulin titration (insulin glargine injected at bedtime and metformin will be 
continued) during each treatment period (either sitagliptin 100 mg/day or matching placebo), aiming at finding the 
insulin dose that, under these conditions, takes individual fasting plasma glucose to a range of 80-120 mg/dl for at 
least one week (with at least 4 out of 7 fasting glucose concentrations falling into this range). Once these conditions 
are met, insulin dose is not changed further, and subjects are invited to an inpatient supervised visit (within the 
following 7 days) with 54-h monitoring for episodes of hypoglycemia while continuing the same glucose-lowering 
treatment. 
Subjects will be admitted to the investigational site the night before beginning a supervised fast. An indwelling venous 
cannula will be placed into a distal forearm vein for blood sampling. A standardised dinner will be served at 
approximately 19:00 h. From 10 hours before starting an oral glucose tolerance test the following morning, only 
carbohydrate- and calorie-free drinks (mineral water, unsweetened tea) are allowed. Baseline venous plasma glucose 
(PG) samples will be taken on day 1, shortly before IMP (sitagliptin or matching placebo) administration. At day 1, at 
approximately 08:00 h, a standard oral glucose load will be administered (75 g OGT, Roche). Subjects will be fasting 
for 24 hours from then on. In the evening of day 1, the insulin glargine dose will be increased by 10 % (to 110 % of 
the results of titration) to further increase the risk of hypoglycaemia. On day 2, at approximately 08:00 h, subjects will 
receive a mixed high lipid meal (to support release of gastro-intestinal peptides like GLP-1 and GIP). Subjects will be 
fasting for another 24 hours from then on. Approximately 3 hours later (at approximately 11:00 h), subjects will 
undergo a 30 min bicycle ergometer test at a workload taking them to a pulse > 120/min (approximately 75 Watt to 
start with, increasing every 5 min until this pulse rate is achieved). In the evening of day 2, the insulin glargine dose 
will be increased by 20 % (to 120 % of the results of titration) to further increase the risk of hypoglycaemia. On day 3, 
another oral glucose tolerance test (75 g) will be administered at approximately 08:00 h, with an additional bicycle 
ergometer test following 3 h later, at the time when reactive hypoglycaemia may be expected following the oral 
glucose load. On day 3 at approximately 13:00h the experimental procedures are completed and subjects are offered an 
ad libitum lunch before they will be discharged. 
Blood samples. Blood will be drawn to characterize the plasma glucose responses to fasting while injecting basal 
insulin, including the detection of any hypoglycaemic episodes. During the in-house period, when low plasma glucose 
values are provoked by interventions like exercise or when low plasma glucose values are less likely, samples will be 
analyzed for glucose, insulin glargine, C-peptide (to detect reductions in insulin secretion in response to low plasma 
glucose) and counter-regulatory hormones (glucagon, cortisol, growth hormone, epinephrine, norepinephrine, 
prolactin).  
Continuous measurement of interstitial glucose concentrations (CGM). For the full duration of the 3-day experiment 
(starting early enough to complete calibration before the supervised fast is initiated), glucose will be determined 
continuously. 
 
Statistical method(s):  
The number of hypoglycemic episodes (primary endpoint and secondary endpoints; varying definitions of 
hypoglycemia) will be compared between sitagliptin and placebo treatment by Fisher's exact test. Time spent at an 
interstitial glucose concentration will be analyzed by ANOVA, with the experimental condition (sitagliptin vs. 
placebo), sequence and period as fixed independent variables, subject within sequence as random effect, and the time 
spent at an interstitial glucose concentration during the 54 h inpatient observation periods as dependent variable. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
13 of 74 
 
 
In case of hypoglycemic episodes, plasma glucose, insulin, C-peptide and counter-regulatory hormones will be 
analysed at the time point of first detecting symptoms or a low plasma glucose (whatever triggers the detection) and 30 
as well as 60 min thereafter, to determine the activity of the counter-regulatory response. Counter-regulatory hormones 
will be analyzed by ANOVA with the experimental condition (sitagliptin vs. placebo), time point (index time point, 
30min and 60 min later) and their interaction, sequence and period as fixed independent variables, subject within 
sequence as random effect, and the counter-regulatory hormones as dependent variable. The rise in counter-regulatory 
hormones will be analyzed by ANCOVA with the experimental condition (sitagliptin vs. placebo), time point (30min 
and 60 min later) and their interaction, sequence and period as fixed independent variables, baseline counter-
regulatory hormones (index timepoint) as covariate, subject within sequence as random effect, and the rise in counter-
regulatory hormones (change from index timepoint) as dependent variable. 
Sample size calculation. It is assumed that the protocol will provoke an average of 2 confirmed episodes of 
hypoglycaemia per 48 hours with the administration of placebo. A reduction by 30% due to sitagliptin would be of 
clinical significance. As the relevant information needed for a sample size calculation is not available no formal 
sample size calculation was performed for the primary objective. The sample size calculation is based on one of the 
secondary objectives, the comparison of the time spent at an interstitial glucose concentration ≤ 70 mg/dL. Assuming a 
variability of 40% for placebo and sitagliptin in this trial and assuming a 25% reduction in the secondary endpoint 
with sitagliptin compared to placebo, there will be an approximate 85% power to detect a statistically significance 
difference (p<0.05) with 18 completers. However, due to the uncertain variability  20 patients will be randomised into 
the study. 
 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
14 of 74 
 
 
2 Schematic Trial Overview 
2.1 
Chronological Structure of the Trial 
 
Figure 1 
Schematic overview of the chronological structure of the trial.   
 
 
 
R = Randomisation at V2. Before V2 oral glucose-lowering agents other than 
 
 
metformin (will be continued) and thiazolidinediones (TZDs; subject is excluded)  
 
 
will be washed out for approximately 1 week. 
 
 
*Duration of the run-in periods will be approximately 1 to 16 weeks. At the  
discretion of the Investigator the duration of the run-in period may be increased to 24 
weeks to achieve target fasting plasma glucose concentrations. 
After V3, the subject will wash off IMP (sitagliptin or matching placebo) and resume 
their pre-trial insulin dose and OAD therapy. Any additional oral glucose lowering 
agents will be washed out for approximately 1 week prior to starting the second run-
in period.   
 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
15 of 74 
 
 
2.2 
Trial Flow Chart 
The trial flow chart is the master representation of the trial schedule. In case of (apparent) 
inconsistencies in the trial protocol the information provided here is the binding one.  
Table 1 
Trial Flow Chart 
Trial Period 
Screening Period 
Treatment Period 
Visit no. 
0 
1 
2 
Outpatient 
3 and 4 
Informed 
Consent 
Screening Randomisation 
Run-in and 
Insulin titration Inhouse Visits 
Timing 
At least 1 
day before 
V1 
At least 1 day 
before V2 
 
1-24 weeks 
between V2-V3, 
between V3-V41 
Day -1 to 3 
In-house Visit 
 
 
 
 
X 
Telephone contacts 
 
 
 
X 
 
Informed consent 
X 
X2 
 
 
 
Fasting 
 
X 
 
 
 
Inclusion/exclusion criteria 
 
X 
X3 
 
 
Demographic data 
 
X 
 
 
 
Smoking and alcohol consumption 
habits 
 
X 
 
 
 
Concomitant 
illness 
and 
medical 
history 
 
X 
X 
 
 
Current diabetes therapy 
 
X 
 
 
 
Diagnosis of diabetes 
 
X 
 
 
 
Weight, height, BMI 
 
X 
 
 
X (weight 
only) 
Waist circumference 
 
X 
 
 
 
Alcohol breath test 
 
X 
 
 
X 
Physical examination 
 
X 
 
 
X 
Vital signs 
 
X 
 
 
X 
12-lead ECG 
 
X 
 
 
X 
Haematology  
 
X 
 
 
X 
Biochemistry 
 
X 
 
 
X 
Coagulation 
 
X 
 
 
 
Urinalysis 
 
X 
 
 
 
Infectious serology  
 
X 
 
 
 
HbA1c 
 
X 
 
 
 
Fasting plasma glucose4 
 
X 
 
X 
X 
Pregnancy test (females only)5 
 
X 
 
 
X 
FSH test (females only)5 
 
X 
 
 
 
Drug screen 
 
X 
 
 
 
Handout diary and glucometer 
 
X8 
X8 
 
X6 
Washout of OADs 
 
 
X7 
X7 
 
Randomisation 
X 
 
 
Handout IMP 
X 
 
X (V3 only) 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
16 of 74 
 
 
Trial Period 
Screening Period 
Treatment Period 
Visit no. 
0 
1 
2 
Outpatient 
3 and 4 
Informed 
Consent 
Screening Randomisation 
Run-in and 
Insulin titration Inhouse Visits 
Timing 
At least 1 
day before 
V1 
At least 1 day 
before V2 
 
1-24 weeks 
between V2-V3, 
between V3-V41 
Day -1 to 3 
In-house Visit 
 
 
 
 
X 
Telephone contacts 
 
 
 
X 
 
IMP administration 
 
 
 
X 
X 
Insulin glargine titration 
 
 
 
X 
 
Check of diary (also by telephone) 
 
 
 
X 
X 
Inhouse visit exclusion and withdrawal 
criteria 
 
 
 
 
X 
CGM 
X 
Standardised food intake 
 
 
 
 
X 
Exercise bouts 
 
 
 
 
X 
Blood sampling for glucose 
 
 
 
 
X 
Blood sampling for insulin, C-peptide, 
glucagon and other counter-regulatory 
hormones 
 
 
 
 
X 
Adverse events 
 
 
 
X 
X 
Concomitant medication 
 
X 
X 
X 
X 
1 The run-in and insulin titration period between V3 and V4 is preceded by a minimum 4-week washout period starting after V3 (see     
   Figure 1) 
2 Check that informed consent has been signed and dated 
3 Confirm subject eligibility 
4 At V1, V3 and V4 fasting plasma glucose will be measured with a laboratory method at the trial site. During the outpatient periods, 
subjects will use a glucometer for self-monitoring of plasma glucose. 
5 Pregnancy test / FSH test in women will be performed according to Section 8.8.2 
6 At V3 a diary for the second run-in period will be provided 
7 OADs in addition to metformin need to washed out for approximately 1 week before V2 (start of first insulin titration period) and 
before starting the second insulin titration period. 
8 If a washout of OADs is necessary, subjects will receive the glucometer and diary at the screening visit. After eligibility is 
confirmed subjetcts will be called to start with the washout period. If subjects do not need to washout medication, diary and 
glucometer will be handed out at visit 2. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
17 of 74 
 
 
2.3 
Assessment Schedules 
The figure and table below give a detailed overview of the timing of assessments performed at 
Visits 3 and 4. 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2 
Schematical representation of the assessment schedule. All times are 
approximate. Sampling of plasma glucose, insulin, C-peptide, glucagon and other 
counter-regulatory hormones will be performed according to table 2. 
 
*: relative to the results of outpatient titration 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
18 of 74 
 
 
 
Table 2 
Assessment Schedule for Visits 3 and 4 
Approx. 
hour 
(hh:mm)1 
Nominal 
timing1 
Activity 
Plasma glucose, 
insulin,  
C-peptide, glucagon 
and other counter-
regulatory 
hormones2
 
Other 
18:00 
Day -1 
Subject arrives at the trial site – check of 
inhouse visit exclusion and withdrawal 
criteria.  
 
 
Vital signs, weight, 
alcohol breath test, 
pregnancy test, ECG, 
physical exam3 
18:15 
 
Insert and initiate CGM sensor 
X (CGM calibration) 
 
19:00 
 
Subject is served a standardised meal 
 
 
 
 
Insulin glargine dose administration – dose is 
100% relative to the outpatient titrated dose 
 
 
22:00 
-10 h 
START 10-hour overnight fasting period 
 
 
07:50 
Day 1 
-10 min 
 
X 
 
07:55 
-5 min 
 
X 
 
08:00 
0 min 
START oral glucose load (75g) 
followed by START 24-hour fasting period 
Metformin intake 
IMP intake 
 
 
09:00 
1 h 
 
X 
 
10:00 
2 h 
 
X 
 
11:00 
3 h 
 
X 
 
12:00 
4 h 
 
X 
 
13:00 
5 h 
 
X 
 
16:00 
8 h 
 
X 
 
20:00 
12 h 
 
X 
 
 
 
Insulin glargine dose administration – dose is 
110% relative to the outpatient titrated dose 
 
 
00:00 
Day 2 
16 h 
 
X 
 
04:00 
20 h 
 
X 
 
07:55 
23h 55 min 
 
X 
 
08:00 
24 h 
START lipid meal intake 
followed by START 24-hour fasting period 
Metformin intake 
IMP intake 
 
 
09:00 
25 h 
 
X 
 
10:00 
26 h 
 
X 
 
11:00 
27 h 
START exercise activity 
X 
 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
19 of 74 
 
 
Approx. 
hour 
(hh:mm)1 
Nominal 
timing1 
Activity 
Plasma glucose, 
insulin,  
C-peptide, glucagon 
and other counter-
regulatory 
hormones2
 
Other 
11:30 
27 h 30 min 
STOP exercise activity 
 
 
12:00 
28 h 
 
X 
 
13:00 
29 h 
 
X 
 
16:00 
32 h 
 
X 
 
20:00 
36 h 
 
X 
 
 
 
Insulin glargine dose administration – dose is 
120% relative to the outpatient titrated dose 
 
 
00:00 
Day 3 
40 h 
 
X 
 
04:00 
44 h 
 
X 
 
07:55 
47 h 55 min 
 
X 
 
08:00 
48 h 
START oral glucose load (75g) 
Metformin intake 
IMP intake 
 
 
09:00 
49 h 
 
X 
 
10:00 
50 h 
 
X 
 
11:00 
51 h 
START exercise activity 
X 
 
11:30 
51 h 30 min 
STOP exercise activity 
 
 
12:00 
52 h 
 
X 
 
13:00 
53 h 
 
X 
 
 
 
Subject is served food of his/her choice and 
can leave the site at the discretion of the 
Investigator after a short medical examination 
 
Vital signs, physical 
exam, ECG, safety 
lab4 
1 All times are approximate and are given as a guidance for the activity schedule only.  The time window for all blood sampling is ±5 
minutes.  
2 Blood samples for the evaluation of plasma glucose, insulin, C-peptide, glucagon and counter-regulatory hormones  are taken (i) at 
the nominal times indicated; (ii) immediately after a plasma glucose value of ≤ 70 mg/dL has been measured if not already sampled 
simultaneously (±5 minutes) and 30 and 60 minutes thereafter; (iii) at the time subject reports symptoms of hypoglycaemia and 30 
and 60 minutes thereafter if the measured plasma glucose value is ≤ 90 mg/dL.  
3 Before meal 
4Before discharge  


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
20 of 74 
 
 
3 Introduction 
In some clinical trials examining the effect of DPP-4 inhibitors used as additional therapy together 
with long-acting insulin preparations like insulin glargine, the DPP-4 inhibitor led to an 
improvement in HbA1c without increasing the risk for hypoglycaemic episodes (1-4). In some 
studies, the risk for hypoglycaemic episodes was even lowered by the use of a DPP-4 inhibitor (1, 
2). Since DPP-4 inhibitors are thought to act through stimulating GLP-1, which leads to a 
suppression of glucagon from pancreatic endocrine -cells (5), a potential -cell sensitization to 
changes in ambient glycaemia has been hypothesized, leading to better suppression of glucagon 
secretion in the case of hyperglycaemia, but on the other hand an augmented counter-regulatory 
glucagon response in the case of hypoglycaemia (6, 7). This could prevent hypoglycaemia 
altogether by initiating counter-regulation early enough to avoid low plasma glucose, or it could 
lead to improved and more rapid recovery from hypoglycaemic episodes, producing less symptoms 
with milder reductions in plasma glucose concentrations. Clinically, this may result in episodes of 
relatively low plasma glucose that are not even noticed as hypoglycaemia. This hypothesis is based 
on experimental results which rely on the hyperinsulinaemic, hypoglycaemic clamp technique (8, 
9), which – in a highly artificial manner – uses relatively high doses of intravenous insulin to drive 
a fall in plasma glucose, while at the same time controlling the reduction in glucose concentrations 
by intravenously infusing glucose guided by repeated measurements of plasma glucose. High 
insulin concentrations (as used under these circumstances) alone may have the potential to alter 
counter-regulatory responses (10). Certainly, the conditions of hyperinsulinaemic, hypoglycaemic 
clamps do not entirely reflect those of hypoglycaemic episodes in subjects with type 2 diabetes 
treated with basal insulin plus oral glucose-lowering agents (11-13). Here, it can be expected that 
hypoglycaemia is not due to excessive insulin concentrations, but rather to slight imbalances 
between insulin levels and requirements, as a consequence of variances in insulin absorption from 
day to day, for example. The risk of hypoglycaemia in real life will be highest during periods of 
fasting and during vulnerable periods following meals, when reactive hypoglycaemia is most likely 
to occur approximately 3-5 h after nutrient ingestion. 
3.1 
Background Information on Investigational Medicinal Product (IMP) Sitagliptin 
The information below is included in the European public assessment report (EPAR) for sitagliptin 
(Januvia®). The full EPAR for Januvia can be found on the European Medicine Agency (EMA) 
website: www.http://www.ema.europa.eu/ema/. Please refer to this document, including the 
Summary of product characteristics (SmPC, Annex 1 of the EPAR) for further details. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
21 of 74 
 
 
3.1.1 Description 
 Januvia® is an approved drug for the treatment of type 2 diabetes in adults and contains 
sitagliptin phosphate monohydrate as active ingredient. 
 Januvia® is a member of a class of oral anti-hyperglycaemic agents called dipeptidyl 
peptidase 4 (DPP-4) inhibitors. The improvement in glycaemic control observed with this 
medicinal product may be mediated by enhancing the levels of active incretin hormones. 
Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent 
insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels 
are increased in response to a meal. The incretins are part of an endogenous system involved 
in the physiologic regulation of glucose homeostasis. When blood glucose concentrations 
are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from 
pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. 
 Treatment with GLP-1 or with DPP-4 inhibitors in animal models of type 2 diabetes has 
been demonstrated to improve beta cell responsiveness to glucose and stimulate insulin 
biosynthesis and release. With higher insulin levels, tissue glucose uptake is enhanced. In 
addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon 
concentrations, along with higher insulin levels, lead to reduced hepatic glucose production, 
resulting in a decrease in blood glucose levels. The effects of GLP-1 and GIP are glucose-
dependent such that when blood glucose concentrations are low, stimulation of insulin 
release and suppression of glucagon secretion by GLP-1 are not observed. For both GLP-1 
and GIP, stimulation of insulin release is enhanced as glucose rises above normal 
concentrations. Further, GLP-1 does not impair the normal glucagon response to 
hypoglycaemia. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which 
rapidly hydrolyzes the incretin hormones to produce inactive products. Sitagliptin prevents 
the hydrolysis of incretin hormones by DPP-4, thereby increasing plasma concentrations of 
the active forms of GLP-1 and GIP. By enhancing active incretin levels, sitagliptin increases 
insulin release and decreases glucagon levels in a glucose-dependent manner. 
 In patients with type 2 diabetes with hyperglycaemia, these changes in insulin and glucagon 
levels lead to lower haemoglobin A1c (HbA1c) and lower fasting and postprandial glucose 
concentrations. The glucose-dependent mechanism of sitagliptin is distinct from the 
mechanism of sulphonylureas, which increase insulin secretion even when glucose levels are 
low and can lead to hypoglycaemia in patients with type 2 diabetes and in normal subjects. 
Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not 
inhibit the closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations. In a two-
day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
22 of 74 
 
 
whereas metformin alone increased active and total GLP-1 concentrations to similar extents. 
Co-administration of sitagliptin and metformin had an additive effect on active GLP-1 
concentrations. Sitagliptin, but not metformin, increased active GIP concentrations.  
 Januvia® is approved as monotherapy and in combination therapy, including as add-on to 
insulin therapy (with or without metformin). 
3.1.2 Non-clinical Findings 
 In vitro studies performed suggest that the risk for clinically meaningful interactions by co-
administered medicinal products is low. 
 Renal and liver toxicity were observed in rodents at systemic exposure values 58 times the 
human exposure level, while the no-effect level was found at 19 times the human exposure 
level. Incisor teeth abnormalities were observed in rats at exposure levels 67 times the 
clinical exposure level; the no-effect level for this finding was 58-fold based on the 14-week 
rat study. The relevance of these findings for humans is unknown. Transient treatment-
related physical signs, some of which suggest neural toxicity, such as open-mouth breathing, 
salivation, white foamy emesis, ataxia, trembling, decreased activity, and/or hunched 
posture were observed in dogs at exposure levels approximately 23 times the clinical 
exposure level. In addition, very slight to slight skeletal muscle degeneration was also 
observed histologically at doses resulting in systemic exposure levels of approximately 23 
times the human exposure level. A no-effect level for these findings was found at an 
exposure 6-fold the clinical exposure level. Sitagliptin has not been demonstrated to be 
genotoxic in preclinical studies. Sitagliptin was not carcinogenic in mice. In rats, there was 
an increased incidence of hepatic adenomas and carcinomas at systemic exposure levels 58 
times the human exposure level. Since hepatotoxicity has been shown to correlate with 
induction of hepatic neoplasia in rats, this increased incidence of hepatic tumours in rats was 
likely secondary to chronic hepatic toxicity at this high dose. Because of the high safety 
margin (19-fold at this no-effect level), these neoplastic changes are not considered relevant 
for the situation in humans. No adverse effects upon fertility were observed in male and 
female rats given sitagliptin prior to and throughout mating. In a pre-/postnatal development 
study performed in rats sitagliptin showed no adverse effects. Reproductive toxicity studies 
showed a slight treatment-related increased incidence of foetal rib malformations (absent, 
hypoplastic and wavy ribs) in the offspring of rats at systemic exposure levels more than 29 
times the human exposure levels. Maternal toxicity was seen in rabbits at more than 29 
times the human exposure levels. Because of the high safety margins, these findings do not 
suggest a relevant risk for human reproduction. Sitagliptin is secreted in considerable 
amounts into the milk of lactating rats (milk/plasma ratio: 4:1). 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
23 of 74 
 
 
3.1.3 Clinical Findings 
 A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of 
sitagliptin (100 mg once daily) added to insulin (at a stable dose for at least 10 weeks) with 
or without metformin (at least 1,500 mg). In patients taking pre-mixed insulin, the mean 
daily dose was 70.9 U/day. In patients taking non-pre-mixed (intermediate/long-acting) 
insulin, the mean daily dose was 44.3 U/day. The addition of sitagliptin to insulin provided 
significant improvements in glycaemic parameters. There was no meaningful change from 
baseline in body weight in either group.  
 A 24-week placebo-controlled study involving 660 patients was designed to evaluate the 
insulin-sparing efficacy and safety of sitagliptin (100 mg once daily) added to insulin 
glargine with or without metformin (at least 1,500 mg) during intensification of insulin 
therapy. Baseline HbA1c was 8.74 % and baseline insulin dose was 37 IU/day. Patients 
were instructed to titrate their insulin glargine dose based on fingerstick fasting glucose 
values. At Week 24, the increase in daily insulin dose was 19 IU/day in patients treated with 
sitagliptin and 24 IU/day in patients treated with placebo. The reduction in HbA1c in 
patients treated with sitagliptin and insulin (with or without metformin) was -1.31 % 
compared to -0.87 % in patients treated with placebo and insulin (with or without 
metformin), a difference of -0.45 % [95 % CI: -0.60, -0.29]. The incidence of 
hypoglycaemia was 25.2 % in patients treated with sitagliptin and insulin (with or without 
metformin) and 36.8 % in patients treated with placebo and insulin (with or without 
metformin). The difference was mainly due to a higher percentage of patients in the placebo 
group experiencing 3 or more episodes of hypoglycaemia (9.4 vs. 19.1 %). There was no 
difference in the incidence of severe hypoglycaemia.  
3.2 
Rationale for the Trial 
It is hypothesized that sitagliptin, through its effects on sensitizing -cell sensitivity to glucose, can 
initiate counter-regulatory glucagon responses at higher glycemic thresholds, thus reducing the 
number of clinically apparent hypoglycemic episodes, and/or ameliorating the severity of 
hypoglycemic episodes in the case that they should occur. This trial is designed such that 
consequences of this hypothesis can be measured and this important research question can be 
answered.  


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
24 of 74 
 
 
4 Objectives and Endpoints 
The hypothesis tested in this trial is that sitagliptin reduces the number of hypoglycaemic episodes 
in patients with type 2 diabetes treated to target with basal insulin glargine and metformin, when 
measures are taken to increase the risk for such episodes (fasting, increases in insulin dosage, lipid 
load to increase incretin hormone release, exercise). The hypothesis that sitagliptin improves 
recovery from such episodes will also be examined. 
4.1 
Objectives 
Key objectives: 
It is the purpose of the present trial to test the influence of DPP-4 inhibition (comparing sitagliptin 
100 mg per day versus placebo in a cross-over design) on:  
(a) the risk to develop hypoglycemia and on 
(b) hormonal responses and recovery from hypoglycemia in the case that they occur. 
4.2 
Endpoints 
Primary endpoint:  
The difference between sitagliptin and placebo treatment regarding the number of hypoglycaemic 
episodes characterized by a plasma glucose nadir of ≤ 70 mg/dl (i.e. in chemical hypoglycaemic 
episodes) occurring during the in-house period. 
 
Secondary endpoints:  
 The difference between sitagliptin and placebo treatment regarding the number of any 
(confirmed or not) symptomatic hypoglycaemic episodes or regarding asymptomatic 
hypoglycaemia occurring during the in-house period.  
 The time spent at an interstitial (plasma-calibrated) glucose concentration ≤ 70 mg/dl as 
determined by CGM.  
 The concentration of counter-regulatory hormones (first of all, glucagon) at times when plasma 
glucose is ≤ 70 mg/dl, as well as 30 and 60 min later will be compared between sitagliptin and 
placebo treatment.  
 The rise in glucose between the index time point and 30 and 60 min later (taking into account 
any compensatory oral carbohydrate administration). 
 
Exploratory endpoint(s):  
 the above-mentioned parameters broken down to specific periods of the supervised fast: 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
25 of 74 
 
 
(a) 8 a.m. to 4 p.m. (8 hours following oral glucose, day 1) 
(b) 4 p.m. to 8 a.m. (fasting period of day 1) 
(c) 8 a.m. to 1 p.m. (5 hours following the lipid meal on day 2, release of incretin hormones 
expected) 
(d) 1 p.m. to 4 p.m. (period following exercise on day 2) 
(e) 4 p.m. to 8 a.m. (fasting period day 2) 
(f) 8 a.m. to 1 p.m. (oral glucose and exercise day 3). 
 the time spent at an interstitial glucose concentration ≥ 180 mg/dl as determined by CGM 
(“hyperglycaemia”) 
 the (relative) difference between sitagliptin and placebo treatment regarding the number of any 
self-reported hypoglycaemic episodes during the insulin titration period. 
 Characterization of the insulin titration algorithm (e.g., number of subjects reaching titration 
goal, reduction in fasting plasma glucose, duration of titration, number of hypoglycaemic 
episodes, change in insulin daily dose). 
 Comparison of venous and capillary blood glucose values (applicable for venous plasma 
glucose values < 90 mg/dL as well as for all hypoglycemia-related measurements) 
 
Safety endpoints: 
 AEs, excluding hypoglycaemic episodes 
 
Vital signs 
 
ECG 
 
Safety laboratory parameters 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
26 of 74 
 
 
5 Trial Design 
5.1 
Type of Trial 
This is a postmarketing phase 2 trial. The trial is designed as single centre, randomised, double 
blind, two-way treatment, placebo controlled crossover trial in subjects with type 2 diabetes 
mellitus treated to fasting plasma glucose targets with insulin glargine and metformin.  
A schematic trial overview is given in Section 2, Figure 1. 
5.2 
Randomisation  
This is a randomised trial. Assignment of treatment sequence will take place at the trial site. There 
will be two randomisation groups. 
The randomisation list will be provided by Profil. A subject will only be randomised if he/she 
complies with all inclusion/exclusion and inhouse visit exclusion criteria. Randomisation should 
occur as close as possible to the first administration of IMP. When a subject is randomised in the 
trial, he/she must always be assigned to the lowest available randomisation number available from 
the randomisation list. Twenty (20) subjects are planned to be randomised in this trial. The drop-out 
rate is expected to be 20% or less. Replacement of drop-outs will be performed at the discretion of 
the sponsor. 
Randomisation numbers will be as follows: 
 Randomisation numbers starting with 101, 102, 103…  
 Corresponding randomisation numbers for replacements: 201, 202, 203… 
Replacement subjects must always be assigned to the same sequence as the subject they replace 
(please see Section 6.6). 
5.3 
Blinding and Code Breaking Procedures 
This is a double-blind randomised trial. Except for the unblinded persons involved in the 
preparation of the IMP (these persons are not involved in any other trial activities), everyone 
involved in the trial will be blinded until completion of the trial and the final data review.  


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
27 of 74 
 
 
Treatment assignment will be kept strictly confidential and accessible only to authorised persons 
until documented un-blinding. Sealed codes with treatment assignment will, however, be readily 
available to the blinded personnel in case of an emergency. 
One set of sealed codes with the subject randomisation number containing information about the 
treatment at each visit will be prepared for each subject. The set will be kept at the trial site in the 
office of the physician on duty (during the entire trial period) and is to be used in case of code break 
need.  
The code for a particular subject may be broken in a medical emergency if knowing the identity of 
the treatment allocation would influence the treatment of the subject. Whenever a code is broken, 
the person breaking the code must record the time, date and reason as well as his/her initials in the 
source documents and on the code envelope. The breaking of blinded codes in case of medical 
emergency for one subject should not unblind the trial personnel to the treatment information of 
other subjects. The person performing the unblinding should inform as few people as possible about 
the result of the unblinding. All persons unblinded for a specific subject should be documented. 
If the trial site needs to break the code, the medical monitor should, if possible, be contacted prior to 
breaking the code. In all cases, the medical monitor and trial monitor must be notified within 24 
hours after the code has been broken. 
All codes (whether broken or not) must be kept throughout the trial period. The codes kept at the 
trial site will be checked by the monitor and the close-out visit report should confirm adequate 
documentation of any code breaks (if applicable).   
5.4 
Treatment of Subjects  
This is an experimental trial in which each subject will receive anti-diabetes medication at doses 
and routes approved for the treatment of their disease. Before starting treatment with IMP and basal 
insulin titration, subjects who are taking oral glucose lowering agents other than metformin will 
need to wash-out the additional medication for approximately 1 week. During two treatment 
periods, all subjects will undergo outpatient insulin titration (insulin glargine injected at bedtime 
and metformin will be continued). The IMP (sitagliptin/placebo) will be administered once daily 
together with a morning dose of metformin during or immediately after food intake in the morning 
The run-in insulin titration period aims at finding the insulin dose that, under these conditions, takes 
individual fasting plasma glucose to a range of 80-120 mg/dL for at least one week (with at least 4 
out of 7 fasting glucose concentrations falling into this range). Once these conditions are met, 
insulin dose is not changed further, and subjects are invited to an inpatient supervised visit (within 
the following 7 days) during which insulin glargine, metformin and sitagliptin/placebo treatment is 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
28 of 74 
 
 
continued. The insulin glargine dose will be increased by 10 % (to 110 % of the titration dose) in 
the evening of Day 1 and increased by 20% (to 120 % of the titration dose) in the evening of Day 2.  
 
After the first treatment period, subjects will be asked to resume their pre-trial insulin dose and 
OAD therapy. IMP will be washed off for 4 weeks before starting the second treatment and run-in 
period. Subjects taking oral glucose lowering agents other than metformin will need to wash off the 
additional medication for approximately 1 week before starting the second treatment and run-in 
period. 
5.5 
Duration  
Planned date for FSFV: 11-2017 
Planned date for LSLV: 05-2019 
The end of the clinical trial is defined as LSLV. 
Actual time-lines may vary. 
The total trial duration for a subject will be about 7 to 53 weeks.  
5.6 
Stopping Rules 
No specific stopping rules in addition to section 6.5 and 14.4 are applicable for this trial. 
5.7 
Rationale for the Trial Design and Treatment 
A crossover design is chosen in order to reduce variability and increase the power as each subject 
acts as its own control. The total number of subjects needed with a crossover design is decreased as 
compared to a parallel group design.  
Randomisation and blinding is used in order to avoid bias introduced through an association 
between allocation order of IMP and subject characteristics. 
A dose of sitagliptin 100 mg/day was chosen as a dose within the clinically relevant range for the 
treatment of diabetes mellitus type 2. The insulin glargine dose is individually titrated to a fasting 
plasma glucose target level of 80 – 120 mg/dL and increased at the inpatient visits under medical 
supervision to increase the risk of hypoglycaemic episodes at the inhouse visits. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
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00/0795-DPP4-Hypo 
Status / Version-No. 
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2016-004480-39 
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A minimum 4-week wash-out period between Visit 3 and Visit 4 is introduced to ensure a sufficient 
wash-out period from previous sitagliptin dosing to avoid any carry-over effect. 
 


 
 
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6 Trial Population 
6.1 
Number of Subjects to be Studied 
Planned number of subjects to be screened: 48  
Planned number of subjects to be randomised: 20 (dropout rate of 20% or less) 
6.2 
Inclusion Criteria 
1. Signed and dated informed consent obtained before any trial-related activities. (Trial-related 
activities are any procedures that would not have been performed during normal management of 
the subject). 
2. Male or female subject with diabetes mellitus type 2.  
3. Age between 18 and 64 years, both inclusive.  
4. HbA1c <= 8.5%.  
5. Total insulin dose of < 1.2 U/kg/day. 
6. Diabetes duration of at least 12 months. 
7. Stable treatment with insulin glargine (any dose) and metformin (>= 1500 mg/day or at highest 
tolerated dose) for at least 3 months prior to inclusion into the trial with or without additional 
oral glucose-lowering agents (except thiazolidinediones). 
8. Considered generally healthy (apart from diabetes mellitus type 2 and associated conditions 
such as hypertension, hyperlipidaemia and hyperuricaemia) upon completion of medical history, 
physical examination, vital signs, ECG and analysis of laboratory safety variables, as judged by 
the Investigator. 
6.3 
Exclusion Criteria 
1. Known or suspected hypersensitivity to sitagliptin or related products. 
2. Previous participation in this trial. Participation is defined as randomised. 
3. Receipt of any medicinal product in clinical development within 30 days before randomisation 
in this trial. 
4. History of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic 
reaction. 


 
 
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Trial ID 
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5. Any history or presence of clinically relevant cardiovascular, pulmonary, respiratory, 
gastrointestinal, hepatic, renal, metabolic, endocrinological (with the exception of conditions 
associated with diabetes mellitus), haematological, dermatological, neurological, osteomuscular, 
articular, psychiatric, systemic, ocular, gynaecologic (if female), or infectious disease, or signs 
of acute illness as judged by the Investigator.  
6. Any serious systemic infectious disease during four weeks prior to screening, as judged by the 
Investigator. 
7. Proliferative retinopathy or maculopathy, based on a recent (< 1.5years) ophthalmologic 
examination and/or severe neuropathy, in particular autonomic neuropathy, as judged by the 
Investigator.  
8. More than one episode of severe hypoglycaemia with seizure, coma or requiring medical 
assistance of another person during the past 6 months or hypoglycaemic unawareness as judged 
by the Investigator. 
9. Current or previous treatment (less than 3 months prior to screening) with insulin products other 
than insulin glargine and/or with GLP-1 receptor agonists and/or with thiazolidinediones.  
10. Unwillingness to wash-off any oral glucose-lowering agents other than metformin. 
11. Significant history of alcoholism or drug abuse as judged by the Investigator or consuming more 
than 24 grams of alcohol per day for male subjects or 12 grams per day (on average) for female 
subjects. 
12. A positive result in the alcohol and/or urine drug screen at the screening visit.  
13. Subject who is not able or willing to refrain from smoking and use of nicotine substitute 
products during the inpatient period. 
14. Positive to the screening test for Hepatitis Bs antigen or Hepatitis C antibodies and/or a positive 
result to the test for HIV-1/2 antibodies or HIV-1 antigen.  
15. Any medication (prescription and non-prescription drugs) intake planned within 7 days before 
start of IMP administration period that is known to influence BG levels or insulin secretion at 
the discretion of the investigator. Stable dose therapy with blood pressure lowering medication, 
thyroid hormones, cholesterol-lowering or uricostatic drugs will be allowed.  
16. Blood donation or blood loss of more than 500 mL within the 3 months prior to screening. 
17. Mental incapacity, unwillingness or language barriers precluding adequate understanding or co-
operation. 
18. Females of childbearing potential who are pregnant, breast-feeding or intend to become 
pregnant or are not using highly effective contraceptive methods (highly effective contraceptive 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
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2016-004480-39 
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methods are considered those with a failure rate less than 1% undesired pregnancies per year 
including surgical sterilisation, hormonal intrauterine devices (coil), oral hormonal 
contraceptives, sexual abstinence or a surgically sterilised partner). Sexual abstinence is 
considered as a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of the study. The reliability of sexual abstinence needs to be 
evaluted in relation to the preferred and usual lifestyle of the subject.  
Females who are postmenopausal can participate in the study without using adequate 
contraceptive methods. Postmenopausal is defined as women aged <52 years and being 
amenorrheic for more than one year with serum FSH level > 40 IU/L or aged >= 52 years and 
being amenorrheic for less than one year and with serum FSH level > 40 IU/L or aged >=52 
years being amenorrheic for more than one year. 
6.4 
Inhouse visit Exclusion Criteria 
Subjects who fulfil one or more of the inhouse visit exclusion criteria (see below) will be excluded 
from participation in the inhouse Visits 3 or 4. The inhouse visit may be rescheduled at the 
discretion of the Investigator.   
1. Consumption of alcohol within the last 24 hours prior to admission or a positive result of the 
breath alcohol test. 
2. Strenuous exercise within the last 48 hours prior to admission.  
3. Any medical condition or AE that could interfere with glucose metabolism, as judged by the 
Investigator. 
4. Any use of prescription or non-prescription medication according to exclusion criterion no. 15. 
6.5 
Withdrawal Criteria 
1. Subjects have the right to withdraw from the trial at any time for any reason.  
2. The subject may be withdrawn from the trial at the discretion of the Investigator if judged non-
compliant with trial procedures or due to a safety concern.  
3. If a protocol violation or concurrent illness occurs, which, in the clinical judgement of the 
Investigator, 
may 
invalidate 
the 
trial 
by 
interfering 
pharmacokinetically 
or 
pharmacodynamically with the IMPs, the subject will be withdrawn by the Investigator. 


 
 
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Trial ID 
DPP4-Hypo 
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4. Adverse event (AE): Subject reports symptoms, which are considered unacceptable by the 
subject and/or the Investigator. An AE form will be completed and the subject will be 
withdrawn from the trial. 
5. More than one episode of severe hypoglycaemia with seizure, coma or requiring medical 
assistance of another person during the treatment period. 
6. If a hypersensitivity reaction is suspected, Januvia® should be discontinued.  
7. If bullous pemphigoid is suspected, Januvia® should be discontinued. 
8. Pregnancy or intention to becoming pregnant.  
The date and reason of withdrawal will be entered on the end of trial page of the CRF. The end of 
trial form will be completed for all prematurely withdrawn subjects.  
6.6 
Subject Replacement 
A total of 20 subjects are planned to be randomised in the trial according to the sample size 
calculation (see Section 13.1). To account for drop-outs (a drop-out is defined as a subject leaving 
the trial after randomisation), drop-out subjects may be replaced at the discretion of the sponsor. A 
replacement subject will be assigned to the same treatment sequence as the subject being replaced. 
6.7 
Rationale for Trial Population 
Sitagliptin is an approved glucose lowering agent for adult patients with type 2 diabetes. This trial is 
therefore performed in adult patients with type 2 diabetes.  
Subjects with a background therapy of metformin and insulin glargine will be recruited to test the 
hypothesis that additional therapy with sitagliptin may improve the risk to develop hypoglyacemia 
in this patient population. Treatment with additional oral glucose lowering agents (except TZDs will 
be allowed to facilitate recruitment, but any oral diabetes therapy other than metformin and IMP 
should be discontinued throughout the entire trial duration to ensure the same background therapy 
in all participants.  
Since insulin glargine doses will be titrated to target as part of the protocol, baseline HbA1c of 
subjects may range from well-controlled to moderately controlled (8.5 %). For each subject, its 
daily metformin dose should be at least 1500 mg/day or at its highest tolerated dose level to ensure 
a homogeneously treated trial population. 


 
 
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Trial ID 
DPP4-Hypo 
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2016-004480-39 
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Both male and female subjects will be allowed to participate in the trial, but pregnant females or 
females who intend to become pregnant are not allowed to participate in the trial due to the risks 
associated with the induction of hypoglycaemic episodes. 


 
 
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Trial ID 
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7 Trial Materials 
7.1 
Investigational Medicinal Products (IMPs) 
The IMPs listed in Table 3 will be used in this trial:  
IMPs 
Kind of 
IMP 
Strength 
Pharmaceutical 
dosage form 
Dose per 
administration 
Route of 
administration 
Januvia® 
(sitagliptin) 
IMP to be 
tested 
50 mg 
Film-coated tablet 
2 tablets 
(100 mg) 
oral 
Matching 
placebo 
IMP for 
comparison 
- 
Film-coated tablet 
2 tablets 
oral 
Lantus® 
(insulin 
glargine) 
Challenging 
agent 
100 U/mL 
Solution for 
injection 
- 
subcutaneous 
injection 
OGT solution 
(glucose) 
Challenging 
agent 
75 g 
glucose/~300 
mL 
Liquid solution 
75 g glucose  
oral 
Table 3: Specification of Investigational medicinal products (IMPs) used in the trial 
 
Manufacturer of sitagliptin and matching placebo tablets is MSD and will be provided by MSD. 
Sitagliptin and matching placebo are referred to as “IMP” in this document if not stated otherwise. 
Sitagliptin  (Januvia® 50mg) received market authorisation in the EU in 2007 for the control of 
blood glucose levels in patients with type 2 diabetes.  
For further information please refer to the SmPC for Januvia® 50 mg.  
On in-house days Lantus® (insulin glargine) will be used as a challenging agent to provoke 
hypoglycaemic episodes. For this purpose it will be sourced from the German market and will be 
used from its original packaging (Lantus 100 U/mL Solostar ready-to-use pen). On outpatient days 
subjects will use their own insulin glargine. Here, insulin glargine is not used as challenging agent 
and consequently not regarded as IMP.  
The OGT in this trial is performed to provoke reactive hypoglycemia. Therefore, the glucose 
solution is defined as challenging agent. The OGT solution will be sourced from the German market 
(manufacturer: Roche) and will be used from its original packaging.  


 
 
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Trial ID 
DPP4-Hypo 
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Metformin may be provided by the investigational site as non-investigational medicinal product 
(NIMP) to those patients who have to discontinue their usual metformin combination product to  
washout any other oral glucose lowering agent. NIMP will be sourced from the German market and 
will be used from its original packaging. 
7.2 
Packaging and Labelling of Investigational Medicinal Product (sitagliptin and placebo) 
IMP (sitagliptin and matching placebo) is provided by MSD in blinded dosing bottles.   
Enough investigational medicinal products will be packed for the scheduled number of subjects. A 
buffer volume of IMPs will be provided in case of replacement of withdrawn subjects or damaged 
IMPs. 
7.2.1 Storage and Drug Accountability of Investigational Medicinal Product 
All IMPs will be stored and handled in accordance with the manufacturer instructions. 
All used, partly used and unused IMP/packaging must be kept by the Investigator in an access-
controlled room. 
For the IMP, the Investigator must keep an accurate record of all IMPs received and the products 
used for each subject in a Drug Accountability Record. Storage locations, batch numbers and expiry 
dates are also documented in this form. 
The drug accountability has to be performed in a timely manner.  
7.2.2 Dispensing of Investigational Medicinal Product(s) 
No IMPs may be dispensed to any person not enrolled in the trial. 
Any dispensing of IMP to an individual subject and return of IMP will be documented by the 
Investigator.  
Upon completion of the trial, the Sponsor will be responsible for destruction of IMP (used, partially 
used or unused) and destruction must be documented in the trial investigator file (TIF). 
7.3 
Retention Samples  
No retention samples will be kept for this trial.  


 
 
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7.4 
Preparation and Application of IMP (sitagliptin and placebo) 
IMP (sitagliptin and matching placebo) is provided in dosing bottles. Two IMP tablets from the 
dosing bottle are to be taken daily together with the morning metformin dose.  


 
 
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Trial ID 
DPP4-Hypo 
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8 Visits and Assessments 
8.1 
Visit Procedures 
Please refer to the information given in Section 2 for a general overview of the trial visits and the 
visit assessments and procedures. The following sections describe details of the visit assessments 
and procedures. 
The Investigator must keep a subject screening and identification log.  
8.2 
Visit 0 – Informed Consent Visit  
Prior to any trial-related activities, potential subjects will be provided with oral and written 
information about the trial course, the employed IMPs and the visit procedures. The subjects will be 
fully informed of their responsibilities and their rights while participating in the trial as well as of 
the possible risks and potential benefits of participation in the trial. They have the opportunity to 
discuss all open questions and will have ample time to consider participation. Subjects who wish to 
participate in the trial will be asked to personally date and sign an informed consent form prior to 
any trial-related activities. Trial-related activities are any procedures that would not have been 
performed during normal management of the subject (including e.g. fasting for screening). 
Likewise, the Investigator must also personally date and sign the informed consent form prior to 
any trial related activities. All subjects will be provided with a copy of their own signed and dated 
informed consent form. 
8.3 
Visit 1 – Screening Visit 
A rescheduling of the screening visit (within 17 days) is allowed once in case subjects have failed 
to be fasting. 
Subjects will receive a screening number in ascending order starting with 001. 
Screened subjects who do not meet or comply with all inclusion and exclusion criteria are excluded 
(screening failures), and their data will be recorded on a screening failure form. The reason for 
exclusion must be recorded on the screening failure form. Detailed information about which data 
will be entered into the trial database will be described in the trial specific data management plan. 
Re-screening of screening failures is generally not allowed according to Profil’s SOPs. Re-
assessment of laboratory parameters will be allowed once if handling issues, damaged samples, or 
haemolysed samples may have confounded the measurement results. 


 
 
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Trial ID 
DPP4-Hypo 
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Status / Version-No. 
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Eligible or potentially eligible subjects (lab results pending) will be provided with a Subject 
Identification Card (ID card), stating that the subject is participating in the trial and whom to 
contact (site address, Investigator name and telephone number). The subjects should be instructed to 
return the ID card to the Investigator at the last visit or to destroy the card after the last visit. 
If a washout of OADs is necessary, subjects will receive the glucometer, test strips and a diary to 
record amongst others daily fasting plasma glucose self-measurements during the washout before 
the randomisation visit. 
Before leaving the site, subjects are offered a breakfast.  
8.4 
Visit 2 – Randomisation Visit 
Results from the screening visit (including laboratory safety parameters) must be available before 
subjects can be invited to return to the trial site for the randomisation visit and assessed to be 
acceptable by the Investigator. These results must be verified by the signing and dating of test 
results by the Investigator. The Investigator should document if out of range results are clinically 
significant.  
Subjects taking oral anti-diabetes medication other than metformin will need to washout the 
additional medication for approximately 1 week before the randomisation visit.  
After the eligibility for trial participation has been confirmed, subjects will be randomised to 
receive first either sitagliptin or placebo (see Section 5.2).  
Subjects will be provided with IMP (sitagliptin or matching placebo) for the insulin titration period, 
a blood glucose meter and test strips (if not already handed out at the screening visit), as well as a 
diary (see Section 8.4.1) to record amongst others daily fasting plasma glucose self-measurements 
during the insulin titration period before the inhouse visit. The correct storage and administration of 
IMP, the correct usage of the glucometer will be explained and instructions on how to fill out the 
diary will be given. 
The investigator will inform the subject on the starting basal insulin glargine dose for the insulin 
titration period and how to change their daily basal insulin dose based on the daily fasting plasma 
glucose levels according to a titration algorithm. Subjects who are used to take their insulin glargine 
dose in the morning or divided over two doses will be instructed how to change their therapy for 
evening dosing. Subjects are informed about the symptoms of hypoglycaemia and about appropriate 
methods to treat hypoglycaemia. 
8.4.1 Insulin titration period 
Subjects will start an insulin titration period, aiming at finding the basal insulin dose that takes 
individual fasting plasma glucose to a range of 80-120 mg/dL for at least one week (with at least 4 


 
 
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Trial ID 
DPP4-Hypo 
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2016-004480-39 
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out of 7 fasting glucose concentrations falling into this range). A guideline for the insulin titration 
can be found in Appendix 1: Insulin titration guideline. Titration of insulin glargine is planned 
every 3-4 days based upon the lowest measured plasma glucose value since the last titration step. 
The trial physician may change the recommend insulin change by this guideline after reviewing the 
plasma glucose concentrations, any safety concerns from the subject and any other feedback (e.g., 
narrative from the subject). 
Subjects will be asked to record the following information in their diary (all data will be transferred 
to CRF): 
 daily fasting plasma glucose; date, time and value  
 daily insulin glargine dose; date and dose  
 any change in concomitant medication; start/stop date, description  
 adverse events; start/stop date and time, description  
 hypoglycaemic episodes; start/stop date and time, glucose value, treatment  
Regular telephone calls (e.g. twice weekly) with the subject will be planned during this period to 
evaluate the recorded fasting plasma glucose levels in the diary and supervise the dose titration. At 
the discretion of the investigator or at the request of the subject, the subject may visit the trial site 
for an unscheduled visit for personal review (by a trial physician) and consultation on the subject’s 
insulin titration and/or to receive more IMP (sitagliptin or matching placebo) or NIMP when 
needed. Once the fasting plasma glucose is in the range of 80-120 mg/dL for 4 out of the last 7 
days, the insulin dose is not changed further and subjects are invited to the supervised inhouse visit 
(within the following 7 days) and are instructed to comply with the dosing day exclusion criteria 
(Section 6.4). Subjects will be reminded to take all medication (insulin glargine, metformin and 
IMP) with them to the trial site. 
After reaching the above defined glucose range for 4 out of 7 days, subjects will continue with the 
documentation of fasting plasma glucose values until the inhouse visit takes place. If it is not 
possible to schedule the inhouse visit within the following 7 days, plasma glucose values have to be 
reconsidered and the titration period may be extended.   
8.5 
Visit 3 and 4 – Inhouse visits 
Please refer to the assessment schedule in Section 2.3 for the procedures and timing of assessments 
at the inhouse visits.  
Day -1 
Patients will be admitted to the trial site in the evening before first dosing (no fasting requirement). 
After a check of inhouse visit exclusion and withdrawal criteria and the subject diary, eligible 
subjects will continue with the visit procedures. A CGM sensor will be inserted and initiated. An 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
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00/0795-DPP4-Hypo 
Status / Version-No. 
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2016-004480-39 
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indwelling venous cannula placed into a distal forearm vein will be used for frequent blood 
sampling (plasma glucose, insulin, C-peptide, glucagon and other counter-regulatory hormones (see 
Table 2); hypoglycemia-related blood sampling will start at Day -1). A standardised dinner will be 
served (approximately at 19:00 hours) and subjects take their titrated dose of insulin glargine at 
their usual time in the evening. After 22:00 hours, approximately ten hours before dosing, only 
carbohydrate-free and calorie-free drinks (e.g., water, unsweetened tea) are allowed.  
Day 1 
At approximately 08:00 hours, a standard oral glucose load will be administered (75 g OGT, 
Roche). Subjects will take their daily morning metformin dose together with two tablets of IMP 
(sitagliptin or placebo, depending on randomisation). Subjects will be fasting for 24 hours from then 
on. In the evening of Day 1, the insulin glargine dose will be increased by 10% (to 110% of the 
results of titration) to further increase the risk of hypoglycaemia.  
Day 2 
On day 2, at approximately 08:00 hours, subjects will receive a mixed high lipid meal (see 
Appendix 2: Mixed high lipid meal examples) to support release of gastro-intestinal peptides like 
GLP-1 and GIP. Subjects will take their daily morning metformin dose together with two tablets of 
IMP (sitagliptin or matching placebo) and be fasting for another period of 24 hours from then on. 
Approximately 3 hours after the lipid meal, subjects will undergo a 30 min bicycle ergometer test at 
a workload taking them to a pulse > 120/min (approximately 75 Watt to start with, increasing the 
workload every 5 min until this pulse rate is achieved). The pulse rate of > 120/min should be kept 
until the end of the test. In the evening of day 2, the insulin glargine dose will be further increased 
by 10% (to 120% of the results of titration) to further increase the risk of hypoglycaemia.  
Day 3 
 
On day 3, another standard oral glucose load (75 g) will be administered at approximately 08:00 
hours. Subjects will take their daily morning metformin dose together with two tablets of IMP. 
Another bicycle ergometer test, under the same conditions as on Day 2, is performed at 
approximately 11:00 hours, the time when reactive hypoglycaemia may be expected following the 
oral glucose load. At approximately 13:00 hours on this day, the sampling period stops and subjects 
are offered food of their choice. After a short medical examination (vital signs, ECG, physical 
examination, safety lab), subjects can leave the site at the discretion of the Investigator. The subject 
may be released from the trial site if the Investigator does not have any safety concerns based on the 
last safety blood glucose value and the general condition of the subject. However, at the discretion 
of the Investigator or per request by the subject, the subject may stay at the trial site for a longer 
period.  


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
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2016-004480-39 
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Before discharge from the clinic, the subject is provided with a diary for the second titration and 
treatment period, test strips for the glucose meter (if needed) and IMP (sitagliptin or matching 
placebo) for the second treatment period. 
8.5.1 Washout and insulin titration period 
After completion of Visit 3, a minimum 4-week washout period starts. During the washout period, 
subjects continue taking their daily metformin and insulin glargine dose (at the pre-trial dose level) 
and should resume their pre-trial oral anti-diabetes medication. Any additional anti-diabetic oral 
medication has to be discontinued at least one week before the start of the insulin titration period. 
The insulin titration period will be conducted as described in Section 8.4.1.    
8.6 
Assessment of Treatment Compliance 
Treatment compliance will be checked by comparing the number of dispensed and returned tablets 
for each subject. Subjects for which treatment compliance is estimated to be less than 50%, will be 
withdrawn. Inhouse administrations will be supervised and recorded in the CRF. 
8.7 
Assessments for Pharmacodynamics 
8.7.1 Hypoglycaemic episodes 
Hypoglycaemia is defined as a: 
(a) symptomatic hypoglycaemic episode, symptoms typical for hypoglycaemia are experienced by 
the subject, irrespective of the plasma glucose concentration;  
(b) confirmed symptomatic hypoglycaemic episode, if in addition to the experienced 
hypoglycaemia symptoms plasma glucose is determined to be ≤ 70 mg/dL;  
(c) chemical hypoglycaemic episode, if a plasma glucose ≤ 70 mg/dL is determined, irrespective of 
the presence of hypoglycaemia symptoms; 
(d) asymptomatic episode, if a plasma glucose ≤ 70 mg/dL is measured in the absence of symptoms 
typical for hypoglycaemia.  
One hypoglycaemic episode can be a combination of the above. E.g., if both symptoms and a 
fasting plasma glucose level ≤  70 mg/dL are recorded, the hypoglycaemic episode can be defined 
as (a), (b) and (c). An episode continuously characterized by hypoglycaemia symptoms or plasma 
glucose levels ≤  70 mg/dL will be counted as one episode. Newly appearing symptoms after some 
time (approximately 30 minutes) without symptoms and with plasma glucose levels > 70 mg/dL or 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
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00/0795-DPP4-Hypo 
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2016-004480-39 
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plasma glucose levels ≤  70 mg/dL after two consecutive measurements > 70 mg/dL will be counted 
as a new episode. 
Each time plasma glucose is ≤ 70 mg/dL, 100 mL juice or dextrose tablets (equivalent to 10 g of 
rapidly absorbable carbohydrate) will be given by mouth. Repeat plasma glucose measurement will 
be made in 10 minute intervals until two consecutive measurements are above 70 mg/dL. 
During the outpatient period, plasma glucose measurements to confirm hypoglycemia are 
performed by the subject (SMPG) and recorded in the diary. During the in-house visits, plasma 
glucose measurements are performed by trained staff on a laboratory analyser (see Section 8.7.2). 
The following information should be recorded for each hypoglyceamic episode: 
-Start / Stop date and time of episode (symptoms, plasma glucose measurement ≤ 70 mg/dL) 
-Plasma glucose value at start of episode and for repeat measurements  
-Symptoms (yes / no, if yes, description of all symptoms) 
-Treatment (to be ticked for every glucose measurement) 
8.7.2 Plasma glucose, Insulin, C-peptide, glucagon and (other) counter-regulatory 
hormones 
Venous blood samples taken for the analysis of glucose concentration will be analysed at the trial 
site using the Super GL glucose analyzer (Dr Müller Gerätebau GmbH, Freital, Germany). The 
device can be programmed to measure the plasma glucose content of each sample. In case of 
venous plasma glucose measurements < 90 mg/dL as well as for all hypoglycemia-related 
measurements, glucose will be additionally measured in capillary blood (e.g., fingerstick; also 
analysed with the Super GL). In that case, the capillary measurement value will be used to trigger 
any subsequent sampling and for analysis of trial related endpoints.  
Insulin, C-peptide, glucagon and other counter-regulatory hormone concentrations (cortisol, human 
growth hormone, adrenaline, noradrenaline, prolactin) will be determined by the PD laboratory.  
Blood samples for the evaluation of plasma glucose, insulin, C-peptide, glucagon other counter-
regulatory hormones are taken (i) at the times indicated in Table 2; (ii) immediately after a plasma 
glucose value of ≤ 70 mg/dL has been measured if not already sampled simultaneously and 30 and 
60 minutes thereafter; (iii) at the time subject reports symptoms of hypoglycaemia and the measured 
plasma glucose value is ≤ 90 mg/dL, as well as 30 and 60 minutes thereafter. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
44 of 74 
 
 
8.7.3 Continuous glucose monitoring (CGM) 
Subjects will use a CGM system during the inhouse visit to evaluate the time spent at low glucose, 
target glucose and high glucose ranges. A commercially available sensor system (e.g., Dexcom G5; 
the same system will be used in all trial subjects) will be inserted and started upon subject arrival on 
Day -1 of the inhouse visit. The system will be calibrated according to the manufacturing 
instructions with the exception that plasma glucose values from venous samples may be used. The 
CGM data will not be blinded and a low sensor glucose alert will be programmed to warn subjects 
for glucose readings below or equal to 70 mg/dL. Subjects should inform study staff of each alert, 
as these may trigger an additional laboratory plasma glucose measurement (if this hypoglycemic 
episode was not detected previously). The sensor will be removed before discharge on Day 3. 
8.8 
Assessments for Safety 
8.8.1 Clinical Assessments 
Adverse events 
Adverse events (AEs) will be recorded in accordance with the procedures described in Section 9. 
Any clinically significant worsening since baseline of a previous finding must be reported as an AE. 
During each contact with the trial site staff (site visits and telephone contacts) the subject must be 
asked about changes of their health status. This must be documented in the subject’s medical 
record. 
Concomitant illness and medical history 
A concomitant illness is any illness that is present prior start of the trial (i.e. prior to randomisation).  
Medical history is an account of medical events that the subject has experienced in the past. 
 Concomitant illnesses present at the start of the trial will be recorded in the CRF prior to 
randomisation.  
 Relevant medical conditions/illnesses in the past will be recorded in the CRF at screening. 
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset, date of resolution or continuation. 
Any change to a concomitant illness should be recorded during the trial, including end date, if 
applicable. A clinically significant worsening of a concomitant illness must be reported according to 
Section 9. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
45 of 74 
 
 
Physical examination 
An examination of the following body systems will be performed: 
 Head, ears, eyes, nose, throat (HEENT), incl. thyroid gland 
 Heart, lung, chest 
 Abdomen 
 Skin and mucosae 
 Musculoskeletal system 
 Nervous system 
 Lymph node 
 Other findings  
At the screening visit, any abnormality will be recorded and described in the CRF including the 
Investigator’s assessment of clinical significance (‘abnormal, not clinically significant’ or 
‘abnormal, clinically significant’). Clinically significant findings at the screening visit should be 
recorded as concomitant illness. 
At subsequent visits, any clinically significant deterioration of a pre-existing condition as well as 
any new clinically significant findings will be recorded as AEs. 
Vital signs 
An examination of the following vital signs will be performed: 
 Diastolic and systolic blood pressure (mmHg) are measured after at least 5 min rest in a supine 
position. At the screening visit blood pressure is measured in both arms. The blood pressure 
from the arm with the higher systolic value is transcribed into the CRF and this arm is used for 
all subsequent measurements of the subject’s blood pressure in this trial.  
 Pulse (beats per min) measured after at least 5 min rest in a supine position. 
 Body temperature, tympanic (oC). 
In addition to the pre-specified assessments in sections 2.2 and 2.3, blood pressure and pulse may 
be assessed at any time during the trial at the discretion of the Investigator. Additional 
measurements will not be recorded in the CRF.  
Electrocardiogram 
A standard 12-lead electrocardiogram (ECG) will be performed. 
ECG parameters (Heart rate, PQ, QRS, QT, QTcB) and any abnormality will be recorded and 
described in the CRF including the Investigator’s assessment of clinical significance (‘abnormal, 
not clinically significant’ or ‘abnormal, clinically significant’). Clinically significant findings at the 
screening visit should be recorded as concomitant illness.  


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
46 of 74 
 
 
At subsequent visits, any clinically significant deterioration of a pre-existing condition as well as 
any new clinically significant findings will be recorded as AEs. 
Plasma glucose for safety 
During the trial, plasma glucose levels will be monitored at the trial site by a laboratory method 
(Super GL Glucose Analyzer; Dr. Müller Gerätebau GmbH, Freital, Germany) for 
pharmacodynamic analysis and safety. At the discretion of the Investigator additional plasma 
glucose measurements may be made when there is a suspicion of a hypoglycaemic (e.g. triggered 
by a CGM alert) or hyperglycaemic episode. All plasma glucose measurements will be recorded in 
the CRF, also if they are not related to a hypoglycaemic episode. 
Treatment of hypoglycaemic episodes is described in Section 8.7.1.  
8.8.2 Laboratory Assessments 
The safety parameters that will be determined at the safety laboratory are listed in Table 4. 
The safety laboratory will perform a first check on their values for safety parameters and flag any 
values outside the reference range. The Investigator must evaluate all results outside the reference 
range (clinically significant or not clinically significant). Before the Investigator starts the trial (i.e. 
obtains informed consent from the first subject), the laboratory reference ranges must be available 
in the Investigator’s Trial File. The results provided by the safety laboratory will be part of the trial 
database. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
47 of 74 
 
 
 
Table 4 
Routine laboratory safety tests 
Haematology 
 
Haematocrit 
Leucocytes 
Haemoglobin 
Neutrophile granulocytes (total count and relative) 
Erythrocytes 
Lymphocytes (total count and relative) 
Mean corpuscular volume (MCV) 
Monocytes (total count and relative) 
Mean corpuscular haemoglobin (MCH) 
Eosinophile granulocytes (total count and relative) 
Mean corpuscular haemoglobin concentration 
(MCHC) 
Basophile granulocytes (total count and relative) 
Thrombocytes (platelets) 
 
 
 
Biochemistry 
 
Sodium 
Uric acid 
Potassium 
Total protein 
Calcium 
Albumin 
Chloride 
Total bilirubin 
Phosphate 
Creatine kinase* 
Creatinine 
Alkaline phosphatase 
Urea 
Gamma-glutamyltransferase (γ-GT) 
AST (aspartate aminotransferase, GOT) 
Lactic dehydrogenase (LDH) 
ALT (alanine aminotransferase, GPT) 
 
Total cholesterol 
High-density lipoprotein (HDL) cholesterol 
Low-density lipoprotein (LDL) cholesterol 
Triglycerides 
 
 
Coagulation (screening only) 
 
International normalised ratio (INR) 
Activated partial thromboplastin time (APTT) 
 
 
Urinalysis# (screening only) 
 
Protein 
Leucocytes 
Glucose 
pH 
Erythrocytes 
Ketones 
 
 
Infectious serology (screening only) 
 
Hepatitis B surface antigen 
HIV-1/2 combi 
Hepatitis C antibodies 
 
 
 
Other 
 
HbA1c (screening only) 
serum β-HCG (females only; screening only) 
 
serum FSH (post-menopausal females only; screening 
only) 
 
 
# In case of specific abnormalities in the urinalysis a urine sediment assessment will be performed. 
* If CK is outside normal range CKMB will be analysed. If CKMB is elevated, Troponin T will be analysed. 
 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
48 of 74 
 
 
Pregnancy test 
For all female participants, a pregnancy test will be performed at the safety laboratory on a blood 
(serum) sample obtained at the screening visit and at Visits 3 and 4 from a urine sample at the trial 
site. The pregnancy test will be performed according to local regulation.  
For women aged < 52 years and being amenorrheic for more than one year or aged ≥ 52 years and 
being amenorrheic for less than one year a serum FSH will be performed at the screening visit to 
confirm the postmenopausal state. Postmenopausal is defined as women aged < 52 years and being 
amenorrheic for more than one year with serum FSH level > 40 IU/L or aged ≥ 52 years and being 
amenorrheic for less than one year and with serum FSH level > 40 IU/L  or aged ≥ 52 years being 
amenorrheic for more than one year. 
8.9 
Other Assessments and Dietary Requirements 
Demography 
 Age 
 Sex 
 Race 
Concomitant medication 
A concomitant medication is any medication, other than the IMPs and current diabetes treatment 
(including oral glucose-lowering agents that need to be washed out), which is taken during the trial, 
including insulin titration and washout periods. 
Details of any concomitant medication must be recorded at trial entry (i.e. at screening). Any 
changes in concomitant medication must be recorded at each visit as they occur. The information 
collected for each concomitant medication includes (at a minimum) trade name or generic name, 
indication, start date and stop date or continuation. A change in medication due to an AE must be 
recorded and reported according to section 9. If the change in medication influences the subject’s 
eligibility to continue in the trial, the Sponsor and monitor must be informed. 
Diagnosis of diabetes and current diabetes treatment 
 Date of diagnosis of diabetes 
 Current diabetes treatment [start date, product name(s), dose(s)] 
Body measurements 
 Height (cm or m), without shoes 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
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49 of 74 
 
 
 Body weight (kg), only wearing underwear 
 Body mass index (kg/m2) calculated by the Investigator based on height and body weight (body 
weight/height2) 
Alcohol breath test 
An alcohol breath test will be performed using an alcohol meter (‰) by standard procedures at the 
trial site.  
Screening for drugs of abuse  
At the screening visit, a urine quick test for the presence of drugs of abuse (e.g. amphetamine, 
barbiturates, benzodiazepines, cannabis, cocaine, methadone, methamphetamine, opiates, 
phencyclidine and tricyclic antidepressants) will be performed at the trial site from at least 5 mL 
fresh mid-stream urine using a stick.  
Fasting 
Fasting is defined as abstinence from food and beverage consumption (other than water) for at least 
10 hours. Intake of rapidly absorbable carbohydrates (not more than 20 g carbohydrate) will be 
allowed if necessary to prevent hypoglycaemia. 
Subjects should arrive fasting prior to screening and will undergo multiple fasting periods at the 
inhouse visits.  
Dietary Requirements 
No specific nutritional regimen is required during the outpatient periods of the trial.  
During the inpatient periods, specific dietary restrictions apply. During the inpatient periods, 
consumption of foods or drinks other than those served at the clinical unit is prohibited. 
8.10 Volume of Blood Sampled during Trial  
The total volume of blood sampled from each subject during the trial depends on the amount of 
additional samples taken in conjuction with hypoglycemic episodes.  
For each inhouse visit (Visit 3 and 4), the blood volume of the planned samples adds up to 
approximate 150 mL blood per subject. Each hypoglycaemic episode will trigger 2 or 3 additional 
blood samples of approximately 7.5 mL each.  
Additional blood samples may be drawn at the discretion of the Investigator (e.g. glucose for 
safety). 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
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50 of 74 
 
 
If blood loss for a subject is expected to exceed 500 mL during a 3-month period, the Investigator 
should confirm that there are no medical concerns (based on a laboratory hemoglobin measurement) 
before blood sampling is continued.  
Blood samples storage 
All blood samples taken will be destroyed at the latest after finalisation of the clinical trial report.  


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
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51 of 74 
 
 
9 Adverse Events 
9.1 
Definitions 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a trial subject after randomisation (Visit 2) and 
which does not necessarily have a causal relationship with the IMP. An AE can therefore be any 
unfavourable and unintended sign (for example, an abnormal laboratory finding), symptom, or 
disease documented during the clinical trial, whether or not considered related to the experimental 
procedures or IMPs.  
AEs include: 
 A clinically significant worsening of a concomitant illness. 
 A clinical laboratory abnormality which is clinically significant, i.e. any abnormality that 
suggests a disease and/or organ toxicity and is of a severity that requires active management. 
Active management includes active treatment or further investigations, for example change 
of medicine dose or more frequent follow-up due to the abnormality. 
 
The following should not be recorded as AEs, if recorded at screening (on Screening Form or 
CRF): 
 Pre-planned procedure, unless the condition for which the procedure was planned has 
worsened from the first trial related activity after the subject has signed the informed 
consent. 
 Pre-existing conditions found as a result of screening procedures (pre-existing conditions 
should be reported as medical history or concomitant illness). 
Serious Adverse Event (SAE) 
A SAE is any untoward medical occurrence that:  
 results in death  
 is life-threatening  
 requires inpatient hospitalisation or prolongation of existing hospitalisation, 
 results in persistent or significant disability or incapacity,  
 is a congenital anomaly or birth defect, 
or events that may require intervention to prevent one of the above listed outcomes. 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
An AE, fulfilling one of the criteria of seriousness and being assessed as related to IMP application 
(all IMPs according to Table 3), the nature or severity of which is not consistent with the applicable 
reference document. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
52 of 74 
 
 
Intensity of an Adverse Event 
The maximum intensity (severity) of all AEs must be assessed by the Investigator and documented. 
Severity should be graded when the AE outcome is known: 
Mild:  
 A type of adverse event 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 adverse event 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 adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
A ‘severe’ reaction does not necessarily deem the AE as ‘serious’ and a SAE may not be ‘severe’ in 
nature. 
Causality relationship to IMP 
The causality of each AE should be assessed by the Investigator according to the following 
classification: 
Probable: 
Good reason and sufficient documentation to assume a causal relationship. 
Possible: 
A causal relationship is conceivable and cannot be dismissed. 
Unlikely: 
The event is most likely related to aetiology other than the trial product. 
Outcome of an Adverse Event 
The outcome of all AEs must be assessed by the Investigator and documented by his/her staff. The 
following definitions should be used: 
Recovered/resolved:  The subject has fully recovered, or by medical or surgical treatment the 
condition has returned to the level observed at the first trial-related activity 
after the subject signed the informed consent.  
Recovering/resolving: The condition is improving and the subject is expected to recover from the 
event. This term is only applicable if the subject has completed the trial. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
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53 of 74 
 
 
Recovered/resolved  
with sequelae:  
The subject has recovered from the condition, but with lasting effect due to a 
disease, injury, treatment or procedure. If a sequela meets an SAE criterion, 
the AE must be reported as an SAE. 
Not recovered/ 
not resolved:  
The condition of the subject has not improved and the symptoms are 
unchanged, or the outcome is not known. 
Fatal:  
This term is only applicable if the subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a subject before he/she died 
should be assessed as "recovered/resolved", "recovering/resolving", 
"recovered/ resolved with sequelae" or "not recovered/not resolved". An AE 
with fatal outcome must be reported as an SAE. 
Unknown:  
This term is only applicable if the subject is lost to follow-up. 
9.2 
Collection, Recording and Reporting of Adverse Events 
All events meeting the definition of an AE must be collected and reported from the randomisation 
visit until the end of Visit 4 (post-treatment follow-up may be performed to assess the outcome of 
the AE). At each contact with the site (visit or telephone) the subject must be asked about AEs. All 
AEs, either observed by the Investigator or reported by the subject, must be recorded by the 
Investigator and evaluated. 
The Investigator should record the diagnosis, if possible. If no diagnosis can be made the 
Investigator should record each sign and symptom as individual AEs. 
All AEs must be recorded by the Investigator. One single Adverse Event Form must be used per AE 
from start to resolution. For SAEs, the Serious Adverse Event Form must also be completed.  
AE information should include the following: 
 Date and time of onset and resolution 
 Date of Investigator’s first information on the (S)AE (not to be recorded in the CRF) 
 Seriousness 
 Severity 
 Causal relationship with IMP 
 Interruption or withdrawal of treatment and other measures taken 
 Outcome 
All AEs are coded; details are described in the trial specific Data Management Plan.  


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
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The Investigator / Sponsor must report initial information in writing (fax or email) on all SAEs to 
the responsible medical monitor of the trial immediately (within 24 hours) after obtaining 
knowledge about the event.  
 
Name:  
Dr. Tim Heise 
 
Profil Institut für Stoffwechselforschung GmbH 
 
Address:  
Hellersbergstr. 9, 41460 Neuss, Germany 
Tel:  
 
+49 2131 4018 411 
Fax:   
+49 2131 4018 511 
E-mail: 
Tim.Heise@profil.com 
 
The Sponsor must inform the Competent Authorities and IRBs/IECs in accordance with the local 
requirements in force and ICH guideline for GCP. The trial monitor must be informed accordingly. 
9.3 
Follow-up of Adverse Events 
Follow-up procedures may be different based on the nature (diagnosis, severity, seriousness) of the 
AE and will follow Profil’s SOP on (S)AE Handling and Reporting.   
Follow-up actions for all SAEs will be determined after internal review and/or sponsor review.  
The follow up information should only include new (updated and/or additional) information that 
reflects the situation at the time of the Investigator’s signature. 
Follow-up information on (S)AEs will be updated using the (S)AE Form. If a non-serious event 
becomes serious during the follow-up the AE Form and SAE Form have to be used and reporting 
timelines follow those of a SAE. 
The Investigator must forward follow-up information on SAEs and if previously non-serious AEs 
become SAEs to the medical monitor (contact details are given in section 9.2).  
9.4 
Hypoglycaemia 
The aim of this trial is provoke hypoglycaemic episodes during the medically supervised, inhouse 
visits. Hypoglycaemic episodes are considered pharmacodynamic responses to the treatment 
administered and experimental procedures. Hypoglycaemic episodes will therefore not be regarded 
as adverse events in this trial and documented separately as efficacy parameter.  


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
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55 of 74 
 
 
However, should a hypoglycaemic episode be considered severe, such an event will be regarded as 
SAE and should be recorded on an AE / SAE form. 
Severe hypoglycaemia (major hypoglycaemia): A hypoglycaemic event requiring assistance of 
another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These 
events may be associated with sufficient hypoglycaemia to induce seizure or coma. Plasma or blood 
glucose measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient evidence that the 
event was induced by a low plasma glucose concentration.  
Any severe hypoglycaemic episode will be accompanied by a narrative giving qualitative 
descriptions of timing of the episodes in relation to drug exposure, time of onset, time after last drug 
administration, time after meal, severity, duration, outcome of hypoglycaemia, dose of treatment. 
9.5 
Pregnancy 
Female subjects must be instructed to notify the Investigator immediately if they become pregnant 
or if they suspect to be pregnant during the trial. The Sponsor has a responsibility to monitor the 
outcome of all pregnancies reported during the clinical trial. 
The Investigator must report all information on pregnancies, including AEs in the subject, the 
foetus, and newborn infant/ toddler. The pregnancy report must be forwarded to the Sponsor 
preferably electronically as PDF or by fax. 
The Investigator must follow the pregnancy until the pregnancy outcome and the newborn infant(s) 
until the age of 1 month. The Investigator must collect information on the pregnancy and pregnancy 
complications as well as the pregnancy outcome including the health of the newborn infant(s) on 
the pregnancy forms.  
The following must be collected:  
 Initial information of the pregnancy.  
 Information on the outcome of the pregnancy - including the health status of the newborn infant 
at the age of 1 month. 
 All AEs in connection with the pregnancy and pregnancy outcome must be reported on the 
pregnancy forms. It must be clear in the description if the event occurs in the subject, the foetus 
or the newborn infant. 
 All SAEs in connection with the pregnancy and pregnancy outcome must be reported on the 
pregnancy forms following the same timelines as required for other SAEs (see Section 9.2). It 
must be clear in the description if the event occurs in the subject, the foetus or the newborn 
infant.  


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
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56 of 74 
 
 
The SAEs that must be reported including abnormal outcome - such as congenital anomalies, foetal 
death and termination of pregnancy (spontaneous or elective abortion), including any anomalies of 
the foetus observed at gross examination or during autopsy - as well as other pregnancy 
complications (ectopic pregnancy) fulfilling the criteria of an SAE. 
9.6 
Precautions 
Normal precautions taken for a human trial, including the provision of emergency equipment, will 
be taken during this trial. Qualified and well-trained physicians and medical staff will instruct the 
subjects. During a subject’s participation in the trial, the Investigator should ensure that adequate 
medical care is provided to the subjects for any AEs, including clinically significant laboratory 
values related to the trial. The Investigator should inform the subject when medical care is needed 
for intercurrent illnesses of which the Investigator becomes aware.  
For further information on safety precautions for sitagliptin, please refer to the current version of 
the SmPC for Januvia® respectively. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
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10 Risk-Benefit Assessment 
Potential Risks 
Trial subjects will have been informed by the Investigator of the potential risks of sitagliptin 
treatment and other trial-related procedures before they enter the trial.  
Treatment with sitagliptin can result in undesired effects or complaints. Undesired effects and 
complaints which have been observed are listed below (please also refer to the SmPC for Januvia®). 
After adding sitagliptin to metformin: 
Common (may affect up to 1 in 10 people): low blood sugar, nausea, flatulence, vomiting 
Uncommon (may affect up to 1 in 100 people): stomach ache, diarrhoea, constipation, 
drowsiness 
Some patients have experienced different types of stomach discomfort when starting the 
combination of sitagliptin and metformin together (frequency is common). 
Some patients have experienced the following side effects while taking sitagliptin in combination 
with insulin (with or without metformin): 
Common: flu 
Uncommon: dry mouth 
Some patients have experienced the following side effects while taking sitagliptin alone in clinical 
studies, or during post-approval use alone and/or with other diabetes medicines: 
Common: low blood sugar, headache, upper respiratory infection, stuffy or runny nose and 
sore throat, osteoarthritis, arm or leg pain  
Uncommon: dizziness, constipation, itching 
Frequency not known: kidney problems (sometimes requiring dialysis), vomiting, joint pain, muscle 
pain, back pain, interstitial lung disease 
Subjects that are required to washout oral anti-diabetes medication before starting the insulin 
titration period may temporarily experience more pronounced fluctuations of their plasma glucose 
levels, with a tendency to elevated glucose levels. As the washout period is relatively short (1 week) 
and is followed by an intensification of their diabetes treatment thereafter, this risk is considered 
low. 
Trial-related risks are mainly associated with an increased risk of hypoglycaemia due to therapy 
intensification with basal insulin titration. The add-on of sitagliptin is hypothesized not to increase 
and potentially reduce the risk of hypoglycaemia. Testing this hypothesis is the objective of the 
current trial. To minimise the risk of (severe) hypoglycaemia during the insulin titration period 
subjects will be educated on the symptoms of hypoglycaemia and how to act in case of 
hypoglycaemia. Subjects will receive a blood glucose meter and test strips for self-measurement of 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
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58 of 74 
 
 
plasma glucose levels during the outpatient periods. The insulin titration scheme used aims to bring 
the subject’s fasting plasma glucose level down into a normal range in a safe manner. The insulin 
titration scheme has been adopted in a previous study at the Ruhr-University Bochum (unpublished 
data), during which basal insulin titration was performed under inhouse conditions in 16 subjects 
with type 2 diabetes. The basal insulin dose was changed under medical supervision on a daily 
basis. At the end of the titration period, all subjects achieved FPG levels below 120 mg/dL without 
any episodes of symptomatic hypoglycaemia. The lowest measured FPG concentration in the study 
was 72 mg/dL, demonstrating both efficacy and safety of this insulin titration algorithm.The insulin 
titration is supervised by medical staff during regular telephone calls and the research physician 
may adjust the insulin titration on an individual basis for safety reasons. Procedures during the 
inhouse visits are designed to increase the risk of hypoglycaemia. To minimise the risk of severe 
hypoglycaemia during the inhouse period, CGM technology to detect low glucose levels in real-
time will be used in addition to regular and frequent plasma glucose checks at times the risk of 
hypoglycaemia is expected to be highest. Medical supervision and emergency equipment will be 
available at all times inhouse. 
Other risks of trial procedures are associated with insertion of intravenous catheters for regular 
venous blood sampling. These risks are minimal, because the blood sampling techniques have been 
used as standard procedure for a long time in human research subjects. 
The long inhouse fasting periods may be regarded as unpleasant with a strong feeling of hunger. 
There is a risk of gastro-intestinal problems with the consumption of the high-fat meal on Day 2. 
Potential Benefits 
Subjects will receive a thorough medical examination at the start of the trial. The insulin titration 
will provide valuable information to the subject on how to adjust their daily basal insulin dose after 
the trial to improve their metabolic control. The trial subjects are a target population for improved 
diabetes treatment with a DPP-4 inhibitor. The results of the trial may possibly contribute to the 
improved treatment of patients with type 2 diabetes taking sitagliptin in addition to basal insulin and 
metformin.  
Risk-Benefit Assessment 
The overall residual risk for subjects participating in this trial is believed to be acceptable.  
While mitigation strategies implemented in the protocol reduce the potential risks of treatment and 
trial-related procedures, most notably hypoglycaemia, the findings of this trial may reveal 
information that can substantially improve medical care for persons with diabetes type 2.  


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
59 of 74 
 
 
11 Data Management 
Data Management is the responsibility of Profil Institut für Stoffwechselforschung GmbH, Neuss 
Germany. 
The complete Data Management process will be described in detail and agreed on in the Data 
Management Plan for this trial. 
11.1 Case Report Forms (CRFs) 
The Data Management Department of Profil Institut für Stoffwechselforschung GmbH will provide 
the CRFs. All further information regarding the CRFs and the data flow will be described and 
agreed on in the Data Management Plan. 
 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
60 of 74 
 
 
12 Monitoring Procedures 
The monitoring procedures for this trial are described in detail in the Monitoring Manual. The 
objectives of the monitoring procedures are to ensure that (i) the safety and rights of the trial 
subjects are respected, (ii) that accurate, valid and complete data are collected, and (iii) that the trial 
is conducted in accordance with the trial protocol, the principles of GCP and local legislation.  
The monitor must be given direct access to the TIF and source documents (original documents, data 
and records). Direct access includes permission to examine, analyse, verify and reproduce any 
record(s) and report(s) that are important to evaluation of the clinical trial. 
Key tasks of the monitor include to verify the presence of informed consent, the adherence to the 
inclusion/exclusion criteria, the documentation of SAEs, and the recording of all safety and efficacy 
variables. The monitor will also confirm the completeness of patient records, the adherence to the 
protocol and the progress in subject enrolment.  
Because no information that could reveal the identity of subjects may ever be removed from the 
trial site, the monitor will visit the site at regular intervals to perform these monitoring tasks. Other 
contact between the Investigator and monitor will be maintained as required through telephone calls 
and e-mail. The Investigator and/or key members of staff involved in the trial must be available to 
assist the monitor during all visits.  
Site Initiation Visit 
During the Site Initiation Visit (SIV) the Sponsor and/or monitor will review information on the 
IMP, the protocol, the CRFs and other key aspects of the trial with the Investigator and the key 
members of staff involved in the trial. The topics of the SIV are documented in a SIV report made 
available to the Investigator. Sponsor’s documentation on the SIV (e.g. power point presentation) 
should be filed by the Investigator. 
Source Data Verification 
Details on source data verification are specified in the Monitoring Manual. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
61 of 74 
 
 
13 Statistical Considerations 
Profil Institut für Stoffwechselforschung GmbH, Neuss, Germany, will be responsible for the 
statistical analysis. The statistical planning and conduct of analyses of the data from this trial will 
follow the principles defined in relevant ICH guidelines. A general description of the statistical 
methods to be used is given in this chapter, specific details will be provided in the Statistical 
Analysis Plan (SAP), which will be prepared before data base lock. All statistical analyses will be 
performed using SAS® (SAS Institute Inc., Cary, North Carolina, United States of America 
[USA]), version 9.4 or later.  
13.1 Sample Size Calculation 
It is assumed that the protocol will provoke an average of 2 confirmed episodes of hypoglycaemia 
per 48 hours with the administration of placebo. A reduction by 30% due to sitagliptin would be of 
clinical significance.  
As the relevant information needed for a sample size calculation is not available no formal sample 
size calculation was performed for the primary objective. The sample size calculation is based on 
one of the secondary objectives, the comparison of the time spent at an interstitial glucose 
concentration ≤ 70 mg/dL. Assuming a variability of 40% for placebo and sitagliptin in this trial 
and assuming a 25% reduction in the secondary endpoint with sitagliptin compared to placebo, 
there will be an approximate 85% power to detect a statistically significance difference (p<0.05) 
with 18 completers. However, due to the uncertain variability 20 subjects are planned to be 
randomised into the study. 
13.2 Selection of Subjects for Analyses 
The following analysis sets are defined in accordance with the ICH-E9 guidance (14): 
 
Full Analysis Set (FAS):  
is based on the intention-to-treat principle and includes all randomised subjects. In exceptional 
cases subjects from the FAS may be excluded (will be decided in the DBR meeting). In such cases 
the exclusion will be justified and documented. Subjects will contribute to the evaluation ‘as 
randomized’. 
 
Per-Protocol Population (PPP):  
includes all subjects of the FAS who completed the trial without any major protocol violations. 
Subjects in the PPP will contribute to the evaluation ‘as treated’. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
62 of 74 
 
 
 
Safety Analysis Set:  
includes all subjects receiving at least one dose of the investigational product or its comparator. 
Subjects in the safety set will contribute to the evaluation ‘as treated’.   
 
Analyses of PD endpoints will be based on the FAS (and PPP if necessary). The analysis of the 
safety endpoints will be based on the Safety Analysis Set.  
 
Before data are released for statistical analysis, a blinded review of all data will take place to 
identify protocol deviations that may potentially affect the results. This review will be performed 
without revealing which IMP the subjects are assigned to. The blinding of the IMPs will be 
maintained for everyone involved in allocating subjects to the analysis sets until data are released 
for statistical analysis. Furthermore, outliers will be identified by data review according to ICH-E9 
(14), using a fake randomisation. In addition, protocol deviations, which may potentially affect the 
results, will be identified and it will be evaluated if subjects and/or data should be excluded from 
the analysis. 
Obviously erroneous data points may be excluded from the analyses or re-analysed (in case of e.g. 
serum concentrations). The decision to re-analyse or exclude data points from the statistical analysis 
is the joint responsibility of the Sponsor, the Scientific Consultants and the Trial Statistician.  
The subjects or observations to be excluded and the reason for their exclusion will be documented 
and signed by those responsible prior to database release. The documentation will be stored together 
with the remaining trial documentation. The subjects and observations excluded from analysis sets, 
and the reason for this, will be described in the clinical trial report. 
13.3 Statistical Methods 
The hypothesis that will be investigated in this trial is that sitagliptin reduces the number of 
hypoglycaemic episodes in patients with type 2 diabetes treated to target with basal insulin glargine 
and metformin, when measures are taken to increase the risk for such episodes (fasting, increases in 
insulin dosage, lipid load to increase incretin hormone release, exercise). The hypothesis that 
sitagliptin improves recovery from such episodes will also be examined. 
The primary analysis is aimed to demonstrate a reduction of 30% in the number of hypoglycaemic 
episodes with sitagliptin compared to placebo during the experimental procedures. Unless otherwise 
stated, all formal tests of hypothesis will be conducted at the two-sided 5% level of significance. No 
alpha adjustment will be done. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
63 of 74 
 
 
All analyses, listings, tables and plots will be performed using all available data unless otherwise 
stated. In general missing data will not be replaced, and obviously erroneous data points will be 
excluded from the analyses or re-analysed (as described in section 13.2).  
In general, descriptive statistics will be performed for all endpoints. Categorical data will be 
presented using counts and percentages, whilst continuous variables will be presented using the 
mean, geometric mean, standard deviation, coefficient of variances, minimum, median, maximum 
and the number of subjects with evaluable data. 
Data from clinical assessments will be presented in summary tables and in individual subject 
listings. Data will be summarized with respect to demographic and other baseline characteristics, 
efficacy and safety observations and other measurements. 
Individual subject listings will be sorted by randomization number, treatment group, and, if 
applicable, visit and/or time. Summary tables will be presented by treatment group. 
13.3.1 Analysis of the Primary Efficacy Endpoint(s) 
The number of hypoglycemic episodes (primary endpoint and secondary endpoints; varying 
definitions of hypoglycemia) will be compared between sitagliptin and placebo treatment by 
Fisher's exact test. 
13.3.2 Analysis of the Secondary Efficacy Endpoints 
Time spent at an interstitial glucose concentration will be analyzed by ANOVA, with the 
experimental condition (sitagliptin vs. placebo), sequence and period as fixed independent variable 
and subject within sequence as random effect, and the time spent at an interstitial glucose 
concentration during the 54 h inpatient observation periods as dependent variable. 
In case of hypoglycemic episodes, plasma glucose, insulin, C-peptide and counter-regulatory 
hormones will be analysed at the time point of first detecting symptoms or a low plasma glucose 
(whatever triggers the detection) and 30 as well as 60 min thereafter, to determine the activity of the 
counter-regulatory response.  Counter-regulatory hormones will be analyzed by ANOVA with the 
experimental condition (sitagliptin vs. placebo), time point (index time point, 30min and 60 min 
later) and their interaction, sequence and period as fixed independent variables, subject within 
sequence as random effect, and the counter-regulatory hormones as dependent variable. The rise in 
counter-regulatory hormones will be analyzed by ANCOVA with the experimental condition 
(sitagliptin vs. placebo), time point (30 min and 60 min later) and their interaction, sequence and 
period as fixed independent variables, baseline counter-regulatory hormones (index timepoint) as 
covariate, subject within sequence as random effect, and the rise in counter-regulatory hormones 
(change from index timepoint) as dependent variable. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
64 of 74 
 
 
All other parameters determined from blood samples or continuous glucose measurements will be 
compared between sitagliptin and placebo treatment by ANCOVA for repeated measures across all 
standard time points for drawing blood for the parameter in question, using the mean baseline 
concentration of the parameter as a covariate (exploratory endpoints). 
13.3.3 Safety Criteria 
The following variables will be evaluated according to treatment for safety purposes: 
Adverse events 
All AEs will be coded.  
Hypoglycaemic episodes 
Severe hypoglycaemia, documented symptomatic hypoglycaemia and asymptomatic hypoglycaemia 
will be fully reported. The number of episodes and the percentage of exposed subjects having at 
least one episode will be provided. 
Laboratory safety assessments 
Laboratory assessments (biochemistry (incl. lipids), haematology, coagulation and urinalysis) will 
be summarised. A listing of abnormal values will be presented in an end of text (EOT) listing.  
Physical examination 
A frequency table will show the number and percentage of physical examinations. Changes to 
physical examination from screening to end of trial will be recorded as AEs if the Investigator 
judges these as being clinically significant.  
Vital signs 
Vital signs will be summarised by descriptive statistics by treatment/time point. 
ECG 
Numeric data (HR, QRS etc) will be summarised by descriptive statistics. Qualitative ECG data will 
be summarised in a frequency table. Abnormal individual evaluations will be listed together with 
the Investigator’s comments. Changes to ECG from screening to end of trial will be recorded as 
AEs if the Investigator judges these as being clinically significant.  
13.4 Interim Analysis 
No interim analysis is planned. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
65 of 74 
 
 
14 Independent Ethics Committee and Competent Authority 
The trial will be conducted according to Profil’s written instructions (SOPs, working instructions or 
process descriptions). Content and definitions of Profil’s written instructions are based on the 
following relevant binding documents and standards  
 the German Drug Law (AMG) 
 the German GCP ordinance (GCP-Verordnung) 
 the Declaration of Helsinki 
 the International Conference on Harmonisation Good Clinical Practice (ICH GCP) 
The trial will be conducted in accordance with the above mentioned standards. 
14.1 Independent Ethics Committee 
Written favourable opinion must be obtained from the responsible independent ethics committee 
(IEC) prior to commencement of the trial. Clinical trial submission and reporting requirements 
before, during and after completion of the trial will be performed in accordance with national law 
and local regulations.   
All amendments that affect subject safety or the trial integrity (substantial amendments) must not be 
implemented before favourable opinion has been obtained, unless necessary to eliminate hazards to 
the subjects. Non-substantial amendments do not require favourable opinion by the IEC but the 
respective IEC will be notified according to local requirements.  
The Sponsor and Investigator must approve any amendment in writing before its implementation. 
The Sponsor must maintain an accurate and complete record of all submissions made to the IEC. 
The records should be filed in the Sponsor’s Trial Master File. 
14.2 Informed Consent Process for Subjects  
In obtaining and documenting informed consent, the Investigator must comply with the applicable 
regulatory requirement(s) and adhere to the ICH GCP guideline (15) and the requirements in the 
Declaration of Helsinki (16). 
Prior to any trial-related activity, the Investigator must give the subject oral and written information 
in a form that the subject can read and understand about all aspects of the trial that are relevant to 
the subject’s decision to participate. The subject will be given ample time to decide whether or not 
to participate in the trial. 
The subject must be informed that his/her personal trial-related data will be used in accordance with 
the local data protection law. The level of disclosure must also be explained to the subject. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
66 of 74 
 
 
The subject must be informed that his/her medical records may be examined by authorised monitors 
or Clinical Quality Assurance auditors appointed by the Sponsor, by appropriate IEC members, and 
by inspectors from regulatory authorities. 
A voluntary, personally signed and dated Informed Consent Form must be obtained from the 
subject prior to any trial-related activity. The Informed Consent Form must also be signed and dated 
by the physician who conducted the informed consent procedure. All subjects will be provided with 
a copy of their own signed and dated informed consent form and with any additional subject 
information.  
The responsibility for taking informed consent must remain with that of a research physician. 
If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the Investigator must inform the subject in a timely manner, and a revised 
written informed consent must be obtained. 
Should a protocol amendment become necessary, the Informed Consent Form may need to be 
revised to reflect the changes to the protocol. It is the responsibility of the Sponsor to ensure that an 
amended consent form is reviewed and has received favourable opinion from IEC, and the 
Investigator has to ensure that the amended consent form is signed by all subjects subsequently 
entered in the trial and those currently in the trial, if affected by the amendment. 
14.3 Competent Authority  
An implicit or explicit approval must be obtained from the Competent Authority prior to 
commencement of the trial. Clinical trial submission and reporting requirements before, during and 
after completion of the trial will be performed in accordance with national law and local 
regulations. 
An implicit or explicit approval will also be mandatory before implementation of substantial 
changes. Non-substantial amendments do not require approval from the Competent Authority but 
will be notified according to local requirements. 
The Sponsor and Investigator must approve the amendment in writing before its implementation. 
The Sponsor must maintain an accurate and complete record of all submissions made to the 
Competent Authority. The records should be filed in the Sponsor’s Trial Master File. 
 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
67 of 74 
 
 
14.4 Premature Termination of the Trial 
The Sponsor, Investigator or a pertinent regulatory authority may decide to stop the trial or part of 
the trial at any time but agreement on procedures to be followed must be obtained. 
Conditions that may warrant termination of the clinical trial include, but are not limited to: 
 Safety or administrative reasons. 
 The discovery of an unexpected, relevant, or unacceptable risk to the subjects enrolled in the 
clinical trial. 
 A decision of the Sponsor to suspend or discontinue investigation of the IMP. 
If a trial is prematurely terminated or suspended, the Investigator should promptly inform the 
subjects and assure appropriate therapy and follow-up. Furthermore, the Sponsor should promptly 
inform the IEC and provide a detailed written explanation. The pertinent regulatory authorities 
should be informed according to national regulations. 
If after the termination of the trial the risk/benefit analysis has changed, the new evaluation should 
be provided to the IEC in case it will have an impact on the planned follow-up of the subjects who 
have participated in the trial. Necessary actions needed to protect the subjects should be described. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
68 of 74 
 
 
15 Administrative Matters 
15.1 Deviations from the Protocol 
A deviation from the protocol is in general an unplanned non-compliance with the protocol that is 
not implemented or intended as a systematic change. The Investigator, or person designated by the 
Investigator, should document and explain any deviation from the protocol and inform the Sponsor 
and/or monitor. The deviation must be evaluated for its root cause and classification 
(important/non-important). Corrections (if possible) and/or corrective/preventive actions are to be 
documented and implemented. The documentation must be kept in the Trial Investigator File and 
the Sponsor’s Trial Master File. Each deviation is listed in a deviation log. 
15.2 Essential Documents 
Essential Documents, as outlined in ICH GCP Chapter 8, are those documents that individually and 
collectively permit evaluation of the conduct of a trial and the quality of the data produced. These 
documents serve to demonstrate the compliance of the Investigator, Sponsor, and monitor with the 
standards of GCP and with all applicable regulatory requirements. 
Essential Documents also serve a number of other important purposes. Filing essential documents at 
the Investigator/institution and Sponsor sites in a timely manner can greatly assist in the successful 
management of a trial by the Investigator, Sponsor, and monitor. These documents are also the ones 
that are usually audited by the Sponsor’s independent audit function and inspected by the regulatory 
authority(ies) as part of the process to confirm the validity of the trial conduct and the integrity of 
data collected. 
Trial files should be established at the beginning of the trial, both at the Investigators’ site (Trial 
Investigator File) and at the Sponsor office (Trial Master File). The Sponsor will nominate a person 
or a group of persons independent from the Project Team responsible for study overview and TMF 
maintenance. A final close-out of a trial can only be done when the monitor has reviewed both 
Investigator/institution and Sponsor files and confirmed that all necessary documents are in the 
appropriate files. 
15.3 Responsibilities 
The term Investigator as used in this study protocol defines the person responsible for the conduct 
of the clinical trial at a trial site. As the trial is conducted by a team of individuals at the trial site, 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
69 of 74 
 
 
the investigator is the responsible leader of the team and may also be called the Principal 
Investigator. 
The Investigator is accountable for the conduct of the trial according to the approved protocol, ICH-
GCP (15) and Declaration of Helsinki (16). For responsibilities delegated, the Investigator should 
maintain a list of appropriately qualified persons to whom he has delegated specified significant 
trial-related duties. The Principal Investigator will discuss and approve the protocol and review and 
sign the Integrated Clinical Trial Report. 
The Investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The Investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. 
15.4 Reports and Publications 
The Principal Investigator of the trial will review and sign the clinical trial report on behalf of Profil 
Institut für Stoffwechselforschung GmbH. A summary of the final clinical trial report will be 
submitted to the IEC and Competent Authority. 
According to the Declaration of Helsinki (16) Investigators and Sponsors ‘have ethical obligations 
with regard to the publication and dissemination of the results of research’.   
The trial design and results may be published as one or more original research manuscripts / 
abstracts and presented at a scientific meeting. The Investigator and Sponsor reserve the right to 
review any proposed presentation of the results of this trial before they are submitted for 
publication. Authorship on any publication(s) resulting from this clinical trial will be assigned 
according to the recommendations of the International Committee of Medicinal Journal Editors 
(ICMJE) (17). 
Participating subjects will not be identified by name in any published reports about the clinical trial.  
15.5 Audits and Inspections  
In the event of an audit, representatives of the Sponsor or designee, or national and international 
regulatory authorities may request access to all trial records for inspection and copying. Such access 
must be stated in the informed consent form signed by the patient. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
70 of 74 
 
 
15.6 Retention of Clinical Trial Documentation 
A subject’s medical file will be mainted by the trial sites according to local regulations. 
The trial sites will archive the documentation pertaining to the trial in an archive after completion or 
discontinuation of the trial if not otherwise notified. Trial sites should not destroy any documents 
without prior permission from the Sponsor. 
The documentation includes all the raw data generated during the clinical trial, the TIF and a copy 
of the clinical report. The documents will be retained for a period of at least 15 years at archives by 
the trial sites, or their sub-contractor.  
The Sponsor will maintain the documentation pertaining to the trial in accordance with national 
regulations. 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
71 of 74 
 
 
Appendix 1: Insulin titration guideline 
Table: Insulin titration standards with „learning“ algorithm on the basis of percentage 
instead of absolute dose changes. Not only the actual fasting plasma glucose value is 
considered but also fasting glucose changes after the last dose adjustment will be incorporated 
in the consideration of the new dose adaptation.  
Fasting plasma 
glucose 
Range 
[mg/dL] 
Decrease in fasting plasma glucose after 
last insulin dose adjustment [mg/dL] 
Change in insulin 
dose [%] 
1 
< 70 
- 
- 15 
2 
70-89 
- 
-5 
3 
90-110 
- 
0 
4 
111-130 
- 
+ 10 
5 
131-150 
< 15 
+ 25 
 
 
15-30 
+ 15 
 
 
> 31 
+ 10 
 
 
No information available* 
+ 10 
6 
151-170 
< 20 
+ 30 
 
 
20-40 
+ 20 
 
 
> 41 
+ 10 
 
 
No information available* 
+ 15 
7 
171-190 
< 25 
+ 35 
 
 
25-50 
+ 25 
 
 
> 51 
+ 15 
 
 
No information available* 
+ 20 
8 
191 -250 
< 30 
+ 40 
 
 
30-60 
+ 30 
 
 
> 61 
+ 20 
 
 
No information available* 
+ 20 
9 
> 250 
< 35 
+ 45 
 
 
35-70 
+ 35 
 
 
> 71 
+ 25 
 
 
No information available* 
+ 25 
*e.g., at the beginning of titration and in case of missing information 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
72 of 74 
 
 
Appendix 2: Mixed high lipid meal examples 
 
DPP4-Hypo, lipid meal 1 (standard option) 
 
 
 Amount Ingredient 
kcal
Protein
Fat 
Carbs
  
 
g
g 
g
  
Lipid meal 
 
  
Frittata with bacon and avocado: 
 
10 Grams 
Bacon  
35
1,4
3,2 
0,1
20 Grams 
Chicken egg white 
9
2,2
0,0 
0,1
30 Grams 
Chicken egg yolk 
106
4,8
9,6 
0,1
23 Grams 
Olive oil 
203
0,0
23,0 
0,0
90 Grams 
Avocado 
212
1,7
21,1 
0,4
  
Salt, Pepper 
 
  
Shake: 
 
80 Grams 
Coconut milk creamy 
144
1,3
12,2 
1,8
50 Grams 
Cream 30% Fat 
152
1,2
15,9 
1,6
30 Grams 
Raspberries (frozen) 
12
0,4
0,1 
1,4
15 Grams 
Sunflower oil 
133
0,0
15,0 
0,0
  
Sweetener 
 
  
Total 
1006
13,0
100,2 
5,5
 
 
DPP4-Hypo, lipid meal 2 (vegetarian option) 
 
 
 Amount Ingredient 
kcal
Protein 
Fat
Carbs
  
 
g 
g
g
  
Lipid meal 
 
150 Grams 
Avocado 
353
2,8 
35,3
0,6
4 Grams 
Olive oil 
35
0,0 
4,0
0,0
  
Salt, Pepper 
 
  
Shake: 
 
80 Grams 
Coconut milk creamy 
144
1,3 
12,2
1,8
50 Grams 
Cream 30% Fat 
152
1,2 
15,9
1,6
30 Grams 
Raspberries (frozen) 
12
0,4 
0,1
1,4
15 Grams 
Sunflower oil 
133
0,0 
15,0
0,0
  
Sweetener 
 
  
Garnish with nuts: 
 
25 Grams 
Walnuts 
181
4,0 
17,6
1,5
  
Total 
1010
9,7 
100,2
6,9
 


 
 
Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
73 of 74 
 
 
16 References 
 
1. 
Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition of 
vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia. 
2007;50(6):1148-55. doi: 10.1007/s00125-007-0633-0. PubMed PMID: 17387446. 
2. 
Fonseca V, Baron M, Shao Q, Dejager S. Sustained efficacy and reduced hypoglycemia 
during one year of treatment with vildagliptin added to insulin in patients with type 2 diabetes 
mellitus. Horm Metab Res. 2008;40(6):427-30. doi: 10.1055/s-2008-1058090. PubMed PMID: 
18401832. 
3. 
Rosenstock J, Rendell MS, Gross JL, Fleck PR, Wilson CA, Mekki Q. Alogliptin added to 
insulin therapy in patients with type 2 diabetes reduces HbA(1C) without causing weight gain or 
increased hypoglycaemia. Diabetes Obes Metab. 2009;11(12):1145-52. doi: 10.1111/j.1463-
1326.2009.01124.x. PubMed PMID: 19758359. 
4. 
Vilsboll T, Rosenstock J, Yki-Jarvinen H, Cefalu WT, Chen Y, Luo E, et al. Efficacy and 
safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes 
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Clinical Trial Protocol 
Trial ID 
DPP4-Hypo 
Date 
22.01.2018 
Profil Studycode 
00/0795-DPP4-Hypo 
Status / Version-No. 
Final 2.1 
EudraCT-No. 
2016-004480-39 
Page 
74 of 74 
 
 
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